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)

Hepatic glucose production is increased in people with type 2 diabetes. Glucose released from storage in liver glycogen by phosphorylase accounts for approximately 50% of the glucose produced after an overnight fast. Therefore, understanding how glycogenolysis in the liver is regulated is of great importance. Toward this goal, we have determined the kinetic characteristics of recombinant human liver glycogen phosphorylase a (HLGPa) (active form) and compared them with those of the purified rat enzyme (RLGPa). The Michaelis-Menten constant (K(m)) of HLGPa for P(i), 5 mM, was about fivefold greater than the K(m) of RLGPa. Two P(i) (substrate) concentrations were used (1 and 5 mM) to cover the physiological range for P(i). Other effectors were added at estimated intracellular concentrations. When added individually, AMP stimulated, whereas ADP, ATP and glucose inhibited, activity. These results were similar to those of the RLGPa. However, glucose inhibition was about twofold more potent with the human enzyme. UDP-glucose, glucose 6-phosphate, and fructose 1-phosphate were only minor inhibitors of both enzymes. We reported previously that when all known effectors were present in combination at physiological concentrations, the net effect was no change in RLGPa activity. However, the same combination reduced HLGPa activity, and the inhibition was glucose dependent. We conclude that a combination of the known effectors of phosphorylase a activity, when present at estimated intracellular concentrations, is inhibitory. Of these effectors, only glucose changes greatly in vivo. Thus it may be the major regulator of HLGPa activity.
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PMID:Integrated effects of multiple modulators on human liver glycogen phosphorylase a. 1206 39

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients.
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PMID:Gliclazide modified release. 1207 88

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
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PMID:Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. 1208 35

1. We have investigated the effects of the sulphonylurea, glimepiride, currently used to treat type 2 diabetes, on ATP-sensitive K(+) (K(ATP)) currents of rat cardiac myocytes and on their cloned constituents Kir6.2 and SUR2A expressed in HEK 293 cells. 2. Glimepiride blocked pinacidil-activated whole-cell K(ATP) currents of cardiac myocytes with an IC(50) of 6.8 nM, comparable to the potency of glibenclamide in these cells. Glimepiride blocked K(ATP) channels formed by co-expression of Kir6.2/SUR2A subunits in HEK 293 cells in outside-out excised patches with a similar IC(50) of 6.2 nM. 3. Glimepiride was much less effective at blocking K(ATP) currents activated by either metabolic inhibition (MI) with CN(-) and iodoacetate or by the K(ATP) channel opener diazoxide in the presence of inhibitors of F(0)/F(1)-ATPase (oligomycin) and creatine kinase (DNFB). Thus 10 microM glimepiride blocked pinacidil-activated currents by >99%, MI-activated currents by 70% and diazoxide-activated currents by 82%. 4. In inside-out patches from HEK 293 cells expressing the cloned K(ATP) channel subunits Kir6.2/SUR2A, increasing the concentration of ADP (1 - 100 microM), in the presence of 100 nM glimepiride, lead to significant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not affect cloned K(ATP) channel activity in the presence of 100 nM glibenclamide. These results are consistent with the suggestion that ADP reduces glimepiride block of K(ATP) channels. 5. Our results show that glimepiride is a potent blocker of native cardiac K(ATP) channels activated by pinacidil and blocks cloned Kir6.2/SUR2A channels activated by ATP depletion with similar potency. However, glimepiride is much less effective when K(ATP) channels are activated by MI and this may reflect a reduction in glimepiride block by increased intracellular ADP.
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PMID:Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K(ATP) channels. 1208 84

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.
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PMID:Synthesis rate of muscle proteins, muscle functions, and amino acid kinetics in type 2 diabetes. 1214 50

Metformin, a drug widely used to treat type 2 diabetes, was recently shown to activate the AMP-activated protein kinase (AMPK) in intact cells and in vivo. In this study we addressed the mechanism for this effect. In intact cells, metformin stimulated phosphorylation of the key regulatory site (Thr-172) on the catalytic (alpha) subunit of AMPK. It did not affect phosphorylation of this site by either of two upstream kinases in cell-free assays, although we were able to detect an increase in upstream kinase activity in extracts of metformin-treated cells. Metformin has been reported to be an inhibitor of complex 1 of the respiratory chain, but we present evidence that activation of AMPK in two different cell types is not a consequence of depletion of cellular energy charge via this mechanism. Whereas we have not established the definitive mechanism by which metformin activates AMPK, our results show that the mechanism is different from that of the existing AMPK-activating agent, 5-aminoimidazole-4-carboxamide (AICA) riboside. Metformin therefore represents a useful new tool to study the consequences of AMPK activation in intact cells and in vivo. Our results also show that AMPK can be activated by mechanisms other than changes in the cellular AMP-to-ATP ratio.
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PMID:The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. 1214 53

When fed a high-energy (HE) diet, diabetes-prone (DP) Psammomys obesus develop type 2 diabetes with altered glucose-stimulated insulin secretion (GSIS). Beta-cell stimulus-secretion coupling was investigated in islets isolated from DP P. obesus fed a low-energy (LE) diet (DP-LE) and after 5 days on a HE diet (DP-HE). DP-LE islets cultured overnight in 5 mmol/l glucose displayed glucose dose-dependent increases in NAD(P)H, mitochondrial membrane potential, ATP/(ATP + ADP) ratio, cytosolic calcium concentration ([Ca(2+)](c)), and insulin secretion. In comparison, DP-HE islets cultured overnight in 10 mmol/l glucose were 80% degranulated and displayed an increased sensitivity to glucose at the level of glucose metabolism, [Ca(2+)](c), and insulin secretion. These changes in DP-HE islets were only marginally reversed after culture in 5 mmol/l glucose and were not reproduced in DP-LE islets cultured overnight in 10 mmol/l glucose, except for the 75% degranulation. Diabetes-resistant P. obesus remain normoglycemic on HE diet. Their beta-cell stimulus-secretion coupling was similar to that of DP-LE islets, irrespective of the type of diet. Thus, islets from diabetic P. obesus display an increased sensitivity to glucose at the level of glucose metabolism and a profound beta-cell degranulation, both of which may affect their in vivo GSIS.
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PMID:Increased glucose sensitivity of stimulus-secretion coupling in islets from Psammomys obesus after diet induction of diabetes. 1214 70

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.
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PMID:The neuroendocrine control of glucose allocation. 1214 83

Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules.
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PMID:Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. 1219 72

The hexosamine biosynthesis pathway plays a role in the modification of cellular proteins via the provision of substrate for addition of O-linked N-acetylglucosamine (GlcNAc). The relative importance of the GlcNAc modification of proteins to insulin secretion from pancreatic beta-cells has not been investigated and so remains unclear. In the present study, we show that inhibition of the hexosamine biosynthesis pathway decreases insulin secretion from mouse islets in response to a number of secretagogues, including glucose. This impairment in beta-cell function could not be attributed to reduced islet insulin content, altered ATP levels, or cell death and was restored with the addition of N-acetylglucosamine, a substrate that enters the pathway below the point of inhibition. Western blot analysis revealed that decreased islet protein glycosylation paralleled the decrease in insulin secretion following inhibition of the pathway. In conclusion, the data suggest a role for the hexosamine biosynthesis pathway in regulating the secretion of insulin by altering protein glycosylation. This finding may have implications for the development of type 2 diabetes, as chronic increase in flux through the hexosamine biosynthesis pathway may lead to the deterioration of beta-cell function via abnormal protein glycosylation.
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PMID:The hexosamine biosynthesis pathway regulates insulin secretion via protein glycosylation in mouse islets. 1222 May 42


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