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)

Diabetes may be associated with many genetic disorders. The scientific importance of these often rare disorders resides in the insight they may provide into the possible mechanisms of common diabetes. The type of diabetes varies in these syndromes. Non-insulin-dependent diabetes (NIDDM), clinically similar to common NIDDM, may be found in some syndromes (e.g. Werner's syndrome). In others there may be considerable insulin resistance, such as that present in ataxia telangiectasia. Extreme insulin resistance due to abnormal insulin receptor function is found in the Mendenhall syndrome. The mechanism of diabetes is more obscure in acute intermittent porphyria (AIP), although haem deficiency affecting the cytochrome chain raises interesting possibilities. In glycogen storage disease type I, the diabetes is associated with insulinopenia, following an earlier period in the disease when hypoglycaemia is the rule. IDDM, clinically similar to the common form, is present in the autoimmune polyglandular syndromes. Although a change in the lean:fat ratio is common in many neuromuscular disorders, mechanisms other than insulin resistance would seem to operate. The increased incidence of diabetes in heterozygotes for some of these genetic disorders raises the possibility that many common diabetics are, in fact, heterozygotes for some other disorder. The increased frequency of diabetes in Klinefelter's syndrome, Turner's syndrome and possibly Down's syndrome leads to the hypothesis that non-disjunction may, in some way be associated with the predisposition to diabetes. In several syndromes there is an increased incidence of diabetes in otherwise unaffected relatives of individuals with these syndromes. It is impossible to assess what proportion of common NIDDM or IDDM is made up of heterozygotes for these genetic syndromes.
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PMID:Diabetes secondary to genetic disorders. 144 74

Rosiglitazone, a thiazolidinedione antidiabetic agent, improves insulin resistance, a key underlying metabolic abnormality in most patients with type 2 (non-insulin-dependent) diabetes mellitus. In animal models of insulin resistance, rosiglitazone decreased plasma glucose, insulin and triglyceride levels and also attenuated or prevented diabetic nephropathy and pancreatic islet cell degeneration. In contrast with troglitazone, rosiglitazone does not induce cytochrome P4503A4 metabolism. It does not interact significantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine or acarbose. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone 2 to 12 mg/day (as a single daily dose or 2 divided daily doses) improved glycaemic control, as shown by decreases in fasting plasma glucose and glycosylated haemoglobin (HbA1c). Addition of rosiglitazone 2 to 8 mg/day to existing sulphonylurea, metformin or insulin therapy achieved further reductions in fasting plasma glucose and HbA1c. Oral combinations improved insulin sensitivity and beta-cell function according to a homeostasis model assessment. Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycaemia (<2% of patients receiving monotherapy). There is no evidence to date that rosiglitazone shares the hepatotoxicity of troglitazone.
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PMID:Rosiglitazone. 1040 Apr 5

Androgen biosynthesis requires 3beta-hydroxysteroid dehydrogenase type II (3betaHSDII) and the 17alpha-hydroxylase and 17,20-lyase activities of cytochrome P450c17. Thiazolidinedione and biguanide drugs, which are used to increase insulin sensitivity in type 2 diabetes, lower serum androgen concentrations in women with polycystic ovary syndrome. However, it is unclear whether this is secondary to increased insulin sensitivity or to direct effects on steroidogenesis. To investigate potential actions of these drugs on P450c17 and 3betaHSDII, we used "humanized yeast" that express these steroidogenic enzymes in microsomal environments. The biguanide metformin had no effect on either enzyme, whereas the thiazolidinedione troglitazone inhibited 3betaHSDII (K(I) = 25.4 +/- 5.1 microm) and both activities of P450c17 (K(I) for 17alpha-hydroxylase, 8.4 +/- 0.6 microm; K(I) for 17,20-lyase, 5.3 +/- 0.7 microm). The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3betaHSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3betaHSDII. These differential effects of the thiazolidinediones do not correlate with their effects on insulin sensitivity, suggesting that distinct regions of the thiazolidinedione molecule mediate these two actions. Thus, thiazolidinediones inhibit two key enzymes in human androgen synthesis contributing to their androgen-lowering effects, whereas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations.
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PMID:Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3beta -hydroxysteroid dehydrogenase. 1127 97

A 68-year-old woman, with type 2 diabetes mellitus, hypercholesterolemia, and prior long-term simvastatin therapy, self-resumed troglitazone after running out of metformin. She developed an acute severe hepatitis with microvesicular steatosis and mysositis. There was subsequent resolution of the myositis but progression of the hepatitis to symptomatic cirrhosis over a period of 12 weeks. Both troglitazone and simvastatin are metabolized by cytochrome P-450 3A4. Troglitazone typically induces metabolism of drugs metabolized by this cytochrome so that simple simvastatin toxicity seems less likely to have been involved. The association with myositis, the severity of the hepatitis with progression to cirrhosis, and the presence of microvesicular steatosis suggests altered mitochondrial metabolism, which has been described with each agent, as the underlying pathogenic mechanism. Although troglitazone (Rezulin) has been withdrawn from the market, other similar agents are available for therapy of type 2 diabetes mellitus. Increased awareness of a potential interaction between these two classes of drugs is warranted.
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PMID:Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin. 1128 Nov 88

Troglitazone, rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) class - antidiabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. All three agents are believed to mediate their effects via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma). Despite this common mechanism of action, they all have unique chemical structures and receptor-binding affinities, and consequently, in addition to the class effects (probably mediated through PPAR gamma), each TZD has a unique safety profile. Side effects have been categorized as unique to individual TZDs, or common to the class of drug. Of the unique effects, the best characterized is hepatotoxicity, which has been associated specifically with troglitazone to date. Studies with rosiglitazone and pioglitazone indicate that hepatotoxicity is not a class effect. Further differences in the safety profiles of these agents arise because the oxidative metabolism for each agent occurs by distinct cytochrome pathways: troglitazone and pioglitazone involve CYP 3A4 and CYP 2C8 whereas rosiglitazone is principally metabolized by CYP 2C8. CYP 3A4 is involved in the metabolism of over 150 drugs, hence the potential for drug interactions with troglitazone and pioglitazone is much greater than with rosiglitazone. Class effects include edema, slight reductions in hemoglobin and hematocrit (due to hemodilution), weight gain and alterations in plasma lipid profiles. This article considers safety data obtained from both clinical trials and clinical practice as a means of differentiating among troglitazone, rosiglitazone and pioglitazone.
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PMID:Differentiating members of the thiazolidinedione class: a focus on safety. 1192 35

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

Abnormalities in fatty acid (FA) metabolism underlie the development of insulin resistance and alterations in glucose metabolism, features characteristic of the metabolic syndrome and type 2 diabetes that can result in an increased risk of cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist. AZ 242 dose-dependently reduced the hypertriglyceridemia, hyperinsulinemia, and hyperglycemia of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that treatment with AZ 242 (1 micromol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays, AZ 242 activated human PPARalpha and PPARgamma with EC(50) in the micro molar range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma effect, and caused up-regulation of liver fatty acid binding protein in HepG-2 cells, a PPARalpha-mediated effect. PPARalpha-mediated effects of AZ 242 in vivo were documented by induction of hepatic cytochrome P 450-4A in mice. The results indicate that the dual PPARalpha/gamma agonism of AZ 242 reduces insulin resistance and has beneficial effects on FA and glucose metabolism. This effect profile could provide a suitable therapeutic approach to the treatment of type 2 diabetes, metabolic syndrome, and associated vascular risk factors.
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PMID:AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. 1240 84

Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state.
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PMID:A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. 1598 91

Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
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PMID:Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells. 1612 48

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder associated with amenorrhoea (or oligomenorrhoea), hyperandrogenism, hirsutism, obesity, insulin resistance, and an approximately 7-fold increased risk of type 2 diabetes mellitus (NIDDM - non-insulin dependent diabetes mellitus). It is a leading cause of female infertility. The prevalence of PCOS among reproductive-age women has been estimated at 4%-12%. Familial aggregation of this syndrome is well established. There are also ethnic and racial variations in the prevalence of the syndrome and its symptoms. Multiple biochemical pathways have been implicated in the pathogenesis of PCOS. Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. Most women with PCOS, both obese and lean, have a degree of insulin resistance. The minisatellite of insulin gene (INS VNTR), especially class III alleles and III/III genotypes might not only determine the predisposition to anovulatory PCOS but also the concomitant risk for development of type 2 diabetes. The function of the insulin receptor (IR) is probably normal in woman with PCOS. However abnormal serine phosphorylation in the receptor may impair signal transduction accounting for a post-binding defect in insulin action. Serine phosphorylation is also involved in the postranslational regulation of 17,20-lyase activity (CYP17). There may be a common aetiology for both insulin resistance and hyperandrogenism. Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of pentanucleotide (TTTTA)n repeats within CYP11A gene, which encodes cytochrome P450scc. It has been hypothesized that up-regulation of this enzyme could lead to increased androgen production. There is no evidence of any association of alleles of CYP19 gene (encoding cytochrome P450arom) with PCOS. Association exists between androgen receptor gene (AR) polymorphisms an androgens action in PCOS. Increased hirustism and decreased CAG repeat length within AR gene has been also demonstrated in women with normal testosterone levels. Expression of estrogen receptor (ERs) as well as 5-alpha-reeducates (SRD5A1-2 genes) activity was analysed in granulosa (GC) and theca cells (TC). The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. On the other hand elevated SRD5A activity in polycystic ovaries supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of the syndrome. The genetic aetiology of PCOS remains unknown. There are a number of interlinking factors that affects expression of PCOS. Single cause of PCOS is unlikely. Other possible mechanisms in pathogenesis of PCOS are discussed.
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PMID:[Genetic aspects of polycystic ovary syndrome]. 1635 Jul 21


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