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)

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

Polycystic ovary syndrome is a reproductive disorder with a significant impact on fertility. It is secondarily, and perhaps for the individual primarily, a disorder with a marked increase risk for diabetes and glucose intolerance. Physicians need to be aware that women who have PCOS are at high risk for impaired glucose tolerance and type 2 diabetes. In the author's opinion, they should be screened for these abnormalities. Minority women with PCOS may have higher prevalence rates of glucose intolerance, and further study of minority groups is indicated. The author's data indicate that fasting glucose levels are inadequate for such screenings. Fasting glucose levels are relatively poor predictors of type 2 diabetes as determined by glucose challenge testing in PCOS. These findings may have substantial clinical relevance. They strongly suggest that all PCOS women should be screened for glucose intolerance, and that basal and 2-hour, glucose-stimulated levels rather than fasting glucose levels alone are required for such screening. Further study is necessary to document conversion rates to worsening glucose tolerance over time, as well as the cardiovascular risk associated with glucose intolerance in PCOS.
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PMID:Diabetes prevalence and risk factors in polycystic ovary syndrome. 1129 7

Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders of reproductive age women, is associated with an increased risk of type 2 diabetes mellitus. Defects in both insulin action and insulin secretion contribute to this predisposition to diabetes, but the extent to which these defects are heritable among PCOS families has not been examined. In the present study we used the frequently sampled iv glucose tolerance test to quantitate insulin secretion (AIRg), insulin action (Si), and their product (AIRg x Si) among women with PCOS (n = 33) and their nondiabetic first degree relatives (n = 48). We then quantitated the heritability of these measures from familial correlations estimated within a genetic model. Familial (spousal, rhoMF; parent-offspring, rhoPO; and sibling, rhoSS) correlations were derived for log-transformed body mass index (BMI) as well as for AIRg, Si, and AIRg x Si, the latter three of which were adjusted for BMI. There was no evidence of significant heritability for either lnBMI or lnSi in these families. In contrast, the sibling correlation (rhoSS = 0.74) for lnAIRg was highly significant (chi(2) = 7.65; 1 df; P = 0.006). In addition, the parameter quantitating insulin secretion in relation to insulin sensitivity [i.e. ln(AIRg x Si)] was significant among siblings (rho(SS) = 0.74; chi(2) = 4.32; 1 df; P = 0.04). In summary, the results of the present study indicate that there is an heritable component to beta-cell dysfunction in families of women with PCOS. We conclude that heritability of beta-cell dysfunction is likely to be a significant factor in the predisposition to diabetes in PCOS.
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PMID:Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. 1134 2

Polycystic ovary syndrome (PCOS) is one of the most frequently encountered endocrine disorders occurring in women of reproductive age. Clinically, a patient usually presents with menstrual irregularities, infertility, and hirsutism. If not treated properly, a patient is at risk for type 2 diabetes, cardiovascular disease, and hyperestrogen-related cancers. The hallmark endocrine disorders of this syndrome are hyperandrogenism and hyperinsulinemia. Great controversy exists as to which state precedes the other. There also appears to be a defect in the hypothalamic-pituitary-adrenal (HPA) axis in patients presenting with polycystic ovary syndrome. Research consistently demonstrates that the first line of treatment for this condition is weight loss. Weight loss and dietary changes appear to affect all parameters of hormonal fluctuation. Due to the vast array of side effects associated with many pharmaceutical agents typically prescribed to treat PCOS, natural therapeutics including nutrient supplementation and botanicals may be a less invasive and equally effective approach. Due to the seriousness of this syndrome when left untreated, prompt evaluation and treatment is essential.
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PMID:Polycystic ovary syndrome: clinical considerations. 1141 72

Women with polycystic ovary syndrome (PCOS) are insulin resistant secondary to a postbinding defect in insulin signaling. Sequential euglycemic glucose clamp studies at 40 and 400 mU. m(-2). min(-1) insulin doses with serial skeletal muscle biopsies were performed in PCOS and age-, weight-, and ethnicity-matched control women. Steady-state insulin levels did not differ, but insulin-mediated glucose disposal was significantly decreased in PCOS women (P < 0.05). Insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI 3K) activity was significantly decreased in PCOS (n = 12) compared with control skeletal muscle (n = 8; P < 0.05). There was no significant difference in the abundance of IR, IRS-1, or the p85 regulatory subunit of PI 3K in PCOS (n = 14) compared with control (n = 12) muscle. The abundance of IRS-2 was significantly increased (P < 0.05) in PCOS skeletal muscle, suggesting a compensatory change. We conclude that there is a physiologically relevant defect in insulin receptor signaling in PCOS that is independent of obesity and type 2 diabetes mellitus.
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PMID:Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). 1144 Sep 17

The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma.
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PMID:[Mechanisms of action of thiazolidinediones]. 1145 21

Polycystic ovary syndrome (PCOS) is classically characterised by ovarian dysfunction (oligomenorrhoea, anovulation and infertility), androgen excess (hirsutism and acne), obesity, and morphological abnormalities of the ovaries (cystic enlargement and stromal expansion). More recently, insulin resistance has been found to be common in PCOS, along with an increased prevalence of other features of the "metabolic syndrome", namely glucose intolerance, type 2 diabetes mellitus, and hyperlipidaemia. Hyperinsulinaemia is likely to contribute to the disordered ovarian function and androgen excess of PCOS. Reducing insulin resistance by lifestyle modifications such as diet and exercise improves endocrine and menstrual function in PCOS. These lifestyle modifications are the best initial means of improving insulin resistance. Metformin, an oral hypoglycaemic agent that increases insulin sensitivity, has been shown to reduce serum concentrations of insulin and androgens, to reduce hirsutism, and to improve ovulation rates. The effect of metformin alone on fertility rates is unknown. Some studies suggest that metformin will reduce total body weight to a small extent, but with a predominant effect on visceral adipose reduction. The effects of metformin on lipid abnormalities, hypertension or premature vascular disease are unknown, but the relative safety, moderate cost, and efficacy in reducing insulin resistance suggest that metformin may prove to be of benefit in combating these components of the "metabolic" syndrome in PCOS. Further properly planned randomised controlled trials are required.
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PMID:Metformin and intervention in polycystic ovary syndrome. Endocrine Society of Australia, the Australian Diabetes Society and the Australian Paediatric Endocrine Group. 1145 23

Thiazolidinediones are a powerful and clinically important new class of oral antidiabetic agents that act by improving insulin sensitivity. Troglitazone is the prototype drug in this class but was withdrawn from the market in March 2000 due to its association with idiosyncratic hepatotoxicity. Currently two thiazolidinediones, rosiglitazone and pioglitazone, are U.S. Food and Drug Administration (FDA) approved for treatment of type 2 diabetes. These agents bind to and activate peroxisome proliferator-activator receptor gamma (PPAR-gamma) and work by altering the expression of genes involved in glucose uptake, glucose disposal, and lipid metabolism. The drugs differ in receptor binding and potency due to differences in their side chain moieties. These agents are rapidly absorbed from the gastrointestinal tract and are metabolized mainly in the liver. Rosiglitazone is FDA approved for monotherapy and for use in combination therapy with metformin or sulfonylureas. Pioglitazone is FDA approved for monotherapy as well as for use in combination therapy with metformin, insulin, or sulfonylureas. These drugs may also cause significant changes in plasma lipid concentrations, and improved insulin sensitivity may improve ovulatory function and fertility in women with polycystic ovary syndrome. The most serious side effect of the thiazolidinediones is hepatotoxicity. Although rosiglitazone and pioglitazone were not associated with hepatotoxicity in premarketing clinical trials, there were two recent case reports of idiosyncratic hepatotoxicity in patients treated with rosiglitazone. In addition, these agents may be associated with edema and some hematological changes. The purpose of this review is to provide an overview of the two currently approved thiazolidinediones and to suggest an approach for their safe and rational use.
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PMID:Thiazolidinediones: a comparative review of approved uses. 1146 45

In humans, the skin is a target tissue for androgen action; hair growth and sebum secretion are under active androgen control. An increased production or metabolism of testosterone, the main active androgen, shows up clinically in dermatological symptoms such as hirsutism, hyperseborrheic acne and alopecia. Polycystic ovary syndrome (PCOS) is the most frequent androgen disorder of ovarian function. PCOS patients have amenorrhea or severe oligomenorrhea, increased testosterone levels and most often enlarged polycystic ovaries on ultrasound examination. In addition, many PCOS patients have a tendency to accumulate abdominal fat and/or to develop obesity. Some also display a particular metabolic pattern including an atherogenic lipid profile, glucose intolerance and an increased fasting insulin level, which is known to be closely linked with an insulin resistant state. Several studies have now reported that PCOS patients show increased incidence of type 2 diabetes and cardiovascular disease. In addition to being a target for androgens the skin has abundant insulin receptors on the keratinocyte surface membrane and acanthosis nigricans is a common symptom of severe insulin resistance among patients with insulin receptor disorders. However, acanthosis nigricans could also be present in PCOS women given evidence of the intensity of their insulin resistance. This presentation will review the mutual relationship between hyperandrogenia and insulin resistance, with particular attention paid to: (1) insulin secretion and insulin sensitivity in PCOS; (2) the complexity of the molecular mechanisms involved in insulin resistance; (3) the paradoxical relationship between insulin resistance and hyperandrogenia; (4) the current genetic studies; and (5) new avenues for long-term treatment of PCOS women.
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PMID:Association of insulin resistance with hyperandrogenia in women. 1159 27

Genetic, environmental, and metabolic risk factors are interrelated and contribute to the development of type 2 diabetes mellitus. A strong family history of diabetes mellitus, age, obesity, and physical inactivity identify those individuals at highest risk. Minority populations are also at higher risk, not only because of family history and genetics, but also because of adaptation to American environmental influences of poor dietary and exercise habits. Women with a history of gestational diabetes as well as their children are at greater risk for progressing to type 2 diabetes mellitus. Insulin resistance increases a person's risk for developing impaired glucose tolerance and type 2 diabetes. Individuals who have insulin resistance share many of the same risk factors as those with type 2 diabetes. These include hyperinsulinemia, atherogenic dyslipidemia, glucose intolerance, hypertension, prothrombic state, hyperuricemia, and polycystic ovary syndrome. Current interventions for the prevention and retardation of type 2 diabetes mellitus are those targeted towards modifying environmental risk factors such as reducing obesity and promoting physical activity. Awareness of risk factors for developing type 2 diabetes will promote screening, early detection, and treatment in high-risk populations with the goal of decreasing both microvascular and macrovascular complications.
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PMID:Risk factors for type 2 diabetes mellitus. 1180 65


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