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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes mellitus is one of the most common metabolic diseases worldwide and its prevalence is rapidly increasing. Due to its chronic nature (diabetes mellitus can be treated but as yet not cured) and its serious complications, it is one of the most expensive diseases with regard to total health care costs per patient. The elevated blood glucose levels in diabetes mellitus are caused by a defect in production and/or secretion of the polypeptide hormone insulin, which normally promotes glucose-uptake in cells. Insulin is produced by the pancreatic 'beta-cells' in the 'islets of Langerhans', which lie distributed within the exocrine pancreatic tissue. In type 2 diabetes mellitus, the initial defect in the pathogenesis of the disease in most of the patients is believed to be 'insulin resistance'. Hyperglycemia (clinically overt diabetes mellitus) will not develop as long as the body is able to produce enough insulin to compensate for the reduced insulin action. When this compensation fails ('beta-cell failure') blood glucose levels will become too high. In this review, we discuss one of the mechanisms that have been implicated in the development of beta-cell failure, i.e. amyloid formation in the pancreatic islets. This islet amyloid is a characteristic histopathological feature of type 2 diabetes mellitus and both in vitro and in vivo studies have revealed that its formation causes death of islet beta-cells. Being a common pathogenic factor in an otherwise heterogeneous disease, islet amyloidosis is an attractive novel target for therapeutic intervention in type 2 diabetes mellitus.
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PMID:Role of islet amyloid in type 2 diabetes mellitus. 1645 27

Increased serum concentrations of low density lipoproteins represent a major cardiovascular risk factor. Low-density lipoproteins are derived from very low density lipoproteins secreted by the liver. Apolipoprotein (apo)B that constitutes the essential structural protein of these lipoproteins exists in two forms, the full length form apoB-100 and the carboxy-terminal truncated apoB-48. The generation of apoB-48 is due to editing of the apoB mRNA which generates a premature stop translation codon. The editing of apoB mRNA is an important regulatory event because apoB-48-containing lipoproteins cannot be converted into the atherogenic low density lipoproteins. The apoB gene is constitutively expressed in liver and intestine, and the rate of apoB secretion is regulated post-transcriptionally. The translocation of apoB into the endoplasmic reticulum is complicated by the hydrophobicity of the nascent polypeptide. The assembly and secretion of apoB-containing lipoproteins within the endoplasmic reticulum is strictly dependent on the microsomal tricylceride transfer protein which shuttles triglycerides onto the nascent lipoprotein particle. The overall synthesis of apoB lipoproteins is regulated by proteosomal and nonproteosomal degradation and is dependent on triglyceride availability. Noninsulin dependent diabetes mellitus, obesity and the metabolic syndrome are characterized by an increased hepatic synthesis of apoB-containing lipoproteins. Interventions aimed to reduce the hepatic secretion of apoB-containing lipoproteins are therefore of great clinical importance. Lead targets in these pathways are discussed.
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PMID:Inhibition of the synthesis of apolipoprotein B-containing lipoproteins. 1659 12

Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 +/- 4.3 to 65.73 +/- 3.22 mumol . kg fat-free mass(-1) . min(-1) at 1 week and to 64.73 +/- 3.42 mumol . kg fat-free mass(-1) . min(-1) at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 +/- 20.07 to 70.0.2 +/- 8.14 and 83.24 +/- 8.28 pmol/min per m(2); P < 0.01) and total insulin output (43.76 +/- 4.07 to 25.48 +/- 1.69 and 30.50 +/- 4.71 nmol/m(2); P < 0.05) dramatically decreased, while a significant improvement in beta-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 +/- 1.99 to 6.58 +/- 1.72 pmol/l at 1 week and 5.83 +/- 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 +/- 0.16 to 3.42 +/- 0.41 pmol/l at 1 week and 3.62 +/- 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing beta-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum.
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PMID:Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. 1680 72

Glucose dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with therapeutic potential for type 2 diabetes due to its insulin-releasing and antihyperglycaemic actions. However, development of GIP-based therapies is limited by N-terminal degradation by DPP IV resulting in a very short circulating half-life. Numerous GIP analogues have now been generated exhibiting DPP IV resistance and extended bioactivity profiles. In this study, we report a direct comparison of the long-term antidiabetic actions of three such GIP molecules, N-AcGIP, GIP(Lys(37)PAL) and N-AcGIP(Lys(37)PAL) in obese diabetic (ob/ob) mice. An extended duration of action of each GIP analogue was demonstrated prior to examining the effects of once daily injections (25nmolkg(-1) body weight) over a 14-day period. Administration of either N-AcGIP, GIP(Lys(37)PAL) or N-AcGIP(Lys(37)PAL) significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to saline treated controls. All three analogues significantly enhanced glucose and nutrient-induced insulin release, and improved insulin sensitivity. The metabolic and insulin secretory responses to native GIP were also enhanced in 14-day analogue treated mice, revealing no evidence of GIP-receptor desensitization. These effects were accompanied by significantly enhanced pancreatic insulin following N-AcGIP(Lys(37)PAL) and increased islet number and islet size in all three groups. Body weight, food intake and circulating glucagon were unchanged. These data demonstrate the therapeutic potential of once daily injection of enzyme resistant GIP analogues and indicate that N-AcGIP is equally as effective as related palmitate derivatised analogues of GIP.
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PMID:Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide. 1685 46

With the rising prevalence of diabetes, new therapies that provide glucose control are needed. Although many medications are available, tight glucose control is still a challenge. In this article, the physiology of glucose homeostasis is explored with respect to type 2 diabetes. The incretin effect is explained in detail, and the incretin hormones, glucose-dependent insulinotrophic polypeptide and glucagon-like peptide 1, are investigated as well as their contribution to type 2 diabetes therapy. Studies involving dipeptidyl-peptidase 4 (DPP-4) inhibitors are summarized as to their effects on glucose homeostasis. Specifically, vildagliptin (Galvus; Novartis International AG, Basel, Switzerland) and sitagliptin (Januvia; Merck & Co, Inc, Whitehouse Station, NJ) are described. The use and efficacy of the currently available incretin mimetic, exenatide (Byetta; Amylin Pharmaceuticals, Inc and Eli Lilly and Company, San Diego, Calif, and Indianapolis, Ind), are briefly discussed. Throughout this article, the rationale for the use of DPP-4 inhibitors is presented.
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PMID:The physiology of incretin hormones and the basis for DPP-4 inhibitors. 1727 93

The incretins are peptide hormones produced by special cell types of the intestines, which are secreted following ingestion of foods, indirectly, through a complex mechanism, by decreasing postprandial blood glucose levels participate in the regulation of the glucose homeostasis. The article beside of summarizing the physiological aspects of the two most important incretins, the glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrope polypeptide (GIP), gives a detailed overview of multifaceted effects of GLP-1 and their potential application in the therapy of type 2 diabetes mellitus. The human GLP-1 because of its very short half-life is not suitable for therapeutic use. However, by inhibition its degradation, by suppression of activity of the serine peptidase type enzyme dipeptidyl peptidase (DPP) IV, its effect can be prolonged. Compounds with this effect have been synthetised, as well as drugs resistant to DPP IV, not being identical with the structure of the human GLP-1, but having agonist effect on its receptor could also be manufactured. Members of the first group are called incretin (GLP-1) enhancers, while of the second one incretin mimetics. Two of the enhancers, the sita- and vildagliptin, and one representative of the incretin mimetics, the exenatide after encouraging preclinical and human experiences have also been registered and introduced in the clinical practice. Their potential place in the treatment of type 2 diabetes is not exactly outlined at present. Though there are arguments underlining their early use in the glucose lowering drug treatment of type 2 diabetes, their application as part of a combination therapy seems to be a real indication.
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PMID:[Incretin enhancers, incretin mimetics: from therapeutic concept to clinical application]. 1738 51

Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic beta cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42). The hormone binds in an alpha-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, alpha-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class.
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PMID:Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. 1771 56

Biotin-dependent multifunctional enzymes carry out metabolically important carboxyl group transfer reactions and are potential targets for the treatment of obesity and type 2 diabetes. These enzymes use a tethered biotin cofactor to carry an activated carboxyl group between distantly spaced active sites. The mechanism of this transfer has remained poorly understood. Here we report the complete structure of pyruvate carboxylase at 2.0 angstroms resolution, which shows its domain arrangement. The structure, when combined with mutagenic analysis, shows that intermediate transfer occurs between active sites on separate polypeptide chains. In addition, domain rearrangements associated with activator binding decrease the distance between active-site pairs, providing a mechanism for allosteric activation. This description provides insight into the function of biotin-dependent enzymes and presents a new paradigm for multifunctional enzyme catalysis.
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PMID:Domain architecture of pyruvate carboxylase, a biotin-dependent multifunctional enzyme. 1771 83

In the recent years, measurement of blood level of fibrinogen has been treated very seriously and this parameter has been considered an individual cardiovascular risk factor. A correlation between serum fibrinogen and the frequency of acute myocardial or cerebral ischemia has been found in a large number of studies. A distinct association between a high fibrinogen level and vascular complications in diabetic patients has been revealed as well. Two types of fibrinogen--high molecular weight fibrinogen (HMWF) weighing 340 kD, and low molecular weight fibrinogen (LMWF), weighing 280 kD and lacking a certain part of A alpha-polypeptide chain, are known today. B. Lipinski created a technique to measure the content of LMWF in blood serum, which made it possible to study the role played by this protein in the clinical presentation of atherothrombosis in diabetic patients. This work presents the results of research into the role of LMWF in the clinical picture of atherothrombosis in patients with type 2 diabetes mellitus. According to the localization of the manifestation of arterial ischemia and the presence of diabetes, three groups ofpatients were formed. The study revealed significantly higher LMWF level in all the three groups compared to controls. The LMWF/total blood fibrinogen ratio was also elevated.
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PMID:[Fibrinogens and their role in atherogenesis in diabetes mellitus]. 1788 12

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul


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