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

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.
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PMID:Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus. 971 Apr 43

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.
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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.
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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 glucoregulatory and hormonal responses to moderate-intensity exercise (50% VO2max for 45 min) were examined in subjects with type 2 diabetes and mild hyperglycemia. We studied seven obese subjects with type 2 diabetes and seven lean and seven obese control subjects (fasting plasma glucose levels, 7.5 +/- 0.5, 4.8 +/- 0.1, and 5.2 +/- 0.1 mmol/l, respectively). Glucose production, utilization, and cycling (flux between glucose and glucose-6-phosphate [G-6-P]) were measured with [6-(3)H]glucose and [2-(3)H]glucose using the constant specific-activity method. Insulin levels decreased normally during exercise in diabetic subjects. Plasma glucose levels decreased in diabetic subjects, but remained constant in control subjects. Basal glucose production was not different among groups and increased similarly during exercise. The decrease in plasma glucose in diabetic subjects was due to greater glucose utilization (867 +/- 83 vs. 726 +/- 143 micromol x m(-2) x min(-1); P < 0.05). This was a consequence of the mass effect of hyperglycemia, since glucose metabolic clearance increased similarly in all groups. Glucose cycling, expressed as a percentage of total glucose output (i.e., flux through G-6-P) was elevated at rest (P < 0.01), but decreased during exercise (P < 0.01). The catecholamine response to exercise was blunted in diabetic subjects, presumably indicating autonomic dysfunction. In conclusion, during moderate-intensity exercise in obese diabetic subjects with mild hyperglycemia, 1) insulin secretory responses were normally regulated; 2) glucose homeostasis was different from that in nondiabetic subjects because glucose levels decreased during exercise; 3) the decrease in plasma glucose was due to greater-than-normal rates of glucose utilization, which were sustained by hyperglycemia; and 4) elevated basal rates of glucose cycling decreased during exercise, presumably because exercise simultaneously lowered plasma glucose, was associated with a blunted catecholamine response, and accentuated an underlying defect in hepatic glucokinase activity in type 2 diabetes.
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PMID:Glucose production, utilization, and cycling in response to moderate exercise in obese subjects with type 2 diabetes and mild hyperglycemia. 979 46

NIDDM has a substantial genetic component, but the nature of the genetic susceptibility is largely unknown. Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of NIDDM characterized by an early age of onset and autosomal dominant inheritance, and linkage studies have identified genes that are mutated in different MODY pedigrees on chromosome 20 (MODY1 locus, hepatocyte nuclear factor-4alpha [HNF-4alpha] gene), chromosome 7 (MODY2 locus, glucokinase gene), and chromosome 12 (MODY3 locus, HNF-1alpha gene). We studied an extended pedigree in which multiple members are affected by late-onset NIDDM associated with insulin resistance and performed linkage analysis with four microsatellite markers in the MODY3 region of chromosome 12q. We found significant evidence for linkage between NIDDM and the MODY3 locus (logarithm of odds score 3.65 at theta = 0.008 telomeric to marker D12S321), but sequencing of the 10 exons and promoter of HNF-1alpha did not identify any causative mutation in this gene. Our results indicate that the region of chromosome 12q close to MODY3 harbors a novel susceptibility gene or genes for NIDDM.
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PMID:Novel susceptibility gene for late-onset NIDDM is localized to human chromosome 12q. 979 50

Glucokinase (GK, EC 2.7.1.2), a member of the enzyme family of hexokinases, has been shown to be linked to maturity-onset diabetes of the young type II (MODY-2). Although nucleotide and amino acid sequence information are available for the human varieties, they are not known for the variety from Bacillus stearothermophilus, which is often used in protein binding studies. Here, a combination of electrospray Fourier transform mass spectrometry (FTMS) and infrared multiphoton dissociation (IRMPD) is used to obtain accurate molecular weight and preliminary amino acid sequence information for the protein. Electrospray FTMS provides evidence of a solution phase dimer. In addition, dithiothreitol reduction shows no shift in high-resolution isotopic distributions, indicating a probable absence of disulfide bonds in the protein. The partial sequence information obtained from IRMPD could be the basis for creating a DNA probe for the protein.
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PMID:High-resolution electrospray ionization Fourier transform mass spectrometry with infrared multiphoton dissociation of glucokinase from Bacillus Stearothermophilus. 979 87

Familial risk, pathogenesis, clinical onset, and treatment of diabetes mellitus vary according to etiology. Although Type 2 diabetes has a higher familial risk, more is known about the genetics of Type 1 diabetes. Genes contributing 60% to 65% of susceptibility to Type 1 diabetes mellitus are known. Type 1 diabetes is associated with susceptibility genes in the HLA region on chromosome 6p21 and the insulin gene on chromosome 11p15, and at least eight additional susceptibility genes are under investigation. Islet cytoplasmic antibodies provide humoral evidence of Type 1 diabetes risk. Only 10% of the genes contributing susceptibility to Type 2 diabetes mellitus are known, and they are primarily associated with uncommon subtypes of the disorder. The insulin receptor gene on chromosome 19p13 and at least five glucose transporter genes contribute to Type 2 diabetes susceptibility, and further associations may emerge from study of the glycogen synthase gene, the glucokinase gene, the MODY genes, and the leptin gene. Diabetes comorbidities may result from genetic and environmental susceptibilities independently or in combination.
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PMID:The genetic basis of diabetes mellitus. 985 64

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disorder and both genetic and nongenetic factors are associated with the development of diabetes. Until now five genes (HNF-4 alpha, glucokinase, HNF-1 alpha, IPF-1 and HNF-1 beta), whose mutation can result in MODY, insulin and insulin receptor genes, and mitochondria DNA have been reported to be responsible for diabetes. Furthermore the mutations in some genes which work for insulin secretion or action also have been reported. This review discusses our current knowledge of these NIDDM susceptibility genes.
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PMID:[NIDDM susceptibility genes]. 1019 31

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI > 26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P < 0.02 and P < 0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindered SA is probably related to the obesity and late-onset NIDDM background present in this family.
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PMID:Specific insulin and proinsulin secretion in glucokinase-deficient individuals. 1034 5

The author presents a review on candidate genes of proteins involved in the metabolism of glucose, lipids and other metabolites (glucose carriers, insulin receptors, proinsulin, glucokinase, amyline, glycogen synthase). One of the main causes of enhanced atherogenesis in patients with type II diabetes (NIDDM) are marked genetically conditioned deviations of the lipid, lipoprotein and apolipoprotein metabolism. In the metabolic dyshomeostasis of multiple metabolic syndrome participate in the process of atherogenesis also: isoforms of apolipoprotein E4, isoforms of apolipoprotein A-IV-1/1, hyperuricaemia, raised levels of the plasminogen activator inhibitor 1 (PAI-1), hyperfibrinogenaemia, hyperhomocysteinaemia and other metabolites (cytokines, endothelin etc.). Patients with a greated genetic sensitivity manifest diabetes sooner and more intensely and die at a younger age in particular from cardiovascular disease, but also on account of a higher incidence of tumours diseases.
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PMID:[Genetic predisposition in multiple metabolic syndrome. Part 2. Candidate genes in type II diabetes mellitus]. 1037 88


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