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)

Weight reduction in non-insulin dependent diabetes mellitus (NIDDM) patients improves metabolic control, reduces cardiovascular risk factors, has blood pressure lowering effects and improves the well-being of the patient. This paper describes the role of very low calorie diets (VLCD), exercise, beta-adrenergic drugs and serotoninergic agents in the treatment of overweight in NIDDM. VLCD reduce body weight and improve glucose metabolism. Physical exercise programmes in addition to dietary restriction substantially contribute to weight loss and metabolic control in NIDDM. New specific beta-adrenergic agents, exhibiting virtually no beta 1 or beta 2 activity, increase energy expenditure and weight loss probably by enhancement of the basal metabolic rate. The target tissue in humans of this beta-adrenergic effect is as yet unknown. These drugs seem to enhance weight loss when used in combination with (very) low calorie diets compared to dietary restriction alone. Serotoninergic drugs reduce body weight by decreasing appetite, in particular for carbohydrates. Furthermore these drugs seem to improve insulin receptor sensitivity.
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PMID:Very low calorie diets and recently developed anti-obesity drugs for treating overweight in non-insulin dependent diabetics. 136 97

Beta 3-adrenoceptors is a term used for atypical beta-adrenoceptors which do not fit into either the beta 1- or beta 2-receptor as classified by pharmacological methods. The receptor has been cloned and is thus also genetically defined. Beta 3-adrenoceptors appear to be widely distributed. Until now their importance has been based on studies using agonists with high potency, but yet not selective for beta 3-adrenoceptors. The distribution and functional importance in humans are unclear, and will probably not be clarified before selective antagonists and labelled ligand are developed. Agonists for the beta 3-adrenoceptors may be of clinical value in the treatment of obesity, non-insulin dependent diabetes mellitus, gastrointestinal disorders like irritable colon, inflammatory lung diseases and depression.
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PMID:[Beta 3-receptors: incidence and properties, possible clinical significance]. 784 60

Protein kinase C (PKC) is known to be activated in experimental model systems by elevated glucose and may play an important role in the pathogenesis of diabetic complications. Since there is no information about its role in humans in vivo we investigated the activation of PKC in human thrombocytes during infusion of glucose and insulin in normal controls and in 19 NIDDM patients by determining membrane and cytosol levels of PKC beta 2 using immune blots. In the 27 subjects investigated (8 controls, 19 NIDDM) membrane-associated levels of PKC beta 2 increased significantly after 60 and 150 min (p < 0.005). In controls an increase of membrane and of cytosolic PKC beta 2 occurred upon elevation of glucose by 5.5 mmol/L or more and the membrane association persisted for at least 60 min. In NIDDM glucose was elevated by 7.5-10 mmol/L during infusions. Increases of both membrane and cytosolic PKC beta 2 (< 20%-300%) occurred in 10 NIDDM patients suggesting that both, translocation and increased synthesis of PKC beta 2 were stimulated by glucose. Nine other patients showed no alteration (i.e. < 20%) of PKC beta 2. The 2 groups were similar regarding parameters of diabetes control, baseline glucose and glucose elevation during the test. However, the PKC beta 2 responsive group had lower levels of serum triglycerides (1.39 +/- 0.19 vs. 2.32 +/- 0.34 g/L; p = 0.038). To assess whether absolute levels of PKC were altered in human diabetes, platelet levels of PKC alpha, beta 1 and beta 2 were determined in 22 controls and 25 NIDDM subjects with poorly controlled diabetes (HbA1c = 9.8 +/- 0.36%). Cytosolic levels of PKC alpha were significantly decreased by 27% compared to controls in NIDDM but there was no change of PKC beta 1 or PKC beta 2. We conclude that 1. acute elevation of glucose by 5.5 mmol/L or more can activate PKC beta 2 translocation in controls and NIDDM patients in vivo irrespective of parameters of metabolic control. 2. NIDDM patients differ in their PKC beta 2-responses to glucose and 3. poor metabolic control leads to moderate downregulation of PKC alpha suggesting continued activation.
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PMID:Activation of human platelet protein kinase C-beta 2 in vivo in response to acute hyperglycemia. 902 43

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.
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PMID:Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. 1033 19

The characterization in 1989 of the gene encoding the beta 3-adrenoceptor helped to interpret the results of pharmacological experiments on atypical effects of catecholamines distinct from the classical activation of beta 1 and beta 2 adrenoceptors. In rodents, the beta 3 adrenoceptor is abundantly expressed in white adipose tissue where energy is stored in the form of triglycerides and in brown adipose tissue that is specialized for thermogenesis. Treatment of rodents with beta 3 adrenoceptor agonists induces a weight loss related to the stimulation of lipolysis in the two types of tissues. These results led to propose the use of these agonists for the treatment of human obesity and NIDDM. However, the poor lipolytic effect of these agonists in human adipose tissue and the recent discovery of functional beta 3 adrenoceptors in the human heart raise new questions on the therapeutic use of beta 3-adrenoceptor agonists in man. In the human ventricle, these agonists induce a negative inotropic effect. In vessels, stimulation of beta 3-adrenoceptors produces a vasodilation. If these effects are conserved in the failing heart, they could shed a new light on the pathogenic role of the hyperadrenergism associated with cardiac failure, as well as on its treatment with beta-adrenoceptor blockers.
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PMID:[Beta 3 adrenergic receptor: physiologic role and potential therapeutic applications]. 1138 23

In patients with type 2 diabetes mellitus, we used nevibolol, a lipophilic high-selective beta 1-blocker. It has been found out that the drug, while augmenting the synthesis of nitrogen oxide, improves antioxidant properties. Therefore, it can be recommended for use in patients with type 2 diabetes mellitus concurrent with arterial hypertension to achieve normalization of arterial pressure and accomplish a correction of endothelial dysfunction.
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PMID:[Effects of nebivolol on serum levels of NO2 and NO3 oxides in patients with type 2 diabetes mellitus]. 1194 52

Type 2 diabetes mellitus is a social and civilization-related disease that leads to various micro- and macroangiopathic complications, including diabetic nephropathy. At present, the most sensitive and non-invasive indicator of the progression of diabetic nephropathy is microalbuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of glomerules' basement membranes are prior to microalbuminuria. The aim of our clinical study was to establish whether urine and serum TGF beta 1 levels may be significant in prognosing and evaluating a risk for developing diabetic nephropathy. The trial was carried out in 68 patients with type 2 diabetes mellitus and a group of 10 healthy subjects served as control. Urine and serum TGF beta 1 concentrations were evaluated, as well as basic laboratory parameters. After one-year-observation serum creatinine level and microalbuminuria value were investigated in 60 patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus both urine and serum TGF beta 1 concentration were elevated. After one-year-observation of patients with type 2 diabetes mellitus it was established that the increase of serum creatinine concentration and that of microalbuminuria value were higher in those patients, whose initial TGF beta 1 levels exceeded normal values. A positive correlation between urine TGF beta 1 level and the progression of renal failure measured by the increase of serum creatinine level was observed. In conclusion, our findings indicate that urine TGF beta 1 level may be a good prognostic factor of the development of diabetic nephropathy in the course of diabetes mellitus.
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PMID:[Urine TGF-beta1 concentration in patients with type II diabetes mellitus--prognostic values]. 1247 94

Physical activity can raise the level of circulating HDL cholesterol. Pre beta 1-HDL is thought to be either the initial acceptor of cellular cholesterol or virtually the first particle in the pathway of the formation of HDL from apolipoprotein A-I and cellular lipids. We have therefore sought to identify pre beta 1-HDL in arterial and venous circulations of exercising legs in healthy individuals and in subjects with stable Type 2 diabetes mellitus. Blood samples were taken simultaneously from the femoral artery and vein before and after 25 min cycling exercise. The major findings were, first, that exercise significantly increased plasma concentration of pre beta 1-HDL (20% increase, P < 0.05) and second, that the pre beta 1-HDL concentration was significantly higher in the venous compared with the arterial blood both before and after exercise in both diabetics and controls. In the combined population, formation of pre beta 1-HDL at rest was 9.9 +/- 5.2 mg/min and exercise enhanced pre beta 1-HDL formation 6.6-fold in both groups.
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PMID:Single session exercise stimulates formation of pre beta 1-HDL in leg muscle. 1256 39

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.
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PMID:Pharmacokinetics and pharmacodynamics of vildagliptin in healthy Chinese volunteers. 1883 95

HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3' UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.
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PMID:The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity. 2944 30


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