Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration ofGLP-1 analogue resistant to DPPIV or therapeutic inhibition ofthe enzymes, allowing for an increase in the levels of GLP-1, are the very new approaches to the treatment of type 2 diabetes mellitus. Incretin therapy has an immense potential of improving unsatisfactory compensation in diabetic patients thus reducing the risk of manifestation of all arterial complications. Low fasting circulating levels of GLP-1 (and also GIP) grow rapidly after eating and are subsequently degraded to inactive forms by dipeptidyl peptidases IV (DPPIV). DPPIV are enzymes widely present in the body which proteolytically degrade GLP-1 and GIP (as well as other active substances). The preventing of their inactivation effect by administering DPPIV inhibitors allows for increasing the GLP-1 levels, which are reduced in type 2 diabetic patients, and subsequently improves glucose homeostasis in such patients. DPPIV inhibitors represent the principal new class of PAD, and their metabolic profile offers a number of unique clinical advantages for the treatment of patients with type 2 diabetes mellitus.
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PMID:[Incretin strategy in the treatment of type 2 diabetes mellitus--DPPIV]. 1801 60

Type 2 diabetes is a heterogeneous, polygenic disorder in which dysfunction in a number of important metabolic pathways appears to play roles. Although it remains unclear exactly which event triggers the disorder, beta-cell dysfunction is a key element in the underlyingpathophysiology. Both impaired insulin secretion and insulin resistance contribute to the hyperglycemic state that causes the devastating cardiovascular, neurologic, and renal effects characteristic of type 2 diabetes. To prevent these complications, the American Diabetes Association recommends maintaining A1C levels below 7%. A1C has long been the target of diabetes therapy, and while this remains true in those with A1C levels above 8.4%, it is now apparent that in those with mild to moderate diabetes, postprandial glucose excursions may be of greater importance. Postprandial hyperglycemia occurs in 74% of those diagnosed with diabetes and 39% of those with optimal A1C levels. Involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 diabetes. As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. The incretins are important gut mediators of insulin release, and in the case of GLP-1, of glucagon suppression. Although GIP activity is impaired in those with type 2 diabetes, GLP-1 insulinotropic effects are preserved, and thus GLP-1 represents a potentially beneficial therapeutic option. However, like GIP, GLP-1 is rapidly inactivated by DPP-IV in vivo. Two therapeutic approaches to this problem have been developed: GLP-1 analogs with increased half-lives, and DPP-IV inhibitors, which prevent the breakdown of endogenous GLP-1 as well as GIP. Both classes of agent have shown promise, with potential not only to normalize fasting and postprandial glucose levels but also to improve beta-cell functioning and mass.
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PMID:Pathophysiology of type 2 diabetes and the role of incretin hormones and beta-cell dysfunction. 1821 45

Glucose-dependent insulinotropic polypeptide has been proposed as a potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24h. Both GIP[mPEG] and GIP concentration-dependently stimulated cAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p < 0.01 to p < 0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p < 0.05) and increased plasma insulin responses (p < 0.05). Furthermore, GIP[mPEG] markedly lowered plasma glucose when administered 4-24h prior to a glucose load (p < 0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p < 0.05). Moreover, glucose tolerance was significantly improved (p < 0.05) together with glucose-mediated plasma insulin responses (p < 0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. In summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and improve biological action thus representing a novel therapeutic option for type 2 diabetes.
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PMID:C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes. 1845 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

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.
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PMID:Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety. 1878 1

Type 2 diabetes mellitus is an increasingly prevalent condition worldwide. The complications of this disease are known to significantly increase the morbidity and mortality of those affected, resulting in substantial direct and indirect costs. Although good glycemic control has been shown to reduce the incidence and progression of diabetes-related microvascular complications, blood glucose levels are not adequately controlled in most individuals with diabetes. The reasons for this are many, and include issues such as poor adherence to complex medication regimes; costs of prescribed therapies; and the failure of traditionally prescribed medications to preserve beta cell function over time. However, our armamentarium of glucose-lowering drugs has expanded recently with the development of medications that act via the incretin pathway. Sitagliptin, the first commercially available dipeptidyl peptidase-4 inhibitor, inhibits the metabolism and inactivation of the incretin hormones GLP-1 and GIP. The subsequent elevation in levels of these hormones and associated prolongation of their actions has been shown to increase insulin secretion and suppress glucagon secretion in a glucose-appropriate fashion. Sitagliptin therapy in individuals with type 2 diabetes has been found to lower significantly hemoglobin A1c (Hb1c) levels with a minimum of adverse side effects such as weight gain or hypoglycemia. Use of sitagliptin in conjunction with the insulin-sensitizing medication metformin has been shown to decrease HbAlc levels more significantly than does either drug alone. This combination of medications is generally well tolerated, with no adverse effects on weight and a very low likelihood of treatment-related hypoglycemia. Use of both drugs will positively affect many of the underlying metabolic abnormalities associated with type 2 diabetes, including the disordered secretion of insulin and glucagon as well as impaired sensitivity to insulin which are known to accompany this disease. Animal studies also suggest that dipeptidyl peptidase-4 inhibitor treatment may help to preserve beta cell mass; however, it is unclear at present whether or not this will prove to be the case in humans.
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PMID:New combination treatments in the management of diabetes: focus on sitagliptin-metformin. 1906 92

Some studies indicate that diabetes mellitus exerts an influence on the gastrointestinal tract and its diffuse neuroendocrine system (DNES) in regard to cellular density and neuroendocrine content. Since there is no data about relationship between experimentally induced non-insulin-dependent (type 2) diabetes mellitus (NIDDM) on the gut K cells, the aim of our study was to investigate immunohistochemical, stereological and ultrastructural changes of rat K cells after 12 days of dexamethasone treatment. Twenty male Wistar rats aged 30 days were given daily intraperitoneally 2 mg kg(-1) dexamethasone (group DEX, 10 rats) or saline (group C, 10 rats) for 12 days. Tissue specimens were obtained from each antrum with corpus and different parts of the small (SI) and large intestine (LI) of all animals. Immunohistochemistry was carried out using antisera against the GIP and insulin. Transmission electron microscopy was also used. Although, according to the literature data, rat K cells are present in the duodenum and jejunum and, to a lesser extent, in the ileum, in the present study we observed that those cells were abundant also in all parts of the LI. We observed generally that GIP-producing K cells were augmented in all parts of SI and decreased in the LI of DEX rats. Insulin immunoreactivity (ir) coexpressed with GIP-ir in K cells and was stronger in the SI of DEX rats as compared with C rats. We also found by electron microscopy that small intestinal K cells have features not only of GIP-secreted but also of insulin-secreted cells. We concluded that dexamethasone treatment caused proliferation of K cells in the rat SI, and simultaneously transformation of GIP-producing K cells to insulin-synthesizing cells.
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PMID:Glucose-dependent insulinotropic polypeptide-producing K cells in dexamethasone-treated rats. 1909 27

Improvement in Type 2 diabetes is seen in 80-98% of obese diabetic patients who undergo gastric bypass or bilio-pancreatic diversion. This improvement is evident early after the operation before significant weight loss has occurred. Although numerous teams have extensively studied the physiology of this early post-bypass amelioration of type 2 diabetes, the exact mechanism of diabetes remission remains unclear. Studies have focused on changes in the entero-insular axis, which is mediated in part by the interaction of insulinotropic hormones GIP and GIP 1 on the beta islet cells of the pancreas. Other mechanisms which have been postulated focus on the adipo-insular axis; the actions of adiponectin and leptin seem to have an important role in insulin resistance but their action is weight-loss dependent. Post-operative caloric restriction may also contribute to the early resolution of type 2 diabetes observed after gastric bypass and bilio- pancreatic diversion.
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PMID:[Early improvement in Type 2 diabetes in obese patients following gastric bypass and bilio-pancreatic diversion: the role of the entero-insular axis]. 1910 85

Emerging as an epidemic of the 21st century type 2 diabetes has become a major health problem throughout the globe. The number of deaths attributable to diabetes reflects the insufficient glycemic control achieved with the treatments used in recent past. DPP-4 inhibitors have been investigated as a new therapy with novel mechanisms of action and improved tolerability. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. As soon as released from the gut in response to food intake, GLP-1 and GIP exert a potent glucose-dependent insulinotropic action, thereby playing a key role in the maintenance of post-meal glycemic control. Consequently, inhibiting DPP-4 prolongs the action of GLP-1 and GIP, which in turn improves glucose homeostasis with a low risk of hypoglycemia and potential for disease modification. Indeed, clinical trials involving diabetic patients have shown improved glucose control by administering DPP-4 inhibitors, thus demonstrating the benefit of this promising new class of antidiabetics. Intense research activities in this area have resulted in the launch of sitagliptin and vildagliptin (in Europe only) and the advancement of a few others into preregistration/phase 3, for example, saxagliptin, alogliptin and ABT-279. Achieving desired selectivity for DPP-4 over other related peptidases such as DPP-8 and DPP-9 (inhibition of which was linked to toxicity in animal studies) and long-acting potential for maximal efficacy (particularly in more severe diabetic patients) were the major challenges. Whether these goals are achieved with the present series of inhibitors in the advanced stages of clinical development is yet to be confirmed. Nevertheless, treatment of this metabolic disorder especially in the early stages of the disease via DPP-4 inhibition has been recognized as a validated principle and a large number of inhibitors are presently in various stage of pre-clinical/clinical development. Sitagliptin is a new weapon in the arsenal of oral antihyperglycemic agents. This review will focus on the journey of drug discovery of DPP-4 inhibitors for oral delivery covering a brief scientific background and medicinal chemistry approaches along with the status of advanced clinical candidates.
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PMID:Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. 1921 90

The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.
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PMID:Human glucagon receptor antagonists with thiazole cores. A novel series with superior pharmacokinetic properties. 1938 13


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