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Message: <blockquote data-quote="Celsus" data-source="post: 865743" data-attributes="member: 185674">Link from Medscape:  <a href="http://www.medscape.com/viterewarticle/512077_4" target="_blank">http://www.medscape.com/viterewarticle/512077_4</a>Androgens, Insulin Resistance and Vascular Disease in Men D. Kapoor; C. J. Malkin; K. S. Channer; T. H. Jones<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','authordisclosures');" target="_blank">Disclosures</a>Clin Endocrinol. 2005;63(3):239-250. Studies in healthy men have shown an inverse correlation between testosterone and insulin levels ( <a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active', 'T2');" target="_blank">Table 1</a> ). The Telecom study involving 1292 healthy adult men demonstrated a significant inverse relationship between levels of plasma total testosterone and insulin independent of age, alcohol consumption, cigarette smoking and plasma glucose.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[14]</a> Even though the association was reduced to some extent by obesity, it still persisted after adjustment for body mass index (BMI) and subscapular skinfold thickness. Another large prospective population-based study of 1009 men, who were followed-up for 12 years, also demonstrated similar inverse correlations between total testosterone levels and fasting blood glucose and BMI.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[15]</a>In diabetic men, an early case–control study showed that androgen levels were lower than in normal men.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[16]</a> Subsequently in a larger cross-sectional study of 985 men from the Rancho Bernardo community in California, of whom 110 were diabetic, testosterone levels were found to be lower in diabetic men, although the association was not as great after controlling for age and BMI.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[17]</a> Of the diabetic men, 21% were hypogonadal compared to 13% of nondiabetic men, and the testosterone levels were related to the degree of glycaemia as assessed by fasting plasma glucose concentrations.Further insight into the potential role of male hormones in the future development of insulin resistance and diabetes is provided by a study performed in relatives of diabetic patients. It is well established that first-degree relatives of type 2 diabetic patients have a higher risk of developing diabetes. Jansson et al.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[31]</a> compared 33 healthy first-degree relatives of type 2 diabetic patients with 33 age-matched controls. Relatives showed decreased insulin sensitivity as measured by the euglycaemic hyperglycaemic clamp method and this difference was significant for males only. Male relatives of the diabetic patients had lower plasma total testosterone levels as compared to the male controls and the total testosterone levels observed in these relatives were positively associated with insulin sensitivity. As SHBG levels were similar between groups, it was postulated that the alterations in total testosterone levels would reflect the free hormone levels as well. Thus it would seem likely that dysregulation of androgen levels could contribute to the development of insulin resistance in male subjects who have a higher genetic predisposition for type 2 diabetes.In summary, these studies suggest that low testosterone levels in men may potentially be a contributory factor to the development of insulin resistance and the subsequent progression to type 2 diabetes.SHBG is the circulating steroid-binding protein produced by the liver that binds testosterone with high affinity. It is an important regulator of androgen homeostasis and functions as a modulator of androgen delivery to the tissues. SHBG concentration falls during puberty in both boys and girls. Serum SHBG levels are primarily regulated by sex steroids and thyroxine.It has been suggested that the link between total testosterone and insulin resistance is due to the negative relationship between SHBG and insulin, with low SHBG leading to low total testosterone. Birkeland et al.,<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[32]</a> using the insulinglucose clamp technique, demonstrated an inverse correlation between insulin resistance and serum SHBG levels in 23 type 2 diabetic men that was independent of serum insulin or C-peptide level as well as being independent of obesity and abdominal fat accumulation. In the Telecom study, healthy men with lower total testosterone levels had significantly higher insulin levels and markedly reduced levels of SHBG.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[33]</a> Bioavailable testosterone levels, however, were not significantly different in the two groups, implying that the link between total testosterone and plasma insulin could be explained by the negative association between SHBG and plasma insulin. Similarly, Andersson et al.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[34]</a> found that total testosterone and SHBG levels were significantly lower in diabetic men than nondiabetic control subjects and had a negative correlation with insulin values. There was no difference in free testosterone levels between the groups, again demonstrating that low total testosterone levels were secondary to the low SHBG. Even in relatives of hypertensive men, an inverse relationship was found between low total testosterone and SHBG concentrations and lower insulin sensitivity, with no change in free testosterone levels.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[35]</a>Insulin is an important regulator of SHBG production by the liver. In vitro studies have shown that insulin in physiological concentrations was a potent inhibitor of SHBG production by cultured hepatoma cells.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[36]</a> Peiris et al.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[37]</a> also showed a significant association between SHBG levels and the insulin secretory pulse interval but not with peripheral insulin sensitivity in 10 nondiabetic men. Furthermore, Pasquali et al.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[38]</a> demonstrated that inhibition of insulin secretion by giving diazoxide to normal weight and obese men led to increased SHBG levels. Acute hyperinsulinaemia has also been found to result in a small but significant reduction in SHBG concentration in healthy men.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[39]</a> Nestler has thus suggested that lower SHBG levels may be a marker for hyperinsulinaemia and insulin resistance.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[40]</a> Men with low SHBG concentrations have an increased risk of developing the metabolic syndrome.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[41]</a> Therefore, the available data, in men, suggest that insulin resistance maybe a determinant of SHBG levels.Obesity is the most common cause of insulin resistance. BMI is traditionally used as an indicator of overall obesity. However, certain patterns of fat distribution are more closely related to increased incidence of diabetes and cardiovascular disease. Abdominal or central obesity, as assessed by waist/hip ratio, is an essential component of metabolic syndrome and more strongly linked to the development of impaired glucose tolerance. Visceral fat, which constitutes a significant proportion of the intra-abdominal fat, has certain characteristic metabolic and anatomical features.<a href="http://www.diabetes.co.uk/forum/javascript:newshowcontent('active','references');" target="_blank">[42]</a> Visceral adipose tissue is more highly metabolically active than any other adipose tissue in the body. Furthermore, the visceral fat is drained through the portal vein to the liver, in contrast to the peripheral fat, which is drained by the systemic circulation. The above two processes result in the liver being exposed to higher concentrations of free fatty acids produced by the adipocytes than in any other organ. Free fatty acids decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance. These effects ultimately lead to peripheral hyperinsulinaemia and systemic insulin resistance (Fig. 2).Role of visceral fat in peripheral hyperinsulinaemia and systemic insulin resistance. Increasing abdominal fat leads to liver being exposed to higher concentrations of free fatty acids. The free fatty acids increase hepatic glucose production and decrease hepatic insulin uptake. This Results in systemic hyperinsulinaemia and skeletal muscle insulin resistance, which in turn causes further release of insulin by the islet cells.</blockquote>

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