MedWorm: Incretin Therapy

Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease

Heart — Mon, 06 Feb 2012 05:00:00 +0100

Conclusion Intravenous infusion of GLP-1 protects the heart from ischaemic LV dysfunction induced by dobutamine stress in patients with CAD. Clinical trial registration URL: http://isrctn.org. Registration number ISRCTN 69686930. (Source: Heart)

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Deploying insulin granule–granule fusion to rescue deficient insulin secretion in diabetes

Diabetologia — Fri, 03 Feb 2012 17:11:34 +0100

Abstract According to our current understanding of insulin exocytosis, insulin granules dock on the plasma membrane, undergo priming and then wait for calcium-triggered fusion. In this issue of Diabetologia, Hoppa et al (doi 10.1007/s00125-011-2400-5) report that cholinergic stimulation induces granule–granule, or multivesicular, fusion to effect more efficient insulin release. Other exocytotic modes of insulin secretion, particularly those induced by incretin stimulation, include orderly granule fusion with granules already fused with the plasma membrane, called sequential exocytosis, and recruitment of newcomer granules to fuse with plasma membrane with minimal time for docking and priming. The molecular machineries that mediate these distinct exocytotic modes of granul...

Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: Yes.

European Journal of Internal Medicine — Fri, 03 Feb 2012 00:27:50 +0100

Authors: Scheen AJ Abstract The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especia...

Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to Glucagon-Like Peptide-1 (GLP-1) agonists: No.

European Journal of Internal Medicine — Fri, 03 Feb 2012 00:27:40 +0100

Authors: Madsbad S Abstract Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor agonists are also more effective in weight and systolic blood pressure control than DPP-4 inhibitors. The side effects of the GLP-1 receptor agonists are primarily nause...

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

Diabetologia — Sat, 28 Jan 2012 16:52:19 +0100

Conclusion/interpretation Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT. Trial registration: ClinicalTrials.gov NCT00784745. Funding: This study was supported by a grant from the Novo Nordisk Foundation. Content Type Journal ArticleCategory ArticlePages 1-11DOI 10.1007/s00125-012-2459-7Authors D. H. Jensen, Department of Endocrinology, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-240...

The Effects of Incretins on Energy Homeostasis: Physiology and Implications for the Treatment of Type 2 Diabetes Mellitus and Obesity.

Current Vascular Pharmacology — Fri, 20 Jan 2012 05:00:00 +0100

Authors: Karras S, Goulis DG, Mintziori G, Katsiki N, Tzotzas T Abstract Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretin physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic appro...

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Initial and subsequent therapy for newly diagnosed type 2 diabetes patients treated in primary care using data from a vendor‐based electronic health record

Pharmacoepidemiology and Drug Safety — Mon, 16 Jan 2012 05:00:00 +0100

ConclusionsClinical and demographic characteristics influence choice and duration of initial oral hypoglycemic treatment as well as regimen changes. Copyright © 2012 John Wiley & Sons, Ltd. (Source: Pharmacoepidemiology and Drug Safety)

Podcast: Incretins for Type 2 Diabetes Mellitus (Part 2)

Consultant Live — Sat, 14 Jan 2012 18:00:01 +0100

In his second podcast, Dr Louis Kuritzky discusses the classes of incretin-based therapies now available for patients with type 2 diabetes mellitus. (Source: Consultant Live)

Comparison of Metabolic Effects of Surgical-Induced Massive Weight Loss in Patients with Long-Term Remission Versus Non-remission of Type 2 Diabetes

Obesity Surgery — Fri, 13 Jan 2012 16:56:44 +0100

Conclusions This study found greater insulin resistance, lower insulin secretion, persistent adiposopathy and chronic subclinical inflammation, and less robust incretin response in the NR group despite a similar level of weight loss. Persistently altered pathophysiological mechanisms can be related to the lack of remission of type 2 diabetes after RYGB. Content Type Journal ArticleCategory Clinical ResearchPages 1-8DOI 10.1007/s11695-012-0589-0Authors Fernanda Filgueira Hirsch, LIMED, Laboratory of Investigation on Metabolism and Diabetes, State University of Campinas, UNICAMP, Rua Carlos Chagas 420, 13082-970 Campinas, BrazilJose Carlos Pareja, Department of Surgery, Diabetic Surgery Unit, State University of Campinas, UNICAMP, Rua Carlos Chagas 420, 13082-970 Camp...

Comparative Effects of Variations in Duodenal Glucose Load on Glycemic, Insulinemic, and Incretin Responses in Healthy Young and Older Subjects.

The Journal of Clinical Endocrinology and Metabolism — Wed, 11 Jan 2012 05:00:00 +0100

Conclusion:When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance. PMID: 22238398 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Endocrinology and Metabolism)

SUMO down-regulates GLP-1 stimulated cAMP generation and insulin secretion.

Am J Physiol Endocri... — Tue, 10 Jan 2012 05:00:00 +0100

The objective of this study is to investigate down-regulation of GLP-1 signaling by Small Ubiquitin related MOdifier protein, (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Over-expression of SUMO-1 in MIN6 cells and primary mouse beta cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1R agonist. GLP1-R was covalently modified by SUMO. Over-expression of SUMO-1 attenuated cell surface trafficking of GLP-1R which resulted in significantly reduced insulin secretion when stimulated by exendin-4, a GLP-1R agonist. Partial knock-down of SUMO conjugating enzyme Ubc-9 resulted in enhanced exendin-4 stimulated insulin secretion in m...

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The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways

Diabetologia — Mon, 09 Jan 2012 19:38:25 +0100

Conclusions/interpretation The ghrelin gene-derived peptides and Ex-4 exert cytoprotective effects in islet MECs. The anti-apoptotic effects involve phosphoinositide 3-kinase (PI3K)/Akt, ERK1/2 and cAMP/PKA pathways. These peptides could therefore represent a potential tool to improve islet vascularisation and, indirectly, islet cell function. Content Type Journal ArticleCategory ArticlePages 1-13DOI 10.1007/s00125-011-2423-yAuthors E. Favaro, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, ItalyR. Granata, Department of Internal Medicine, Division of Endocrinology, Diabetology and Metabolism, University of Turin, Turin, ItalyI. Miceli, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy...

Evolving treatment strategies for the management of type 2 diabetes.

The American Journal of the Medical Sciences — Sun, 01 Jan 2012 02:56:40 +0100

Authors: Cefalu WT Abstract ABSTRACT:: It is well known that improved metabolic control significantly reduces both micro- and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This "stepwise" strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been de...

A pilot study of the efficacy of miglitol and sitagliptin for type 2diabetes with a continuous glucose monitoring system and incretin-related markers

Cardiovascular Diabetology — Thu, 22 Dec 2011 02:35:50 +0100

Conclusions: In conclusion, CGM measurements revealed that a combination of the alpha-GI miglitol and the DPP-4 inhibitor sitagliptin effectively reduced postprandial glucose fluctuation and stabilized blood glucose levels. Completely different response patterns of insulin, glucagon, GLP-1, and GIP were observed among the study subjects with either medication alone or in combination, suggesting that individual hormone-dependent glycemic responses to the alpha-GI and DPP-4 inhibitors are complicated and multifactorial. (Source: Cardiovascular Diabetology)

Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2.

Diabetes — Wed, 21 Dec 2011 05:00:00 +0100

Authors: Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM Abstract Interest in how the gut microbiome can influence the metabolic state of the host has recently heightened. One postulated link is bacterial fermentation of "indigestible" prebiotics to short-chain fatty acids (SCFAs), which in turn modulate the release of gut hormones controlling insulin release and appetite. We show here that SCFAs trigger secretion of the incretin hormone glucagon-like peptide (GLP)-1 from mixed colonic cultures in vitro. Quantitative PCR revealed enriched expression of the SCFA receptors ffar2 (grp43) and ffar3 (gpr41) in GLP-1-secreting L cells, and consistent with the reported coupling of GPR43 to Gq signaling pathways, SCFAs raised ...

DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials.

Diabetes and Metabolism — Wed, 21 Dec 2011 05:00:00 +0100

Authors: Scheen AJ Abstract Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerabili...

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Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice

Journal of Clinical Investigation — Tue, 20 Dec 2011 06:52:29 +0100

Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor–dependent (GLP-1R–dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r–/– mice). Transgene expression restored GLP-1R–dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R–dependent stimulation of β cell proliferatio...

Novel Biological Action of the Dipeptidylpeptidase-IV Inhibitor, Sitagliptin, as a Glucagon-Like Peptide-1 Secretagogue.

Endocrinology — Tue, 20 Dec 2011 05:00:00 +0100

Authors: Sangle GV, Lauffer LM, Grieco A, Trivedi S, Iakoubov R, Brubaker PL Abstract Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted into the circulation by the intestinal L cell. The dipeptidylpeptidase-IV (DPP-IV) inhibitor, sitagliptin, prevents GLP-1 degradation and is used in the clinic to treat patients with type 2 diabetes mellitus, leading to improved glycated hemoglobin levels. When the effect of sitagliptin on GLP-1 levels was examined in neonatal streptozotocin rats, a model of type 2 diabetes mellitus, a 4.9 ± 0.9-fold increase in basal and 3.6 ± 0.4-fold increase in oral glucose-stimulated plasma levels of active GLP-1 was observed (P < 0.001), in association with a 1.5 ± 0.1-fold increase in the total number of intestinal L cells (P < 0.01). ...

The increased dipeptidyl peptidase‐4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin‐treated patients

Diabetes, Obesity and Metabolism — Thu, 15 Dec 2011 05:00:00 +0100

Conclusion. DPP‐4 activity is increased in T2D, but is not lowered by glucose control, suggesting that hyperglycemia is not a direct determinant of DPP‐4 activity. On the other hand, metformin may indirectly reduce DPP‐4 activity. (Source: Diabetes, Obesity and Metabolism)

Impaired incretin effect and fasting hyperglucagonaemia characterising type 2 diabetic subjects are early signs of dysmetabolism in obesity

Diabetes, Obesity and Metabolism — Thu, 15 Dec 2011 05:00:00 +0100

Conclusions: Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin resistant state have NGT. (Source: Diabetes, Obesity and Metabolism)

Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity

Diabetes, Obesity and Metabolism — Thu, 15 Dec 2011 05:00:00 +0100

Conclusions: Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin‐resistant state have NGT. (Source: Diabetes, Obesity and Metabolism)

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18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

European Journal of Nuclear Medicine and Molecular Imaging — Wed, 14 Dec 2011 16:42:25 +0100

Conclusion [18F]FBEM-[Cys40]-exendin-4 and [18F]FBEM-[Cys0]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [18F]FBEM-[Cys40]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R. Content Type Journal ArticleCategory Original ArticlePages 1-11DOI 10.1007/s00259-011-1980-0Authors Dale O. Kiesewetter, Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), 31 Center Drive, Suite 1 C14, Bethesda, MD 20892, USAHaokao Gao, Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioenginee...

GIP Controls Adipose Insulin Sensitivity [Signal Transduction]

Journal of Biological Chemistry — Fri, 09 Dec 2011 05:00:00 +0100

Gastric inhibitory peptide (GIP) is an incretin hormone secreted in response to food intake. The best known function of GIP is to enhance glucose-dependent insulin secretion from pancreatic β-cells. Extra-pancreatic effects of GIP primarily occur in adipose tissues. Here, we demonstrate that GIP increases insulin-dependent translocation of the Glut4 glucose transporter to the plasma membrane and exclusion of FoxO1 transcription factor from the nucleus in adipocytes, establishing that GIP has a general effect on insulin action in adipocytes. Stimulation of adipocytes with GIP alone has no effect on these processes. Using pharmacologic and molecular genetic approaches, we show that the effect of GIP on adipocyte insulin sensitivity requires activation of both the cAMP/protein kinase A/CREB ...

Miglitol more effective than voglibose at improving incretin level in diabetes

MedWire News - Diabetes — Wed, 07 Dec 2011 08:14:41 +0100

Miglitol is more effective than voglibose at modifying the postprandial response of plasma incretins in Japanese Type 2 diabetes patients, say researchers. (Source: MedWire News - Diabetes)

Glucose-sensing by Gut Endocrine Cells and Activation of the Vagal Afferent Pathway is Impaired in a Rodent Model of Type 2 Diabetes Mellitus.

Wed, 07 Dec 2011 05:00:00 +0100

Authors: Lee J, Cummings BP, Martin E, Sharp JW, Graham JL, Stanhope KL, Havel PJ, Raybould HE Abstract Glucose in the gut lumen activates gut endocrine cells to release 5-HT, GLP-1/2 and GIP which act to change GI function and regulate postprandial plasma glucose. There is evidence that both release and action of incretin hormones is reduced in type 2 diabetes (T2D). We measured cellular activation of enteroendocrine and enterochromaffin cells, enteric neurons and vagal afferent neurons in response to intestinal glucose in a model of type 2 diabetes mellitus, the UCD-T2DM rat. Pre-diabetic (PD), recent-diabetic (RD, 2 wks post-onset), and 3-month diabetic (3MD) fasted UCD-T2DM rats were given an orogastric gavage of vehicle (water, 0.5 ml /100 gm body weight) or glucose (330 μmol...

Glucagon-Like Peptide-1 Regulation of Carbohydrate Intake Is Differentially Affected by Obesogenic Diets.

Obesity — Thu, 01 Dec 2011 05:00:00 +0100

Authors: Pritchett CE, Hajnal A Abstract The incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in the regulation of appetite by acting as an anorexigenic gut-brain signal. The postprandial release of GLP-1 can be blunted in obese humans and animals. However, it remains unknown whether obesogenic diets with varying fat and carbohydrate content may differentially influence the effectiveness of GLP-1 feedback. To investigate this, male Sprague-Dawley rats were fed a standard (low fat) chow diet, or one of two high-energy diets varying in fat content (45 or 60 kcal%) for 28 weeks. Intake of sucrose and fructose solutions, two commonly added sugars in the Western diet, was then tested in nondeprived rats following administration of the GLP-1 receptor agonist, Exendin-...

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Incretin based therapies. Do they hold their promise?

Journal of Diabetes — Thu, 01 Dec 2011 05:00:00 +0100

(Source: Journal of Diabetes)

Treating diabetes today: a matter of selectivity of sulphonylureas

Diabetes, Obesity and Metabolism — Mon, 28 Nov 2011 08:11:53 +0100

It is well known that sulphonylureas (SUs), commonly used in the treatment of type 2 diabetes mellitus, stimulate insulin secretion by closing ATP‐sensitive K+ (KATP) channels in pancreatic β‐cells by binding to the SU receptor SUR1. SUs are now known also to activate cAMP sensor Epac2 (cAMP‐GEFII) to Rap1 signalling, which promotes insulin granule exocytosis. For SUs to exert their full effects in insulin secretion, they are required to activate Epac2 as well as to inhibit the β‐cell KATP channels. As Epac2 is also necessary for potentiation of glucose‐induced insulin secretion by cAMP‐increasing agents, such as incretin, Epac2 is a target of both cAMP and SUs. The distinct effects of various SUs appear to be because of their different actions on Epac2/Rap1 signalling as wel...

Na+-d-glucose Cotransporter SGLT1 is Pivotal for Intestinal Glucose Absorption and Glucose-Dependent Incretin Secretion.

Diabetes — Mon, 28 Nov 2011 05:00:00 +0100

Authors: Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H Abstract To clarify the physiological role of Na(+)-d-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1(-/-) mice were generated and characterized phenotypically. After gavage of d-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GIP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1(-/-) mice were compared. The impact of SGLT1 on renal glucose handling was investigated by ...

[The physiology of incretins].

Orvosi Hetilap — Sun, 27 Nov 2011 05:00:00 +0100

Authors: Winkler G Abstract The discovery of incretins-glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrop peptide (GIP)-, clarification of their physiological properties as well as therapeutic application of incretin-based blood glucose lowering drugs opened new perspectives in the medical management of type 2 diabetes. New results of basic research investigations led to revaluation of the role of GIP in metabolic processes and a more established use of GLP-1 action. The article overviews the most relevant data of production and effects of incretins, as well as future possibilities of their therapeutic use. PMID: 22167829 [PubMed - in process] (Source: Orvosi Hetilap)

Glucose-Dependent Insulinotropic Polypeptide Receptors in Most Gastroenteropancreatic and Bronchial Neuroendocrine Tumors.

The Journal of Clinical Endocrinology and Metabolism — Wed, 23 Nov 2011 05:00:00 +0100

Conclusions:The numerous GIP receptors in gastroenteropancreatic and bronchial NET represent novel universal molecular targets for clinical applications, in particular for in vivo scintigraphy and targeted radiotherapy. These results may also be the basis for multiple targeting, with concomitant use of GIP, somatostatin, and GLP-1 analogs as radiotracers. PMID: 22112810 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Endocrinology and Metabolism)

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[Incretin-based therapy for treating patients with type 2 diabetes].

Orvosi Hetilap — Sun, 20 Nov 2011 21:38:30 +0100

Authors: Jermendy G Abstract In the last couple of years, a new class of antidiabetic drugs became available for the clinical practice. Due to the intensive research, several new drugs reached the market. Among the incretinmimetics both the GLP-1 (glucagon like peptide-1)-receptor agonist exenatide and the GLP-1-analogue liraglutide can be used for treatment. As for incretin enhancers (dipeptidyl-peptidase-4 [DPP-4]-inhibitors), sitagliptin, vildagliptin and saxagliptin are available in Hungary, linagliptin will be introduced to the market in the near future. In clinical practice, any incretin-based new drugs can be used for treating patients with type 2 diabetes, preferably in combination with metformin. The clinical experiences with these new drugs are reviewed focusing on both t...

The Pharmacologic Basis for Clinical Differences Among GLP-1 Receptor Agonists and DPP-4 Inhibitors

Postgraduate Medicine Online — Tue, 15 Nov 2011 16:03:17 +0100

Javier Morales, MD DOI: 10.3810/pgm.2011.11.2508 Abstract: The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists—which can be dosed to pharmacologic levels—act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial g...

Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice.

European Journal of Pharmacology — Sat, 12 Nov 2011 05:00:00 +0100

Authors: Faivre E, Hamilton A, Hölscher C Abstract Type 2 diabetes is a risk factor for Alzheimer's disease. Insulin receptor desensitisation has been found in Alzheimer brains, which may be the underlying link. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling in diabetes. GIP and the GIP receptors are widely expressed in the brain, and GIP has been shown to have growth factor and neuroprotective properties. Here we investigate the potential therapeutic properties of different doses of the protease resistant long-lasting GIP receptor agonist D-Ala2GIP and the antagonist (Pro3)GIP in C57Bl/6 mice. We found that after acute injection, D-Ala2GIP had few effects on general behaviour in the open field at any dose tested (2.5, 25, 10...

Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice

Diabetologia — Thu, 10 Nov 2011 06:45:25 +0100

Conclusions/interpretation Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation. Content Type Journal ArticleCategory ArticlePages 1-9DOI 10.1007/s00125-011-2365-4Authors Y. Takeda, Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, 078-8510 JapanY. Fujita, Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, 078-8510 JapanJ. Honjo, Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical Universit...

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Chitosan-based therapeutic nanoparticles for combination gene therapy and gene silencing of in vitro cell lines relevant to type 2 diabetes.

European Journal of Pharmaceutical Sciences — Wed, 09 Nov 2011 05:00:00 +0100

In this study, the glucosamine-based polymer chitosan was used as a cationic polymer-based in vitro delivery system for GLP-1, DPP-IV resistant GLP-1 analogues and siRNA targeting DPP-IV mRNA. We found chitosans to form spherical nanocomplexes with these nucleic acids, generating two distinct non-overlapping size ranges of 141-283nm and 68-129nm for plasmid and siRNA, respectively. The low molecular weight high DDA chitosan 92-10-5 (degree of deacetylation, molecular weight and N:P ratio (DDA-Mn-N:P)) showed the highest plasmid DNA transfection efficiency in HepG2 and Caco-2 cell lines when compared to 80-10-10 and 80-80-5 chitosans. Recombinant native GLP-1 protein levels in media of transfected cells reached 23ng/L while our DPP-IV resistant analogues resulted in a fivefold increase of G...

The role of glp‐1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

Diabetes, Obesity and Metabolism — Thu, 03 Nov 2011 04:00:00 +0100

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of DPP‐4 inhibitors and GLP‐1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP‐1 receptor agonists/analogues are currently approved for the treatment of T2DM – exenatide (Byetta®, Eli Lilly and Co.) and liraglutide (Victoza®, Novo Nordisk); a once‐weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency.The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LE...

The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

AJP: Regulatory, Integrative and Comparative Physiology — Wed, 02 Nov 2011 04:00:00 +0100

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the...

Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures: A meta-analysis of randomized clinical trials.

Diabetes Care — Tue, 01 Nov 2011 04:00:00 +0100

CONCLUSIONS The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures. PMID: 22025784 [PubMed - in process] (Source: Diabetes Care)

The design and rationale of the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 Study

American Heart Journal — Tue, 01 Nov 2011 04:00:00 +0100

Objectives: Saxagliptin, a dipeptidyl peptidase 4 inhibitor, improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing endogenous active, intact glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release.Research Design and Methods: SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled trial conducted in 25 countries that is designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of approximately 16,500 patients with T2DM. Eligible patients who are either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk f...

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Pro- or Anti-inflammatory Properties of the Adipokine Dipeptidyl Peptidase-4?

Gastroenterology — Mon, 31 Oct 2011 04:00:00 +0100

In the July 2011 issue of Gastroenterology, Elashoff et al reported an increased incidence of pancreatitis in diabetic subjects undergoing glucagon-like peptide (GLP)-1–based therapies. In light of the recently emerging and proliferating discussion about the clinical use and the associated risks of incretin-based therapies, we would like to comment on this article and contribute evidence supporting the role of adipose-derived dipeptidyl peptidase (DPP)-4 in the context of the metabolic syndrome. (Source: Gastroenterology)

Glucagon-like peptide 1 (GLP-1) in the gastrointestinal tract of the pheasant (Phasianus colchicus).

Acta Histochemica — Fri, 28 Oct 2011 04:00:00 +0100

Authors: Pirone A, Ding BA, Giannessi E, Coli A, Stornelli MR, di Cossato MM, Piano I, Lenzi C Abstract The distribution of Glucagon-like peptide 1 (GLP-1) was investigated in the gastrointestinal tract of the pheasant using immunohistochemistry. GLP-1 immunoreactive cells were common in the small intestine, in the proventriculus and in the pancreas. Immunostained cells were not seen in the crop, in the gizzard and in the large intestine. Double labelling demonstrated that GLP-1 and pituitary adenylate cyclase-activating polypeptide (PACAP) were occasionally co-localized only in the duodenal villi. In contrast to what was previously described in the chicken and ostrich, we noted GLP-1 positive cells in the duodenum. These data were consistent with the presence of proglucagon mRNA i...

Glucagon-like peptide analogues for type 2 diabetes mellitus

NeLM - Drug Class Focused Reviews — Sat, 22 Oct 2011 04:00:00 +0100

Source: Cochrane Library Area: Evidence > Drug Class Focused Reviews Background Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety. Objectives To assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus. Search strategy Studies were obtained from electronic searches of The Cochrane Library (las...

Pharmacotherapy for the Metabolic Syndrome.

Current Vascular Pharmacology — Fri, 21 Oct 2011 04:00:00 +0100

Authors: Swislocki AL, Siegel D, Jialal I Abstract The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapies for hypertension but invariably a combination therapy...

The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database

Acta Diabetologica — Wed, 19 Oct 2011 05:56:03 +0100

Abstract In patients with diabetes, disease per se, co-morbidities and drugs, including novel agents acting on the incretin system, have all been associated with pancreatitis with controversial data. We investigated the publicly available FDA Adverse Event Reporting System (FDA_AERS) database to gain insight into the possible association between antidiabetic agents and pancreatitis. To this aim, a case/non-case method was retrospectively performed on the FDA_AERS database (2004–2009 period). Cases were defined as reports of pancreatitis according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. All other reports associated with antidiabetics were considered non-cases. The Reporting Odds Ratio (RORs), with corresponding 95% confidential interval (...

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Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes

Diabetic Medicine — Mon, 17 Oct 2011 04:00:00 +0100

Conclusions In patients with well‐controlled Type 2 diabetes, blood glucose, insulin and GLP‐1 responses are critically dependent on the small intestinal glucose load, and GLP‐1 responses are not deficient. (Source: Diabetic Medicine)

GIP-dependent expression of hypothalamic genes.

Physiological Research — Wed, 12 Oct 2011 04:00:00 +0100

Authors: Ambati S, Duan J, Hartzell DL, Choi YH, Della-Fera MA, Baile CA Abstract GIP (glucose dependent insulinotrophic polypeptide), originally identified as an incretin peptide synthesized in the gut, has recently been identified, along with its receptors (GIPR), in the brain. Our objective was to investigate the role of GIP in hypothalamic gene expression of biomarkers linked to regulating energy balance and feeding behavior related neurocircuitry. Rats with lateral cerebroventricular cannulas were administered 10 microg GIP or 10 microl artificial cerebrospinal fluid (aCSF) daily for 4 days, after which whole hypothalami were collected. Real time Taqman(TM) RT-PCR was used to quantitatively compare the mRNA expression levels of a set of genes in the hypothalamus. Administratio...

A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats.

Biochemical Pharmacology — Wed, 12 Oct 2011 04:00:00 +0100

This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2h and 10h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1-10mg/kg) did not cause...

mTOR links incretin signaling to HIF induction in pancreatic beta cells [Biochemistry]

Proceedings of the National Academy of Sciences — Tue, 11 Oct 2011 04:00:00 +0100

Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1α in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta...

Glucagon-like peptide analogues for type 2 diabetes mellitus.

Cochrane Database of Systematic Reviews — Tue, 11 Oct 2011 01:20:04 +0100

CONCLUSIONS: GLP-1 agonists are effective in improving glycaemic control. PMID: 21975753 [PubMed - in process] (Source: Cochrane Database of Systematic Reviews)

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Mechanism‐Based Pharmacokinetic Modelling in Diabetic Patients: Vildagliptin as a Tight Binding Inhibitor and Substrate of Dipeptidyl Peptidase IV

British Journal of Clinical Pharmacology — Mon, 10 Oct 2011 04:00:00 +0100

Conclusions: Vildagliptin is both an inhibitor and substrate for DPP‐4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP‐4 was confirmed in patients and the half‐life of hydrolysis by DPP‐4 estimated. This model can be used to predict DPP‐4 inhibition effects of other dosage regimens and be modified for other DPP‐4 inhibitors to differentiate their properties. (Source: British Journal of Clinical Pharmacology)

The incretin effect, GLP‐1 analogues and DPP‐4 inhibitors

Prescriber — Wed, 05 Oct 2011 04:00:00 +0100

AbstractIn this short article, the author explains the reduced ‘incretin effect’ in type 2 diabetes and the mode of action of GLP‐1 analogues and DPP‐4 inhibitors. Copyright © 2011 Wiley Interface Ltd (Source: Prescriber)

Gastric bypass surgery: Improving psoriasis through a GLP-1-dependent mechanism?

Medical Hypotheses — Tue, 04 Oct 2011 04:00:00 +0100

Abstract: Psoriasis is a common inflammatory skin disease and obesity constitutes a risk factor for the disease. Obese patients with psoriasis are often more difficult to treat and are at increased risk for dyslipidemia, diabetes, hypertension and cardiovascular disease. Case reports suggest that gastric bypass surgery in patients with psoriasis may result in complete remission of the disease. A substantial weight loss is achieved in the months following surgery, which is likely to reduce psoriasis symptoms and risk of comorbidities. Interestingly, however, it has been described that improvement of psoriasis is initiated immediately following surgery before any weight loss could have happened. We hypothesize that the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1) is ...

[Pharmacogenetics of insulin secretagogue antidiabetics.]

Orvosi Hetilap — Sat, 01 Oct 2011 04:00:00 +0100

Authors: Winkler G, Gerő L Abstract Type 2 diabetes is making up to 90% of the all diabetic cases. In addition to insulin resistance, insufficient B-cell function also plays an important role in the pathogenesis of the disease. The insufficient production and secretion of insulin can be increased by secretagogue drugs, like sulfonylureas and incretin mimetics/enhancers. In recent years growing number of genetic failures of the B-cells has been detected. These genetic variants can influence the efficacy of secretagogue drugs. Some of these gene polymorphisms were identified in the genes encoding the KATP channel (KCNJ11 and ABCC8). These mutations are able either to reduce or increase the insulin secretion and can modify the insulin response to sulfonylurea treatment. Other polymor...

Device Mimics Bariatric Surgery's Antidiabetic Effects

Clinical Endocrinology News — Sat, 01 Oct 2011 04:00:00 +0100

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes. (Source: Clinical Endocrinology News)

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GLP‐1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice

Diabetes, Obesity and Metabolism — Thu, 29 Sep 2011 06:56:11 +0100

Conclusions: These data show that the peripheral nerve of diabetic rodents exhibits functional GLP‐1R and suggest that GLP‐1R‐mediated ERK‐signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control. (Source: Diabetes, Obesity and Metabolism)

Current evidence for a role of GLP‐1 in Roux‐en‐Y gastric bypass‐induced remission of type 2 diabetes

Diabetes, Obesity and Metabolism — Mon, 26 Sep 2011 04:00:00 +0100

Weight reducing surgical procedures such as Roux‐en‐Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM. Interestingly, the majority of remissions occur almost immediately following the operation and long before significant weight loss has taken place. Following RYGB dramatic increases in postprandial plasma concentrations of the incretin hormone glucagon‐like peptide‐1 (GLP‐1) have been recorded; and the known anti‐diabetic effects of GLP‐1 are thought to be key mediators in RYGB‐induced remission of T2DM. However, the published studies on the impact of RYGB on GLP‐1 secretion are...

53 Effects Of GLP-1 eluting stem cell therapy on collagen remodelling in a porcine model of myocardial infarction

Heart — Fri, 23 Sep 2011 04:00:00 +0100

This study investigated the effects of GLP-1 CellBeads on post-MI healing in a porcine model. GLP-1 CellBeads were delivered to coronary artery branches, creating micro-infarcts and mild LV dysfunction. Cell-free beads (empty) and CellBeads containing hMSCs but not secreting GLP-1 (hMSC-beads) were delivered as controls. Left ventricular (LV) function, infarct size, myocyte cross-sectional area, total collagen content (picrosirius red staining) and collagen -1 and -3 levels (qRT-PCR) were analysed to determine therapeutic potential. Four weeks post-MI, only GLP-1 CellBead treatment produced significantly improved LV function compared to 30 min post-MI (44.00%±1.29% vs 49.75%±1.03%, p<0.001). This was also associated with less infarct (3.21%±0.90%) compared...

Pharmacological control of blood sugar

Anaesthesia and intensive care medicine — Wed, 21 Sep 2011 16:38:58 +0100

Abstract: Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight ...

Safety of incretin-based therapies for type 2 diabetes.

Med J Aust — Mon, 19 Sep 2011 04:00:00 +0100

Authors: Davis TM Abstract Australian database linkages could be used for postmarketing surveillance of antidiabetic therapy side effects. PMID: 21929482 [PubMed - in process] (Source: Med J Aust)

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EASD: Debate Brings Incretin Risks to Forefront (with video)

MedPage Today Endocrinology — Sun, 18 Sep 2011 16:00:00 +0100

LISBON (MedPage Today) -- Whispered concerns about a higher risk of certain cancers linked with incretin therapies for diabetes have become more audible after a debate here between top researchers. (Source: MedPage Today Endocrinology)

Linagliptin: A Novel Xanthine-Based Dipeptidyl Peptidase-4 Inhibitor for Treatment of Type II Diabetes Mellitus.

Current Diabetes Reviews — Thu, 15 Sep 2011 04:00:00 +0100

Authors: Ghatak SB, Patel DS, Shanker N, Srivastava A, Deshpande SS, Panchal SJ Abstract Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the de...

Next-Generation GLP-1 Therapy:

Postgraduate Medicine Online — Thu, 15 Sep 2011 04:00:00 +0100

An Introduction to Liraglutide Thomas Repas, DO, FACP, FACOI, FACE, CDE DOI: 10.3810/pgm.2011.09.2480 Abstract: Liraglutide, a once-daily human glucagon-like peptide-1 (GLP-1) analog, was approved by the US Food and Drug Administration in 2010 for the treatment of type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 enhances insulin secretion and inhibits glucagon in a glucose-dependent manner. The efficacy and safety of liraglutide were evaluated in 6 phase 3 trials in > 4000 patients in the Liraglutide Effect and Action in Diabetes (LEAD) program, in another trial in comparison with sitagliptin, and in another trial where basal insulin was added to liraglutide + metformin. At liraglutide doses of 1.2 mg or 1.8 mg once daily, significant mean reductions in g...

[Dipeptidyl-peptidase-4 inhibitors (gliptins): a new class of oral antidiabetic drugs].

Orvosi Hetilap — Thu, 08 Sep 2011 04:00:00 +0100

Authors: Jermendy G Abstract Nearly 90% of the diabetic patients are suffering of type 2 diabetes while approximately 60-65% of patients with type 2 diabetes are treated with oral antidiabetic drugs. In the last couple of years a new treatment option, namely incretin-based therapy, became available. The dipeptidyl-peptidase-4-inhibitors (gliptins) are designated as incretin enhancers. Using gliptins, sustained glycemic control can be achieved without gaining weight and increasing the risk of hypoglycemia. All gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin) can be used as tablets without a need for dose titration. For treating patients with type 2 diabetes, gliptins can primarily be used in combination with metformin. Orv. Hetil., 2011, 152, 1471-1476. PMID: 21893...

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Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin

Acta Diabetologica — Tue, 06 Sep 2011 15:48:22 +0100

In this study, we compared the effectiveness of the administration of miglitol alone just before breakfast on the plasma glucose, serum insulin and glucagon, and plasma incretin levels in sitagliptin-treated patients with type 2 diabetes. We measured the plasma glucose, serum insulin and glucagon, plasma active GLP-1, and total glucose-dependent insulinotropic polypeptide levels before breakfast, at 120 min after breakfast, before lunch, and 60 and 120 min after lunch in patients with diabetes who are receiving sitagliptin. This trial was performed for the following 2 days on each subject (Day 1: no miglitol, Day 2: miglitol alone [50 mg] administered just before breakfast). The area under the curve (AUC) of the plasma glucose levels after lunch in the miglitol-tr...

The potential of incretin-based therapies in type 1 diabetes.

Drug Discovery Today — Tue, 06 Sep 2011 04:00:00 +0100

Authors: Suen CS, Burn P Abstract Finding a cure for type 1 diabetes (T1D) has been elusive. Incretin-based therapies, since their approval, have demonstrated their clinical utilities in type 2 diabetes (T2D). Yet, their potential clinical benefits in T1D remain to be appraised. GLP-1, in addition to its insulinotropic action in alleviating hyperglycemia, possesses beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass and suppression of glucagon secretion, gastric emptying and appetite. Preclinical data using incretin-based therapies in diabetic NOD mice demonstrated additional effects including immuno-modulation, anti-inflammation and β-cell regeneration. Thus, data accumulated hold the promise that incretin-based the...

Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology

Diabetologia — Sun, 04 Sep 2011 10:56:18 +0100

Abstract Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert ant...

Incretin Receptors in Non-Neoplastic and Neoplastic Thyroid C Cells in Rodents and Humans: Relevance for Incretin-Based Diabetes Therapy

Neuroendocrinology — Thu, 01 Sep 2011 23:00:00 +0100

Neuroendocrinology (DOI:10.1159/000330447) (Source: Neuroendocrinology)

Gastric bypass surgery enhances glucagon-like Peptide 1-stimulated postprandial insulin secretion in humans.

Diabetes — Wed, 31 Aug 2011 23:00:00 +0100

CONCLUSIONS Increased GLP-1-stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia. PMID: 21868791 [PubMed - in process] (Source: Diabetes)

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Incretin-Based Therapy and the Quest for Sustained Improvements in {beta}-Cell Health.

Diabetes Care — Wed, 31 Aug 2011 23:00:00 +0100

Authors: Drucker DJ PMID: 21868783 [PubMed - in process] (Source: Diabetes Care)

Hypolipidemic effect of Smallanthus sonchifolius (yacon) roots on diabetic rats: Biochemical approach.

Chemico-Biological Interactions — Sun, 28 Aug 2011 04:00:00 +0100

In conclusion, yacon root flour is a natural product rich in FOS that could be well positioned as a nutraceutical product since the present results demonstrate its beneficial effects on diabetes-associated hyperlipidemia. PMID: 21907189 [PubMed - as supplied by publisher] (Source: Chemico-Biological Interactions)

New gene targets for glucagon-like peptide-1 during embryonic development and in undifferentiated pluripotent cells

AJP: Endocrinology and Metabolism — Tue, 23 Aug 2011 23:00:00 +0100

In humans, glucagon-like peptide (GLP-1) functions during adult life as an incretin hormone with anorexigenic and antidiabetogenic properties. Also, the therapeutic potential of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and in bolstering the maintenance of human mesenchymal stem cell (hMSC) stores by promoting the proliferation and cytoprotection of hMSC seems to be relevant. Since these observations suggest a role for GLP-1 during developmental processes, the aim of the present work was to characterize GLP-1 in early development as well as its gene targets in mouse embryonic stem (mES) cells. Mouse embryos E6, E8, and E10.5 and pluripotent mES were used for the inmunodetection of GLP-1 and GLP-1 receptor. Quantitative real-time PCR was used to determine the exp...

Effect of lectin-like oxidized LDL receptor-1 polymorphism on liver disease, glucose homeostasis, and postprandial lipoprotein metabolism in nonalcoholic steatohepatitis.

The American Journal of Clinical Nutrition — Tue, 23 Aug 2011 23:00:00 +0100

CONCLUSION: In NASH, the LOX-1 polymorphism is associated with liver disease severity and may predispose to CVD through modulation of postprandial small TRLPs and adipokine balance and to diabetes by affecting both insulin secretion and insulin sensitivity. PMID: 21865331 [PubMed - as supplied by publisher] (Source: The American Journal of Clinical Nutrition)

Beyond glucose lowering: Glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system.

Diabetes and Metabolism — Tue, 23 Aug 2011 23:00:00 +0100

CONCLUSION: These compounds may play an important role in the treatment of patients with T2DM as their potential effects go beyond glucose-lowering (weight loss, potential improvement of cardiovascular risk factors). However, to better understand their place in the management of T2DM, further experimental and clinical prospective studies are required. PMID: 21871831 [PubMed - as supplied by publisher] (Source: Diabetes and Metabolism)

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Do we really know why diabetes remits after gastric bypass surgery?

Endocrine — Fri, 19 Aug 2011 06:40:02 +0100

Abstract Roux-en-Y gastric bypass surgery (GBP) results in 30–40% sustained weight loss and improved type 2 diabetes in up to 80% of patients. The relative contribution of the gut neuroendocrine changes after GBP versus the weight loss has not been fully elucidated. There are clear differences between weight loss by GBP and by dietary intervention or gastric banding. One of them is the enhanced post-prandial release of incretin hormones and the recovery of the incretin effect on insulin secretion after GBP, not seen after diet-induced weight loss. The favorable changes in incretin hormones after GBP result in recovery of the early phase insulin secretion and lower post-prandial glucose levels during oral glucose administration. The enhanced incretin response may be relat...

The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1.

Tue, 16 Aug 2011 23:00:00 +0100

Authors: Hayes MR, Kanoski SE, De Jonghe BC, Leichner TM, Alhadeff AL, Fortin SM, Arnold M, Langhans W, Grill HJ Abstract The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like-peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. CNS processing of GLP-1R-driven vagal afferents results in satiation signaling, and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal L-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal (GI) origin, contributes to glycemic and food intake control. However, syste...

Contributions of fat and protein to the incretin effect of a mixed meal.

The American Journal of Clinical Nutrition — Tue, 16 Aug 2011 23:00:00 +0100

CONCLUSIONS: Fat ingestion, in an amount typical of a standard meal, increases insulin secretion during physiologic hyperglycemia and thus contributes to the incretin effect. In contrast, ingestion of protein typical of normal meals does not contribute to the augmentation of postprandial insulin secretion. This trial was registered at clinicaltrials.gov as NCT00869453. PMID: 21849595 [PubMed - as supplied by publisher] (Source: The American Journal of Clinical Nutrition)

New treatments for diabetes type 2

Clinical Cases and Images — Tue, 16 Aug 2011 13:31:00 +0100

There is urgent need for new treatment strategies for diabetes type 2. Some new approaches include: - Long acting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor - they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety - inhibitors of dipeptidyl peptidase 4 (DPP-4), which enhance the effect of endogenous incretin hormones - inhibitors of the sodium—glucose cotransporter 2, which increase renal glucose elimination - inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat - Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are also being as...

Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus

Diabetes Research and Clinical Practice — Thu, 11 Aug 2011 04:00:00 +0100

Conclusion: Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress. (Source: Diabetes Research and Clinical Practice)

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Incretin hormones and the expanding families of glucagon‐like sequences and their receptors

Diabetes, Obesity and Metabolism — Wed, 10 Aug 2011 17:50:04 +0100

Peptide hormones encoded by the proglucagon (Gcg) and glucose‐dependent insulinotropic polypeptide (Gip) genes are evolutionarily related glucagon‐like sequences and act through a subfamily of G‐protein‐coupled receptors. A better understanding of the evolutionary history of these hormones and receptors should yield insight into their biological functions. The availability of a large number of near‐complete vertebrate genome sequences is a powerful resource to address questions concerning the evolution of sequences; here, we utilize these resources to examine the evolution of glucagon‐like sequences and their receptors. These studies led to the discovery of novel genes for a glucagon receptor‐like receptor (Grlr) and a glucagon‐like sequence (exendin) in vertebrates. Both e...

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

Cell Death and Differentiation — Thu, 04 Aug 2011 23:00:00 +0100

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels Cell Death and Differentiation advance online publication, August 5, 2011. doi:10.1038/cdd.2011.102 Authors: S-J Kim, S B Widenmaier, W S Choi, C Nian, Z Ao, G Warnock & C H S McIntosh (Source: Cell Death and Differentiation)

Glucose‐dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity‐associated disorders

Obesity Reviews — Wed, 03 Aug 2011 23:00:00 +0100

SummaryGlucose‐dependent insulinotropic polypeptide (GIP) is a hormone secreted from the intestinal K‐cells with established insulin‐releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the adipose tissue, gut, bone and brain, where GIP modulates energy intake, cell metabolism and proliferation, and lipid and glucose metabolism, eventually promoting lipid and glucose storage. In diabetes and obesity, the incretin effect of GIP is blunted, while the extrapancreatic tissues keep a normal sensitivity to this hormone. As GIP levels are normal or elevated in obesity and diabetes, mounting evidence from chemical or genetic GIP deletion in animal models of obesity‐related diabetes suggests that GIP may have a pro‐obesogenic action and that a...

Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1

AJP: Renal Physiology — Tue, 02 Aug 2011 23:00:00 +0100

This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 µg·kg–1·min–1) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na+/H+ exchanger isoform 3 (NHE3)-mediated bicarbonate ...

Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal.

The American Journal of Clinical Nutrition — Tue, 02 Aug 2011 23:00:00 +0100

CONCLUSIONS: Women with BN secrete abnormally low amounts of GLP-1 and PP, possibly because of the adaption to large meals in the form of enlarged gastric capacity and reduced muscle tone in the gastric wall. Attenuated secretion of these gastrointestinal satiety peptides may play a role in the maintenance of bulimic behavior. PMID: 21813805 [PubMed - as supplied by publisher] (Source: The American Journal of Clinical Nutrition)

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Pleiotropic Effects of GIP on Islet Function Involves Osteopontin.

Diabetes — Sun, 31 Jul 2011 23:00:00 +0100

CONCLUSIONS These findings support β-cell-proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans. PMID: 21810601 [PubMed - as supplied by publisher] (Source: Diabetes)

Mechanisms of action of the dipeptidyl peptidase‐4 inhibitor vildagliptin in humans

Diabetes, Obesity and Metabolism — Thu, 28 Jul 2011 03:48:03 +0100

Inhibition of dipeptidyl peptidase‐4 (DPP‐4) by vildagliptin prevents degradation of glucagon‐like peptide‐1 (GLP‐1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP‐4, eliciting prolonged enzyme inhibition. This raises intact GLP‐1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose‐dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin s...

Saxagliptin: A Clinical Review in the Treatment of Type 2 Diabetes Mellitus.

Clinical Therapeutics — Tue, 26 Jul 2011 23:00:00 +0100

CONCLUSIONS: Saxagliptin, used as monotherapy and in combination regimens, has been associated with significant reductions in HbA(1c) and significant increases in the rate of achieving target HbA(1c) in patients with T2DM. It has been reported to be well tolerated compared with other oral antihyperglycemic agents. Based on the findings from the studies in this review, the primary role of saxagliptin is expected to be in combination therapy with other antihyperglycemic agents. PMID: 21802144 [PubMed - as supplied by publisher] (Source: Clinical Therapeutics)

Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice

Diabetologia — Sat, 23 Jul 2011 15:48:11 +0100

Conclusions/interpretation Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins. Content Type Journal ArticlePages 1-11DOI 10.1007/s00125-011-2241-2Authors M. Nagashima, Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666 JapanT. Watanabe, Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, JapanM. Terasaki, Department of Medicine, Division of Diabetes, M...

Dipeptidyl Peptidase‐4 Inhibitors and Preservation of Pancreatic Islet‐Cell Function: A Critical Appraisal of the Evidence

Diabetes, Obesity and Metabolism — Sat, 16 Jul 2011 16:47:33 +0100

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive beta‐cell dysfunction in the presence of insulin resistance. None of the currently‐available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)‐4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose‐lowering agents enhances endogenous glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) levels by blocking the incretin‐degrading enzyme DPP‐4. DPP‐4 inhibitors may restore the deranged islet‐cell balance in T2DM, by stimulating meal‐related insulin secretion and by decreasing postprandial glucagon leve...

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Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection

Acta Diabetologica — Fri, 15 Jul 2011 05:54:06 +0100

Abstract The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY...

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis

Diabetologia — Sat, 09 Jul 2011 06:11:59 +0100

Conclusions/interpretation The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis. Content Type Journal ArticlePages 1-10DOI 10.1007/s00125-011-2232-3Authors A. E. Hogan, Department of Endocrinology, St Vincent’s University Hospital, University College Dublin, Dublin 4, IrelandA. M. Tobin, Obesity Immunology Group, ERC, Conway Institute, St Vincent’s University Hospital, UCD, Dublin, IrelandT. Ahern, Department of Endocrinology, St Vincent’s University Hospital, University College Dublin, Dublin 4, IrelandM. A. Corrigan, Department of Endocrinology, St Vincent’s University Hospital, University College Dublin, Dublin 4, ...

[New Horizons] Management of type 2 diabetes: new and future developments in treatment

LANCET — Fri, 08 Jul 2011 23:00:00 +0100

SummaryThe increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. (Source: LANCET)

Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

Cardiovascular Diabetology — Wed, 06 Jul 2011 23:00:00 +0100

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a...

A physiological role of glucagon-like peptide-1 receptors in the central nervous system of Suncus murinus (house musk shrew).

European Journal of Pharmacology — Tue, 05 Jul 2011 23:00:00 +0100

Authors: Chan SW, Lin G, Yew DT, Rudd JA Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut as an incretin hormone to stimulate glucose-stimulated insulin secretion. GLP-1 is also produced in the central nervous system (CNS) as a neurotransmitter that regulates feeding behaviour. By using polyclonal antiserum against GLP-1 and GLP-1 receptors, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the ventromedial hypothalamus of Suncus murinus (house musk shrew). In functional studies, subcutaneous administration of exendin-4 (1 - 30nmol/kg) reduced blood glucose levels dose-dependently by up to 49% during an intraperitoneal glucose tolerance test (P<0.001). The glucose-lowering effects were also observed after an int...

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Efficacy and Safety of Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Compared with Exenatide Twice Daily and Sitagliptin in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis (July/August).

The Annals of Pharmacotherapy — Mon, 04 Jul 2011 23:00:00 +0100

CONCLUSIONS Compared with other incretin-based therapies, LA-GLP-1RAs produce greater improvement in A1C and FPG. They provide lesser effect on PPG, similar reduction in body weight, and result in a potentially favorable adverse event profile compared with exenatide twice daily. PMID: 21730278 [PubMed - as supplied by publisher] (Source: The Annals of Pharmacotherapy)

The safety of incretin-based therapies--review of the scientific evidence.

The Journal of Clinical Endocrinology and Metabolism — Thu, 30 Jun 2011 23:00:00 +0100

Conclusions: The available data on incretin action and incidence of cardiovascular events, pancreatitis, or cancer are not yet sufficient or robust enough to permit firm conclusions regarding associations with incretin-based therapies in humans with diabetes. The forthcoming results of long-term cardiovascular safety studies should provide more conclusive information about the safety of GLP-1R agonists and dipeptidyl peptidase-4 inhibitors in diabetic patients. PMID: 21734003 [PubMed - in process] (Source: The Journal of Clinical Endocrinology and Metabolism)

Evolutionary expression of glucose-dependent-insulinotropic polypeptide (GIP).

Regulatory Peptides — Thu, 30 Jun 2011 23:00:00 +0100

We examined the functional evolution of GIP and its relationship with insulin to delineate their respective roles in promoting nutrient efficiency. Expression patterns were examined in the sea lamprey (Petromyzon marinus), a basal vertebrate lacking a distinct pancreas, and in the zebrafish, Xenopus laevis, chicken, and mouse, organisms possessing extraintestinal pancreata. Although sea lamprey genomic analysis predicted a potential GIP-like gene, transcripts were not detected, and insulin expression was confined to the caudal pancreatic bud. GIP was detected in both the intestine and pancreas of the zebrafish and X. laevis. In contrast, GIP and insulin expression were limited to the intestine and pancreas, respectively, in chicken and mouse. Phylogenetic analysis of the glucagon-like liga...

The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

Archives of Pharmacal Research — Thu, 30 Jun 2011 23:00:00 +0100

In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864. PMID: 21811909 [PubMed - in process] (Source: Archives of Pharmacal Research)

Postprandial metabolic response to a fat- and carbohydrate-rich meal in patients with chronic kidney disease

Nephrology Dialysis Transplantation — Sun, 26 Jun 2011 23:00:00 +0100

Conclusions. The postprandial state in CKD is characterized by impaired insulin sensitivity with increased incretin levels, along with GH/IGF-1 axis uncoupling and an elevation in an oxidative stress marker. (Source: Nephrology Dialysis Transplantation)

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Incretin‐Based Therapies

Journal of Diabetes — Sun, 26 Jun 2011 23:00:00 +0100

AbstractIncretin‐based therapies have established a foothold in the diabetes armamentarium through the introduction of oral agents, the DPP‐4 inhibitors, and the injectable class, the GLP‐1 receptor agonists. In 2009, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) authored a revised consensus algorithm for the initiation and adjustment of therapy in type 2 diabetes. The revised algorithm accounts for the entry of incretin‐based therapies into common clinical practice, especially where control of body weight and hypoglycemia are concerns.The gut‐borne incretin hormones have powerful effects on glucose homeostasis, particularly in the postprandial period, where approximately two‐thirds of the beta‐cell response to a given meal ...

Diabetes mellitus: new drugs for a new epidemic

British Journal of Anaesthesia — Thu, 16 Jun 2011 23:00:00 +0100

The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the ‘Black Death’ of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues...

GLP‐1R and Amylin Agonism in Metabolic Disease: Complementary Mechanisms and Future Opportunities

British Journal of Pharmacology — Tue, 14 Jun 2011 23:00:00 +0100

SummaryThe discoveries of the incretin hormone glucagon‐like peptide‐1 (GLP‐1) and the β‐cell hormone amylin have translated into hormone‐based therapies for diabetes. Both classes of molecules also exhibit weight‐lowering effects and have been investigated for their anti‐obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP‐1 and amylin agonism. Despite their similarities (e.g., both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake) there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds i...

In Vivo Suppression of Visfatin by Oral Glucose Uptake: Evidence for a Novel Incretin-Like Effect by Glucagon-Like Peptide-1 (GLP-1).

The Journal of Clinical Endocrinology and Metabolism — Tue, 14 Jun 2011 23:00:00 +0100

Conclusions: Insulin and GLP-1 are responsible for the rapid suppression of visfatin levels upon an oral glucose uptake in healthy probands. The inhibitory effect of GLP-1 on adipocytic visfatin release together with the absence of direct glucose effects on visfatin release suggests the existence of a novel incretin-like effect represented by a GLP-1/visfatin/axis. PMID: 21677044 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Endocrinology and Metabolism)

The effects of L-arabinose on intestinal sucrase activity: dose-response studies in vitro and in humans.

The American Journal of Clinical Nutrition — Tue, 14 Jun 2011 23:00:00 +0100

CONCLUSIONS: l-Arabinose inhibits sucrase activity from Caco-2 cells; 4% l-arabinose in sucrose beverages reduces postprandial glucose, insulin, and C-peptide responses and enhances the GLP-1 response in humans without gastrointestinal adverse effects. This trial is registered at clinicaltrials.gov as NCT00302302. PMID: 21677059 [PubMed - as supplied by publisher] (Source: The American Journal of Clinical Nutrition)

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The Incretin Effect and Secretion in Obese and Lean Women with Polycystic Ovary Syndrome: A Pilot Study

Journal of Women — Tue, 14 Jun 2011 19:54:38 +0100

Journal of Women's Health Jun 2011, Vol. 20, No. 6: 971-976. (Source: Journal of Women)

Advances in the Etiology and Management of Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass

Journal of Gastrointestinal Surgery — Tue, 14 Jun 2011 06:03:53 +0100

Conclusions Treatment of hypoglycemia after RYGB should begin with strict dietary (low carbohydrate) alteration and may require a trial of diazoxide, octreotide, or calcium-channel antagonists, among other drugs. Surgical therapy should include consideration of a restrictive form of bariatric procedure, with or without reconstitution of gastrointestinal continuity. Partial or total pancreatic resection should be avoided. Content Type Journal ArticlePages 1-10DOI 10.1007/s11605-011-1585-8Authors Yunfeng Cui, Department of Surgery, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Baltimore, MD 21224, USADariush Elahi, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA...

Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice.

Endocrinology — Mon, 13 Jun 2011 23:00:00 +0100

Authors: Waget A, Cabou C, Masseboeuf M, Cattan P, Armanet M, Karaca M, Castel J, Garret C, Payros G, Maida A, Sulpice T, Holst JJ, Drucker DJ, Magnan C, Burcelin R Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestin...

ENDO: Incretin May Work in Type 1 Diabetes (CME/CE, with video)

MedPage Today Nephrology — Wed, 08 Jun 2011 20:13:04 +0100

BOSTON (MedPage Today) -- Adding type 2 diabetes drug liraglutide (Victoza) to insulin therapy improves glycemic control in patients with type 1 disease, researchers said here. (Source: MedPage Today Nephrology)

Anti-Inflammatory Properties of Exenatide in Human Pancreatic Islets.

Cell Transplantation — Mon, 06 Jun 2011 23:00:00 +0100

In conclusion, we describe anti-inflammatory and cytoprotective properties of Exenatide in human islets. Exenatide-mediated PI-9 expression, the only known Granzyme B inhibitor, unveils potential immunoregulatory properties. PMID: 21669040 [PubMed - as supplied by publisher] (Source: Cell Transplantation)

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Weight-Independent Changes in Blood Glucose Homeostasis After Gastric Bypass or Vertical Sleeve Gastrectomy in Rats

Gastroenterology — Sun, 05 Jun 2011 23:00:00 +0100

Conclusions: In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss. (Source: Gastroenterology)

The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells

Breast Cancer Research and Treatment — Fri, 03 Jun 2011 05:55:02 +0100

Abstract The incretin hormone glucagon-like peptide (GLP)-1 is secreted from intestinal L cells in response to food intake, and promotes insulin secretion and pancreatic β-cell proliferation. Reduced GLP-1 levels are observed in obesity and type 2 diabetes mellitus (T2DM) and are associated with reduced insulin secretion and increased insulin resistance. GLP-1 mediates its activities through activation of a G-protein coupled receptor, which is expressed in the pancreas, as well as other tissues. Long-acting GLP-1 receptor (GLP-1R) agonists, such as exendin-4, are currently approved for the treatment of T2DM. As obesity and T2DM are associated with increased risk of breast cancer, we aimed to explore the effects of GLP-1 and exendin-4, on breast cancer cells. Treatment wit...

Dietary‐resistant starch improves maternal glycemic control in Goto–Kakizaki rat

Nahrung / Food — Thu, 02 Jun 2011 23:00:00 +0100

Conclusion: Dietary RS is potentially of great therapeutic importance in the treatment of diabetes and improvement in outcomes of pregnancy complicated by diabetes. (Source: Nahrung / Food)

GLP‐1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice.

Diabetes, Obesity and Metabolism — Wed, 01 Jun 2011 23:00:00 +0100

Conclusions: These data demonstrate that the peripheral nerve of diabetic rodents exhibits functional GLP‐1R and suggest that GLP‐1R‐mediated ERK‐signaling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control. (Source: Diabetes, Obesity and Metabolism)

Functional association of the N‐terminal residues with the central region in glucagon‐related peptides

Journal of Peptide Science — Tue, 31 May 2011 23:00:00 +0100

We report that substitution of Ex‐4 amino acids Glu16, Leu21, and Glu24 to the GLP‐1 sequence enabled Gly2 tolerance. The coordination of the N‐terminus with these central residues shows an interaction of substantial importance not only to DPP‐IV stability but also to receptor activation. Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.Biochemical signaling at glucagon‐related peptide receptors is highly dependent on proper orientation of the peptide's N‐terminal histidine within the recepto...

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Cardiovascular effects of DPP-4 inhibition: Beyond GLP-1.

Vascular Pharmacology — Mon, 30 May 2011 23:00:00 +0100

Authors: Fadini GP, Avogaro A Dipeptydil-peptidase-4 (DPP-4) inhibitors are available as oral anti-hyperglycemic drugs for the treatment of type 2 diabetes. Their metabolic effect is mediated through sparing incretin hormones (such as glucagon-like peptide-1, GLP-1) from the rapid degradation by DPP-4. In turn, GLP-1 improves meal-stimulated insulin secretion by pancreatic β-cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert beneficial effects. However, DPP-4 has several non-incretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inflammation, immunity, and vascular function. Owing to these off-ta...

Dual-Monoclonal, Sandwich Immunoassay Specific for Glucose-Dependent Insulinotropic Peptide1-42, the Active Form of the Incretin Hormone [Endocrinology and Metabolism]

Clinical Chemistry — Thu, 26 May 2011 23:00:00 +0100

CONCLUSIONS: The use of an N-terminal–specific monoclonal antibody in a sandwich ELISA format provides a robust and convenient method for measuring concentrations of GIP1-42, the active form of the incretin hormone. This ELISA should help to improve our understanding of the role of GIP1-42 in regulating glucose-dependent insulin secretion. (Source: Clinical Chemistry)

Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test

AJP: Endocrinology and Metabolism — Tue, 24 May 2011 23:00:00 +0100

The rate of appearance (Ra) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the Ra time course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was th...

Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R-/- mice

Biological Chemistry — Mon, 23 May 2011 15:25:18 +0100

Biological Chemistry 392 (6): 539-546 Abstract Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1 in vitro in STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected for in vivo studies in normal and GLP-1R-/- mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal m...

Impaired Insulin Secretion and Enhanced Insulin Sensitivity in Cholecystokinin-Deficient Mice.

Diabetes — Thu, 19 May 2011 23:00:00 +0100

CONCLUSIONS CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions. PMID: 21602512 [PubMed - as supplied by publisher] (Source: Diabetes)

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Mechanisms mediating the diuretic and natriuretic actions of the incretin-hormone glucagon-like peptide-1.

Am J Physiol Renal P... — Tue, 17 May 2011 23:00:00 +0100

This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 μg/kg×min) was intravenously administered in rats for the period of 60 minutes. GLP-1 infused-rats displayed increased urine flow, fractional excretion of sodium, potassium and bicarbonate compared to those rats which received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced NHE3-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism...

Incretin Hormone and Insulin Responses to Oral Versus Intravenous Lipid Administration in Humans.

The Journal of Clinical Endocrinology and Metabolism — Tue, 17 May 2011 23:00:00 +0100

Conclusions: At matching triglyceride levels and with no difference in glucose and free fatty acid levels, oral lipid ingestion but not iv lipid infusion elicits a clear insulin response in association with increased GIP and GLP-1 concentrations. This may suggest that the incretin hormones also contribute to the islet response to noncarbohydrate nutrients. PMID: 21593115 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Endocrinology and Metabolism)

Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a K(ATP) Channel-Independent Mechanism.

Biological and Pharmaceutical Bulletin — Mon, 16 May 2011 09:15:09 +0100

In this study, we investigated the effect of nateglinide on GLP-1 release in vivo and in vitro. The GLP-1 level in the portal blood at 20 min after oral administration of nateglinide to Wistar rats was about twice that in vehicle-treated rats. To clarify whether this effect of nateglinide was related to direct stimulation of intestinal cells, in vitro studies were performed using human intestinal L cells (NCI-H716). Nateglinide stimulated GLP-1 release in a concentration-dependent manner from 500 µM, along with transient elevation of the intracellular calcium level. However, diazoxide, nitrendipine, and dantrolene did not block this effect of nateglinide. In addition, the major metabolite of nateglinide, tolbutamide, and mitiglinide, all of which augment insulin secretion by the pancreati...

Evidence for a Gut–Brain Axis Used by Glucagon‐like Peptide‐1 to Elicit Hyperglycaemia in Fish

Journal of Neuroendocrinology — Sat, 14 May 2011 19:11:20 +0100

In mammals, glucagon‐like peptide‐1 (GLP‐1) produces changes in glucose and energy homeostasis through a gut–pancreas–brain axis. In fish, the effects of GLP‐1 are opposed to those described in other vertebrates, such as stimulation of hyperglycaemia and the lack of an effect of incretin. In the present study conducted in a teleost fish such as the rainbow trout, we present evidence of a gut–brain axis used by GLP‐1 to exert its actions on glucose and energy homeostasis. We have assessed the effects of GLP‐1 on glucose metabolism in the liver as well as the glucose‐sensing potential in the hypothalamus and hindbrain. We confirm that peripheral GLP‐1 administration elicits sustained hyperglycaemia, whereas, for the first time in a vertebrate species, we report that cen...

The metabolic syndrome influences the response to incretin-based therapies

Acta Diabetologica — Sat, 14 May 2011 16:03:47 +0100

In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated. Content Type Journal ArticlePages 1-7DOI 10.1007/s00592-011-0296-7Authors Gian Paolo Fadini, Department of Clinical and Experimental Medicine, Chair and Division of Metabolic Diseases, University of Padova, Medical School, Via Giustiniani, 2., 35100 Padova, ItalySaula Vigili de Kreutzenberg, Department of Clinical and Experimental Medicine, Chair and Division of Metabolic Diseases, University of Padova, Medical School, Via Giustiniani, 2., 35100 Padova, ItalyRomelda Gjini, Department of Clinical and Experimental Medicine, Chair and Division of Metabolic Diseases, University of Padova, Medical School, Via Giust...

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The effects of six months of treatment with exenatide for type 2 diabetes

Journal of Human Nutrition and Dietetics — Fri, 06 May 2011 21:11:29 +0100

Conclusion: After 6 months, Byetta therapy was associated with significant reductions in weight, BMI and HbA1C, which supports the findings of previous research (Buse et al., 2004; DeFronzo et al., 2005). This audit did not include a control group, and future studies could compare the outcomes of treatment with Byetta against outcomes after conventional treatment. The management of patients on Byetta followed the NICE guidance for the majority of the time. However, data for some patients was missing from ‘Diabeta’, suggesting that staff were not always recording information after each consultation with the patient. In future, a larger sample size would increase the validity of results, and future audits within the hospital could focus on record keeping.References: Buse J.B., He...

Dissociated incretin hormone response to protein versus fat ingestion in obese subjects

Diabetes, Obesity and Metabolism — Fri, 06 May 2011 16:47:49 +0100

Protein elicits a stronger early (30 min) glucose‐dependent insulinotropic polypeptide (GIP) response than fat ingestion in lean individuals, with no difference in glucagon‐like peptide‐1 (GLP‐1). We assessed the incretin hormone response to protein versus fat ingestion in obesity. Equicaloric (8 kcal/kg) fat (olive oil) or protein (whey protein) was ingested by non‐diabetic obese male volunteers (BMI >30kg/m2; n=12) and plasma GIP and GLP‐1 were determined. We found no difference in the early GIP or GLP‐1 responses to fat vs. protein. However, the total 300 min GIP response was greater after fat than after protein ingestion (20.3±3.9 vs. 10.0±2.8 nmol/l x 300 min; P=0.026), whereas the 300 min GLP‐1 responses were the same. Thus, in obesity, protein and fat ingestion ...

GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice.

Regulatory Peptides — Tue, 03 May 2011 23:00:00 +0100

CONCLUSIONS: GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome. PMID: 21549160 [PubMed - as supplied by publisher] (Source: Regulatory Peptides)

Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides.

The Journal of Clinical Endocrinology and Metabolism — Tue, 03 May 2011 23:00:00 +0100

Conclusion: Both enhanced insulin sensitivity and incretin hormones, such as GLP-1, contribute to the early control of glucose homeostasis. Progressively increasing postprandial levels of enteroglucagon (oxyntomodulin) and GLP-1 facilitate weight loss and enhance insulin effectiveness. PMID: 21543426 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Endocrinology and Metabolism)

FDA Okays New Incretin Therapy for Diabetes

MedPage Today Primary Care — Mon, 02 May 2011 21:43:08 +0100

(MedPage Today) -- The FDA has approved another dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin (Tradjenta), for treatment of type 2 diabetes, the agency announced. (Source: MedPage Today Primary Care)

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Therapy in the early stage: incretins.

Diabetes Care — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Cernea S, Raz I The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with ...

Incretin effects on β-cell function, replication, and mass: the human perspective.

Diabetes Care — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Garber AJ PMID: 21525465 [PubMed - in process] (Source: Diabetes Care)

Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes.

Diabetes Care — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S PMID: 21525464 [PubMed - in process] (Source: Diabetes Care)

SFR-115 Incretin and insulin levels are unaltered following repair of gastro-gastric fistula after Roux-en-Y gastric bypass

Surgery for Obesity and Related Diseases — Sat, 30 Apr 2011 23:00:00 +0100

In this study, we investigate the metabolic effects of restoring duodenal bypass in patients with GGF by examining the changes in various gut peptides before and after GGF repair. (Source: Surgery for Obesity and Related Diseases)

P-113 Incretin effect is markedly enhanced after sleeve gastrectomy in type 2 diabetes patients

Surgery for Obesity and Related Diseases — Sat, 30 Apr 2011 23:00:00 +0100

Type II diabetes mellitus (T2DM) patients are known to have defect in incretin effect and are markedly enhanced after gastric bypass surgery. However, data after sleeve gastrectomy in T2DM patients with BMI < 35 kg/m2 is lacking. (Source: Surgery for Obesity and Related Diseases)

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Clinical pharmacology of incretin therapies for type 2 diabetes mellitus: implications for treatment.

Clinical Therapeutics — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Neumiller JJ Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus (T2DM). Incretin therapies are premised on 1 of 2 approaches: (1) augmenting the activity of the hormone glucagon-like peptide (GLP)-1 (GLP-1 receptor agonists) and (2) inhibiting the degradation of GLP-1 by dipeptidyl peptidase (DPP)-4 (DPP-4 inhibitors). PMID: 21665041 [PubMed - in process] (Source: Clinical Therapeutics)

Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus.

Clinical Therapeutics — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Campbell RK Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes. PMID: 21665040 [PubMed - in process] (Source: Clinical Therapeutics)

Molecular Basis of GLP1 Binding [Signal Transduction]

Journal of Biological Chemistry — Thu, 28 Apr 2011 23:00:00 +0100

The glucagon-like peptide 1 (GLP1) receptor is an important drug target within the B family of G protein-coupled receptors. Its natural agonist ligand, GLP1, has incretin-like actions and the receptor is a recognized target for management of type 2 diabetes mellitus. Despite recent solution of the structure of the amino terminus of the GLP1 receptor and several close family members, the molecular basis for GLP1 binding to and activation of the intact receptor remains unclear. We previously demonstrated molecular approximations between amino- and carboxyl-terminal residues of GLP1 and its receptor. In this work, we study spatial approximations with the mid-region of this peptide to gain insights into the orientation of the intact receptor and the ligand-receptor complex. We have prepared tw...

Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery

AJP: Gastrointestinal and Liver Physiology — Tue, 26 Apr 2011 23:00:00 +0100

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route ...

Mechanisms of Action of the DPP‐4 Inhibitor Vildagliptin in Man

Diabetes, Obesity and Metabolism — Fri, 22 Apr 2011 16:44:22 +0100

Inhibition of dipeptidyl peptidase‐4 (DPP‐4) by vildagliptin prevents degradation of glucagon‐like peptide‐1 (GLP‐1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP‐4, eliciting prolonged enzyme inhibition. This raises intact GLP‐1 levels, both after meal ingestion and in the fasting state.Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose‐dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determine...

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Current Advances and Therapeutic Potential of Agents Targeting Dipeptidyl Peptidases-IV, -II, 8/9 and Fibroblast Activation Protein.

Current Topics in Medicinal Chemistry — Thu, 21 Apr 2011 23:00:00 +0100

Authors: Chen SJ, Jiaang WT Dipeptidyl peptidase-IV (DPP-IV), a serine protease that specifically cleaves the N-terminal dipeptide with a preference for L-proline or L-alanine at the penultimate position, is involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels and offers therapeutic benefit for patients with type 2 diabetes. However, the therapeutic application of GLP-1 is severely compromised by its lack of oral activity and its rapid degradation by plasma DPP-IV....

Evidence for a gut‐brain axis used by glucagon‐like peptide‐1 to elicit hyperglycemia in fish

Journal of Neuroendocrinology — Mon, 18 Apr 2011 23:00:00 +0100

AbstractIn mammals, glucagon‐like peptide‐1 (GLP‐1) produces changes in glucose and energy homeostasis through a gut‐pancreas‐brain axis. In fish, GLP‐1 effects are opposed to those described in other vertebrates such as stimulation of hyperglycemia and lack of incretin effect. In the present study we present evidence in a teleost fish like rainbow trout of a gut‐brain axis used by GLP‐1 to exert its actions on glucose and energy homeostasis. We have assessed GLP‐1 effects on glucose metabolism in the liver as well as glucose sensing potential in hypothalamus and hindbrain. We have confirmed that peripheral GLP‐1 administration elicits sustained hyperglycemia, while for the first time in a vertebrate species we have reported that central GLP‐1 treatment increases plas...

Glucose-dependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis

Journal of Neurophysiology — Thu, 14 Apr 2011 23:00:00 +0100

In this study, we used a mouse strain with GIPR gene deletion (GIPR KO) to elucidate the role of the GIPR in neuronal communication and brain function. Compared with C57BL/6 control mice, GIPR KO mice displayed higher locomotor activity in an open-field task. Impairment of recognition and spatial learning and memory of GIPR KO mice were found in the object recognition task and a spatial water maze task, respectively. In an object location task, no impairment was found. GIPR KO mice also showed impaired synaptic plasticity in paired-pulse facilitation and a block of long-term potentiation in area CA1 of the hippocampus. Moreover, a large decrease in the number of neuronal progenitor cells was found in the dentate gyrus of transgenic mice, although the numbers of young neurons was not change...

Acute Effects of Decaffeinated Coffee and the Major Coffee Components Chlorogenic Acid and Trigonelline on Incretin Hormones

Medscape Today Headlines — Thu, 14 Apr 2011 11:06:15 +0100

Previous studies have shown coffee consumption to be associated with a lower risk of type 2 diabetes. What might the mechanism of action be? Nutrition and Metabolism (Source: Medscape Today Headlines)

Effects of Gastric Bypass Surgery on Insulin Resistance and Insulin Secretion in Nondiabetic Obese Patients.

Obesity — Wed, 13 Apr 2011 23:00:00 +0100

This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time-courses of glucose, insulin, C-peptide, and the incretin glucagon like peptide-1 (GLP-1) following an oral glucose load. Insulin-sensitivity was measured by a hyperinsulinemic-isoglycemic-clamp-test; glucose-turnover was determined using D-[6,6-(2)H(2)] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m(2)) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m(2)), in a lean (CON: BMI: 22.6 ± 0.6 kg/m(2)) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m(2)). RYGB reduced fasting plasma concentrations of insulin and C-peptide (P < 0.01, respectively) whereas fasting glu...

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Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Journal of Clinical Investigation — Wed, 13 Apr 2011 04:17:32 +0100

Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr–/– mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr–/– mice by generating Gcgr–/–Glp1r–/– mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr–/–Glp1r–/– mice. Elimination of the Glp1r normalized gastric emptying and impaired intra...

Prevention and current onset delay approaches of type 2 diabetes mellitus (T2DM)

European Journal of Clinical Pharmacology — Wed, 06 Apr 2011 06:44:52 +0100

Abstract The urgent need to treat type 2 diabetes mellitus (T2DM), which is currently reaching epidemic proportions, has been a major focus of healthcare systems and policy makers worldwide. Pharmacological treatment and lifestyle interventions together with the control of cardiovascular risk factors are the main strategies to prevent or delay the onset of T2DM. The present review discusses the state of the art knowledge of effective therapeutic approaches (metformin, thiazolidinediones, nateglinides, α-glucosidase inhibitors, incretin-based and angiotensin-based therapies, weight reducers, statins, fibric acid derivatives), including surgery, and identifies the major lifestyle changes for specific target groups. Content Type Journal ArticlePages 1-9DOI 10.1007/s00228...

Incretin‐based therapies – review of the physiology, pharmacology and emerging clinical experience

Internal Medicine Journal — Thu, 31 Mar 2011 23:00:00 +0100

AbstractDiabetes therapies based on manipulation of the incretin system are now widely available, with millions of people receiving treatment. The incretin hormones, glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, but those most relevant to metabolic dysfunction include stimulation of insulin and suppression of glucagon secretion, with resultant reduction in fasting and postprandial glucose. Incretin secretion and/or action is impaired in type 2 diabetes, leading to development of strategies aimed at redressing this abnormality. These strategies include pharmacological inhibition of dipeptidyl peptidase‐4, the enzyme resp...

Understanding the incretin effect.

The Journal of Clinical Endocrinology and Metabolism — Thu, 31 Mar 2011 23:00:00 +0100

Authors: Seino Y PMID: 21474688 [PubMed - in process] (Source: The Journal of Clinical Endocrinology and Metabolism)