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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are physiological gut peptides with insulin-releasing and extrapancreatic glucoregulatory actions. Incretin analogues/mimetics activate GLP-1 or GIP receptors whilst avoiding physiological inactivation by dipeptidyl peptidase 4 (DPP-4), and they represent one of the newest classes of antidiabetic drug. The first clinically approved GLP-1 mimetic for the treatment of type-2 diabetes is exenatide (Byetta/exendin) which is administered subcutaneously twice daily. Clinical trials of liraglutide, a GLP-1 analogue suitable for once-daily administration, are ongoing. A number of other incretin molecules are at earlier stages of development. This review discusses the various attributes of GLP-1 and GIP for diabetes treatment and summarises current clinical data. Additionally, it explores the therapeutic possibilities offered by preclinical agents, such as non-peptide GLP-1 mimetics, GLP-1/glucagon hybrid peptides, and specific GIP receptor antagonists.
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PMID:Incretin hormone mimetics and analogues in diabetes therapeutics. 1805 32

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). Insulin signaling is often impaired in AD, contributing to the neurodegeneration observed in AD patients. One potential strategy to overcome this impairment is to normalize insulin signaling in the brain. In the present study, we have examined the effects of an enzyme-resistant analogue of glucose-dependent insulinotropic polypeptide (GIP), N-AcGIP, on synaptic plasticity. N-AcGIP is a stable, long-acting peptide hormone that regulates glucose homeostasis and insulin release. We tested the effects of native GIP and the agonist N-AcGIP on synaptic plasticity [long-term potentiation (LTP)] in the hippocampus [15 nmol, administered intracerebroventricularly (icv)] and report for the first time that both peptides have enhancing effects on LTP. In contrast, the antagonist of GIP, Pro(3)GIP (15 nmol icv), reduced LTP. Injection of beta-amyloid(25-35) (100 nmol), a peptide that aggregates in brains of AD patients, also impaired LTP. The injection of N-AcGIP (15 nmol icv) 30 min prior to injection of amyloid(25-35) (100 nmol icv) fully reversed the impairment of LTP induced by beta-amyloid. The results demonstrate for the first time that GIP (particularly enzyme-resistant forms) not only directly modulates neurotransmitter release and LTP formation, but also protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation. The use of enzyme-resistant analogues of GIP show great promise as a potential novel treatment for preventing neurodegenerative processes in AD and other related disorders.
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PMID:Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. 1823 83

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are intestinal postprandial hormones that stimulate insulin release from the pancreas as long as circulating glucose concentrations are raised. In addition to their effect on insulin secretion and consequent glucose lowering, GIP and GLP-1, especially the latter, have a number of physiological effects such as inhibition of glucagon release, gastric emptying and food intake, as well as a tropic action on pancreatic B-cell mass. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate both in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of type 2 diabetes (T2D). There is increasing evidence that current treatments do not address the issue of progressive B-cell failure in T2D. Since obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D.
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PMID:Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. 1837 45

Strong evidence exists demonstrating the benefits of tight glycemic control in type 1 and type 2 diabetes mellitus patients, but glycemic goals are not adequately achieved for many patients. Advancement in the knowledge surrounding the physiology of endogenous glucoregulatory peptide hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, has led to new therapeutic targets for the treatment of type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide practitioners with a novel mechanism of action to use for combination therapies for the treatment of type 2 diabetes mellitus. This article, part 3 of a 3-part series, reviews the new class of medications known as DPP-4 inhibitors as well as discusses a future buccal insulin formulation, Oral-Lyn, on the horizon for the treatment of diabetes mellitus.
Diabetes Educ
PMID:Looking to the future: focus on DPP-4 inhibitors for the treatment of type 2 diabetes and emerging therapies. 1837 72

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that play important roles in maintaining glucose homeostasis and are being actively pursued as novel therapeutic agents for diabetes. GIP is produced by dispersed enteroendocrine cells and interestingly at times is coexpressed with GLP-1. We sought to determine the factors that selectively define GIP- vs. GLP-1-expressing cells. We performed comparative immunostaining of Pax6 and Pdx1 in GIP- and GLP-1-secreting cells. We investigated whether Pax6 and Pdx1 activate the human GIP promoter in control IEC-6 cells and GIP-expressing STC-1 cells. EMSA was performed to assess the binding of these transcription factors to the GIP promoter. Pax6 and Pdx1 consistently colocalized in GIP-immunoreactive cells. Cells that coexpress GIP and GLP-1 were Pax6 and Pdx1 positive, whereas cells expressing only GLP-1 were Pax6 positive but did not express Pdx1. GIP promoter activity was enhanced in IEC-6 cells by exogenous Pax6 or Pdx1 and diminished in STC-1 cells by inhibition of endogenous Pax6 or Pdx1 by dominant-negative forms. Promoter truncation analysis revealed a major loss of promoter activity when the sequence between -184 to -145 bp was deleted. EMSA studies indicated that Pax6 and Pdx1 bind to this proximal sequence of the human GIP promoter. Our findings indicate that concomitant expression of Pax6 and Pdx1 is important for GIP expression. Our results also suggest that the presence of Pdx1 defines whether GLP-1-expressing gastrointestinal L cells also coexpress GIP.
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PMID:Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide in proglucagon-expressing L cells. 1859 49

In the pathogenesis of diabetes type 2, increasing insulin resistance is accompanied by dysfunction of pancreatic islet b cells. It is hypothesized that at the basis of this pathology lies an incretin defect of insulinotropic gut-derived hormones, relying on decreased secretion of GLP-1 (glucagon-like peptide 1), with preserved insulinotropic effect, whereas GIP (glucose-dependent insulinotropic polypeptide) secretion remains within physiological limits, but its action is mostly impaired due to total loss of possibility for stimulation of the second phase insulin secretion. Possibilities for pharmacological correction of incretin defect create an opportunity of causative treatment of diabetes and provide basis for development of research on a new group of drugs which promote hypoglycemia. In the presence of these findings there are many ongoing clinical studies with the use of GLP-1 analogues or GLP-1 receptors activators (GLP-1 agonists), as well as the inhibitors of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for incretin proteolysis, in the treatment of type 2 diabetes. Multidirectional, glucoregulative mechanism of action of these drugs, aiming at the pathogenesis of the disease, restores the proper function of the intestinal-pancreatic axis in subjects with type 2 diabetes and ensures good metabolic control and improvement in quality of life in this group of patients.
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PMID:[Incretin hormones in the treatment of type 2 diabetes. Part II. Incretins - new possibilities for pharmacotherapy of type 2 diabetes]. 1877 3

The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both incretins. Enhancement of incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.
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PMID:The incretin system and its role in type 2 diabetes mellitus. 1878 5

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). This is most likely due to the desensitisation of insulin receptors in the brain. Insulin acts as a growth factor and supports neuronal repair, dendritic sprouting, and differentiation. This review discusses the potential role that insulin-like hormones could play in ameliorating the reduced growth factor signalling in the brains of people with AD. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have very similar properties in protecting neurons from toxic effects, and are capable of reversing the detrimental effects that beta-amyloid fragments have on synaptic plasticity. Therefore, incretins show great promise as a novel treatment for reducing degenerative processes in AD.
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PMID:New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer's disease? 1893 May 64

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic beta-cells. Agents that either mimic GLP-1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP-1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development.
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PMID:RD Lawrence Lecture 2008: Targeting GLP-1 release as a potential strategy for the therapy of Type 2 diabetes. 1895 99

Vildagliptin (Galvus) is an antihyperglycaemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme. Such inhibition prevents the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in improved glycaemic control as determined by glycated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) levels, and, in addition, an enhancement of pancreatic alpha- and beta-cell function. Vildagliptin is indicated in the EU and elsewhere in the world for the management of type 2 diabetes mellitus in combination with metformin, a sulfonylurea or a thiazolidinedione in patients with inadequate glycaemic control following monotherapy. Vildagliptin is also available as a fixed-dose formulation with metformin (Eucreas).Oral vildagliptin in combination with metformin, a sulfonylurea or a thiazolidinedione improved glycaemic control in adults with type 2 diabetes and appeared to slow the progression of beta-cell degeneration in trials of 24-52 weeks' duration. In trials in patients with diabetes inadequately controlled with metformin, vildagliptin provided an additional reduction of HbA(1c) levels of 1.1% and was shown to be as effective as pioglitazone as add-on therapy in a noninferiority trial. Vildagliptin had a low risk of hypoglycaemia, was weight-neutral overall and was generally well tolerated. Further investigation is required to accurately position vildagliptin relative to other, well established antidiabetic agents. However, the addition of vildagliptin expands the range of treatment options available, and as such, offers further potential for the management of patients with type 2 diabetes that is inadequately controlled with monotherapy.
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PMID:Vildagliptin: a review of its use in the management of type 2 diabetes mellitus. 1897


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