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

We investigated the role of glucose-6 phosphatase (Glc6Pase), glucokinase (GK), and glucose-6 phosphate (Glc6P) in liver insulin resistance, an early characteristic of type 2 diabetes, and its correction by metformin. We determined hepatic glucose production (HGP) by tracer dilution, and enzyme activities and substrate concentrations after saline or insulin perfusions during euglycemic clamps in rats fed: 1) a standard hyperglucidic diet (S); 2) a high-fat diet (HF); and 3) a high-fat diet and treated with the oral antidiabetic metformin (HF/Met). Basal HGP was similar in the 3 groups: 75+/-8, 65+/-9.5 and 71+/-3 micromol x kg(-1) x min(-1) (means+/-SEM, N=5) in S, HF and HF/Met rats, respectively. Upon insulin perfusion at 240 pmol/hr, HGP was decreased by 35% in S rats (49+/-4.5 micromol x kg(-1) x min(-1), P < 0.01 vs. basal) and 65% in HF/Met rats (23+/-10 micromol x kg(-1) x min(-1), P < 0.01 vs basal), whereas it was not decreased in HF rats (60+/-12 micromol x kg(-1) x min(-1)), revealing insulin resistance. GK activity was lower (by 65%, P < 0.01) in HF and HF/Met rats (0.8+/-0.1 and 0.9+/-0.1 U/g liver, respectively) than in S rats (2.4+/-0.3 U/g). Microsomal Glc6Pase activity was lower (by 35%, P < 0.01) in HF and HF/Met rats (0.25+/-0.01 and 0.27+/-0.02 micromol r min(-1) x mg prot x (-1), respectively) than in S rats (0.39+/-0.03 micromol x min(-1) x mg prot x (-1)). Glc6P concentration was decreased by insulin perfusion at 480 pmol/hr in S and HF/Met rats (P < 0.05 vs. saline), but not in HF rats, in agreement with insulin resistance in the latter group. However, the differential inhibitions of HGP by insulin could not be ascribed to the variations in Glc6P concentrations. Metformin was present in the liver at a concentration of 27+/-2 nmol/g wet tissue and was not detected in the plasma. These results strongly suggest that the regulation of HGP by insulin additionally involves short-term regulatory mechanism(s) of Glc6Pase, occurring in vivo, and lost under in vitro conditions. These might be impaired in HF rats, in keeping with insulin resistance of HGP, and restored by metformin.
 ...
PMID:Role of glucose-6 phosphatase, glucokinase, and glucose-6 phosphate in liver insulin resistance and its correction by metformin. 971 75

Insulin resistance, as is found in skeletal muscle of individuals with obesity and NIDDM, appears to involve a reduced capacity of the hormone to stimulate glucose uptake and/or phosphorylation. The glucose phosphorylation step, as catalyzed by hexokinase II, has been described as rate limiting for glucose disposal in muscle, but overexpression of this enzyme under control of a muscle-specific promoter in transgenic mice has had limited metabolic impact. In the current study, we investigated in a cultured muscle model whether expression of glucokinase, which in contrast to hexokinase II is not inhibited by glucose-6-phosphate (G-6-P), would have a pronounced metabolic impact. We used a recombinant adenovirus containing the cDNA-encoding rat liver glucokinase (AdCMV-GKL) to increase the glucose phosphorylating activity in cultured human muscle cells by fourfold. G-6-P levels increased in AdCMV-GKL-treated cells in a glucose concentration-dependent manner over the range of 1-30 mmol/l, whereas the much smaller increases in G-6-P in control cells were maximal at glucose concentrations <5 mmol/l. Further, cells expressing glucokinase accumulated 17 times more 2-deoxyglucose-6-phosphate than control cells. In AdCMV-GKL-treated cells, the time-dependent rise in G-6-P correlated with an increase in the activity ratio of glycogen synthase. AdCMV-GKL-treated cells also exhibited a 2.5- to 3-fold increase in glycogen content and a four- to fivefold increase in glycolytic flux, proportional to the increase in glucose phosphorylating capacity. All of these observations were made in the absence of insulin. Thus we concluded that expression of glucokinase in cultured human muscle cells results in proportional increases in insulin-independent glucose disposal, and that muscle glucose storage and utilization becomes controlled in a glucose concentration-dependent manner in AdCMV-GKL-treated cells. These results encourage testing whether delivery of glucokinase to muscle in vivo has an impact on glycemic control, which could be a method for circumventing the failure of insulin to stimulate glucose uptake and/or phosphorylation in muscle normally in insulin-resistant subjects.
 ...
PMID:Expression of glucokinase in cultured human muscle cells confers insulin-independent and glucose concentration-dependent increases in glucose disposal and storage. 972 26

The soluble form of the insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6-P) receptor has been detected in serum from a variety of mammalian species. We report the development of a highly sensitive quantitative human IGF-II/M6-P receptor immunoassay. Antibodies raised to receptor purified from a human hepatoma cell line by phosphomannan affinity chromatography were used to develop a specific enzyme-linked immunosorbent assay. In this assay, the serum level of soluble receptor for healthy adult subjects was 0.70 +/- 0.23 mg/L. We have shown that soluble receptor is developmentally regulated, with levels in infant (1.12 +/- 0.28 mg/L) and prepubertal (1.18 +/- 0.6 mg/L) subjects dropping by 40% during adolescence (0.73 +/- 0.61 mg/L) and remaining constant throughout adulthood. Further, the receptor is gestationally regulated, with a highly significant association between gestational age and maternal serum receptor levels (r = 0.947; P < 0.0001). Noninsulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) and insulin-dependent diabetes mellitus (0.98 +/- 0.25 mg/L) mildly elevated soluble receptor levels, whereas end-stage renal failure (0.75 +/- 0.23 mg/L) and acromegaly (0.79 +/- 0.25 mg/L) did not affect receptor levels. Additionally, we have shown that soluble receptor is present in amniotic fluid, but at a 100-fold lower concentration than serum levels. The ability to quantitate soluble IGF-II/M6-P receptor levels in serum and other fluids provides a valuable tool that will help to further elucidate the role of the receptor in human physiology and disease states.
 ...
PMID:Regulation of soluble insulin-like growth factor II/mannose 6-phosphate receptor in human serum: measurement by enzyme-linked immunosorbent assay. 1002 25

In skeletal muscle of normal subjects, the concentration of glucose 6-phosphate (G6P) at which the activity of glycogen synthase (GS) is half maximal (Ka) is decreased by in vivo insulin, and the fractional activity is increased without a change in GS maximal activity (Vmax). We have shown that moderate chronic calorie restriction, previously shown in rodents to be effective in slowing aging, resulted in the prevention of obesity and type 2 diabetes in primates (rhesus monkeys, Macaca mulatta). However, unexpectedly, in a subgroup of calorie-restricted monkeys, insulin during a euglycemic hyperinsulinemic clamp caused an unanticipated decrease in skeletal muscle GS fractional activity. These same monkeys had the lowest whole-body glucose disposal rate (M), the greatest increase in skeletal muscle G6P content and the greatest increase in skeletal muscle glycogen phosphorylase activity during the euglycemic hyperinsulinemic clamp compared to the remaining calorie-restricted monkeys with normal insulin action. To determine whether this highly unusual insulin-mediated decrease in GS fractional activity was due to increased phosphorylation (increased Ka), we measured the activity of skeletal muscle GS at 9 different G6P concentrations before and during the euglycemic hyperinsulinemic clamp in 6 calorie-restricted monkeys. G6P Ka increased (n = 4) and Vmax decreased (n = 5) during the clamp. Basal G6P Ka was inversely related to basal GSfv (r = -0.94, p < 0.002). G6P Ka and skeletal muscle G6P content were positively related under insulin-stimulated conditions (r = 0.93, p < 0.005). The change in G6P Ka (insulin-stimulated minus basal) was inversely related to M (r = -0.94, p < 0.002) and positively related to the change in skeletal muscle G6P content (r = 0.93, p < 0.005). We conclude that moderate calorie restriction results in a reversal of normal insulin action at the skeletal muscle with inactivation of glycogen synthase which is likely to be due to an increase in phosphorylation of GS together with a decrease in Vmax of GS during a euglycemic hyperinsulinemic clamp in most of the calorie-restricted monkeys. These alterations are likely to be involved in the anti-diabetogenic effects of calorie restriction.
 ...
PMID:Insulin unexpectedly increases the glucose 6-phosphate Ka of skeletal muscle glycogen synthase in calorie-restricted monkeys. 1021 41

Zucker diabetic fatty rats develop type 2 diabetes concomitantly with peripheral insulin resistance. Hepatocytes from these rats and their control lean counterparts have been cultured, and a number of key parameters of glucose metabolism have been determined. Glucokinase activity was 4.5-fold lower in hepatocytes from diabetic rats than in hepatocytes from healthy ones. In contrast, hexokinase activity was about 2-fold higher in hepatocytes from diabetic animals than in healthy ones. Glucose-6-phosphatase activity was not significantly different. Despite the altered ratios of glucokinase to hexokinase activity, intracellular glucose 6-phosphate concentrations were similar in the two types of cells when they where incubated with 1-25 mM glucose. However, glycogen levels and glycogen synthase activity ratio were lower in hepatocytes from diabetic animals. Total pyruvate kinase activity and its activity ratio as well as fructose 2,6-bisphosphate concentration and lactate production were also lower in cells from diabetic animals. All of these data indicate that glucose metabolism is clearly impaired in hepatocytes from Zucker diabetic fatty rats. Glucokinase overexpression using adenovirus restored glucose metabolism in diabetic hepatocytes. In glucokinase-overexpressing cells, glucose 6-phosphate levels increased. Moreover, glycogen deposition was greatly enhanced due to the activation of glycogen synthase. Pyruvate kinase was also activated, and fructose-2,6-bisphosphate concentration and lactate production were increased in glucokinase-overexpressing diabetic hepatocytes. Overexpression of hexokinase I did not increase glycogen deposition. In conclusion, hepatocytes from Zucker diabetic fatty rats showed depressed glycogen and glycolytic metabolism, but glucokinase overexpression improved their glucose utilization and storage.
 ...
PMID:Glucokinase overexpression restores glucose utilization and storage in cultured hepatocytes from male Zucker diabetic fatty rats. 1054 7

Streptozotocin has been widely used to create animal models of diabetes. Structurally, streptozotocin resembles N-acetylglucosamine, with a nitrosourea group corresponding to the acetate present in N-acetylglucosamine. Streptozotocin has recently been shown to inhibit O-GlcNAc-selective N-acetyl-beta-d-glucosaminidase, which removes O-linked N-acetylglucosamine from proteins. Compared to other cells, beta-cells express much more of the enzyme O-GlcNAc transferase, which catalyzes addition of O-linked N-acetylglucosamine to proteins. This suggests why beta-cells might be particularly sensitive to streptozotocin. In this report, we demonstrate that both streptozotocin and glucose stimulate O-glycosylation of a 135 kD beta-cell protein. Only the effect of glucose, however, was blocked by inhibition of fructose-6-phosphate amidotransferase, suggesting that glucose acts through the glucosamine pathway to provide UDP-N-acetylglucosamine for p135 O-glycosylation. The fact that both glucose and streptozotocin stimulate p135 O-glycosylation provides a possible mechanism by which hyperglycemia may cause streptozotocin-like effects in beta-cells and thus contribute to the development of type 2 diabetes.
 ...
PMID:Glucose and streptozotocin stimulate p135 O-glycosylation in pancreatic islets. 1062 69

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY 3), which is characterized by a severe impairment of insulin secretion and early onset of the disease. Although the majority of patients with type 1 diabetes have type 1A, immune-mediated diabetes, there is a significant percentage of the patients who have no evidence of an autoimmune disorder at the onset of disease. The aim of this study was to estimate the prevalence of MODY 3 in antiislet autoantibody negative patients with type 1 diabetes. From a large population-based sample of unrelated Japanese patients with type 1 diabetes, 28 patients who lacked autoantibodies to glutamic acid decarboxylase, islet cell antigen 512/insulinoma-associated antigen-2, phogrin (phosphate homolog of granules of insulinoma)/insulinoma-associated antigen-2beta, and insulin at the onset of type 1 diabetes were examined by PCR-based direct sequencing of the 10 exons, flanking introns, and the promoter region of the HNF-1alpha gene. Two (7.1%) of 28 autoantibody-negative patients with type 1 diabetes were identified as carrying mutations in the HNF-1alpha gene. One patient carried a frameshift mutation (Pro379fsdelCT) in exon 6, and another patient carried a novel 2-bp substitution at nucleotides +45 (G to A) and +46 (C to A) from the transcriptional site of the promoter region. These mutations were identified in heterozygous form and were not identified in 64 unrelated healthy control subjects or 54 unrelated islet autoantibody-positive patients with type 1 diabetes. Functional analysis of the mutant HNF-1alpha gene indicated that the Pro379fsdelCT mutation had no transcriptional trans-activation activity and acted in a dominant negative manner. The +45/46 GC to AA mutation in the promoter region showed reduced promoter activity by 10-20% compared to the wild-type sequence. In conclusion, about 7% of Japanese diabetic patients lacking antiislet autoantibodies initially classified as having type 1 diabetes could have diabetes caused by mutations in the HNF-1alpha gene.
 ...
PMID:Identification and functional analysis of mutations in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes. 1063 7

Recent studies suggest that high glucose concentrations impair insulin receptor phosphorylation and kinase activation in certain cell models. To examine whether such an effect of glucose can also be demonstrated in vivo, insulin receptor kinase activation was studied in erythrocytes from 11 patients with non-insulin-dependent diabetes (NIDDM), before and after reduction of hyperglycemia (from 14.6+/-1.6 to 6.6+/-0.5 mmol/l fasting plasma glucose within 8.6+/-0.6 days). For the measurement of receptor kinase activation, cells were incubated with insulin (0-400 nmol/l), solubilized and insulin receptors immobilized to microwells coated with anti-insulin receptor antibody. Kinase activity towards insulin receptor substrate-1 and insulin binding were then measured in these wells. Kinase activities (expressed as amol phosphate transferred per min and per fmol insulin binding activity) were similar before (2.4+/-0.4 and 32.2+/-2.0 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) and after improvement of metabolic control (2.4+/-0.5 and 32.0+/-2.3 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). Moreover, activities were also similar in 22 hyperglycemic patients with NIDDM (2.1+/-0.3 and 35.1+/-1.4 amol/min per fmol with 0 and 400 nmol/l insulin, respectively) compared with those in 21 non-diabetic control individuals (2.1+/-0.3 and 34.2+/-1.2 amol/min per fmol with 0 and 400 nmol/l insulin, respectively). We conclude that insulin activation of erythrocyte insulin receptor kinase is not impaired in NIDDM and is not influenced by hyperglycemia.
 ...
PMID:Insulin activation of insulin receptor kinase in erythrocytes is not altered in non-insulin-dependent diabetes and not influenced by hyperglycemia. 1092 17

In type 2 diabetes mellitus, insulin secretory deficiency is an important process linking asymptomatic insulin resistance and diabetes. Fatty acids could play a role in the reduction of beta cell insulin secretion. On a short term basis (< 24 h), fatty acids stimulate glucose-dependent insulin secretion through an increase of ATP availability (due to acyl-CoA mitochondrial oxidation) and an extramitochondrial diacylglycerol and inositol tri phosphate (IP3) production (which stimulate insulin-containing granule exocytosis). Such effects were observed in human both in vitro and in vivo. By contrast, a chronic exposure (> 24 h) of beta cells to fatty acids leads to a reduction in glucose-dependent insulin secretion. Current explanation relies in the effect of fatty acids on beta cell gene expression through PPARs (peroxysome proliferator activated receptor). Thus, in rodents, fatty acids can increase the expression of carmitine palmitoyl transferase gene (CPT-1, the key enzyme involved in fatty acid internalization in mitochondria) while reducing the gene expression of acetyl carboxylase (this enzyme synthesis malonyl CoA, which inhibits fatty acid oxidation). Thus, a chronic exposure to fatty acids will preferentially distribute these nutrients towards mitochondria (as malonyl CoA is reduced and CPT-1 is increased), which in turn reduces their extramitochondrial metabolism as well as IP3 production that is needed for secretory granule exocytosis. Finally, in Zucker Fatty rat, diabetes is associated with a triglyceride accumulation in beta cells. This is correlated with a reduction in insulin secretion and an increase in cellular apoptosis phenomena. Thiazolidinediones prevent intracellular lipid accumulation and delay diabetes. The prevention of lipotoxicity could represent a new therapeutic strategy to preserve insulin secretion in type 2 diabetic patients.
 ...
PMID:[Fatty acids and beta cells]. 1094 43

Plasma nonesterified fatty acids (NEFA) at elevated concentrations antagonize insulin action and thus may play a critical role in the development of insulin resistance in type 2 diabetes. Plasma NEFA and glucose concentrations are regulated, in part, by their uptake into peripheral tissues. Cellular energy uptake can be increased by enhancing either energy transport or metabolism. The effects of overexpression of 1-acylglycerol-3-phosphate acyltransferase (AGAT)-alpha, which catalyzes the second step in triglyceride formation from glycerol-3-phosphate, was studied in 3T3-L1 adipocytes and C2C12 myotubes. In myotubes, overexpression of AGAT-alpha did not affect total [14C]glucose uptake in the presence or absence of insulin, whereas insulin-stimulated [14C]glucose conversion to cellular lipids increased significantly (33%, P = 0.004) with a concomitant decrease (-30%, P = 0.005) in glycogen formation. [3H]oleic acid (OA) uptake in AGAT-overexpressing myotubes increased 34% (P = 0.027) upon insulin stimulation. AGAT-alpha overexpression in adipocytes increased basal (130%, P = 0.04) and insulin-stimulated (27%, P = 0.01) [3H]OA uptake, increased insulin-stimulated glucose uptake (56%, P = 0.04) and conversion to cellular lipids (85%, P = 0.007), and suppressed basal (-44%, P = 0.01) and isoproterenol-stimulated OA release (-45%, P = 0.03) but not glycerol release. Our data indicate that an increase in metabolic flow to triglyceride synthesis can inhibit NEFA release, increase NEFA uptake, and promote insulin-mediated glucose utilization in 3T3-L1 adipocytes. In myotubes, however, AGAT-alpha overexpression does not increase basal cellular energy uptake, but can enhance NEFA uptake and divert glucose from glycogen synthesis to lipogenesis upon insulin stimulation.
 ...
PMID:Overexpression of 1-acyl-glycerol-3-phosphate acyltransferase-alpha enhances lipid storage in cellular models of adipose tissue and skeletal muscle. 1127 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>