Are the adverse effects of glitazones linked to induced testosterone deficiency?

<p>Abstract</p> <p>Background</p> <p>Adverse side-effects of the glitazones have been frequently reported in both clinical and animal studies, especially with rosiglitazone (RGZ) and pioglitazone (PGZ), including congestive heart failure, osteoporosis, weight gain, oedema and anaemia. These led to consideration of an evidence-based hypothesis which would explain these diverse effects, and further suggested novel approaches by which this hypothesis could be tested.</p> <p>Presentation of hypothesis</p> <p>The literature on the clinical, metabolic and endocrine effects of glitazones in relation to the reported actions of testosterone in diabetes, metabolic syndrome, and cardiovascular disease is reviewed, and the following unifying hypothesis advanced: "<it>Glitazones induce androgen deficiency in patients with Type 2 Diabetes Mellitus resulting in pathophysiological changes in multiple tissues and organs which may explain their observed clinical adverse effects</it>." This also provides further evidence for the lipocentric concept of diabetes and its clinical implications.</p> <p>Testing of the hypothesis</p> <p>Clinical studies to investigate the endocrine profiles, including measurements of TT, DHT, SHBG, FT and estradiol, together with LH and FSH, in both men and women with T2DM before and after RGZ and PGZ treatment in placebo controlled groups, are necessary to provide data to substantiate this hypothesis. Also, studies on T treatment in diabetic men would further establish if the adverse effects of glitazones could be reversed or ameliorated by androgen therapy. Basic sciences investigations on the inhibition of androgen biosynthesis by glitazones are also warranted.</p> <p>Implications of the hypothesis</p> <p>Glitazones reduce androgen biosynthesis, increase their binding to SHBG, and attenuate androgen receptor activation, thus reducing the physiological actions of testosterone, causing relative and absolute androgen deficiency. This hypothesis explains the adverse effects of glitazones on the heart and other organs resulting from reversal of the action of androgens in directing the maturation of stem cells towards muscle, vascular endothelium, erythroid stem cells and osteoblasts, and away from adipocyte differentiation. The higher incidence of side-effects with RGZ than PGZ, may be explained by a detailed study of the mechanism by which glitazones down-regulate androgen biosynthesis and action, resulting in a state of androgen deficiency.</p

A Novel Three-Filament Model of Force Generation in Eccentric Contraction of Skeletal Muscles

We propose and examine a three filament model of skeletal muscle force generation, thereby extending classical cross-bridge models by involving titin-actin interaction upon active force production. In regions with optimal actin-myosin overlap, the model does not alter energy and force predictions of cross-bridge models for isometric contractions. However, in contrast to cross-bridge models, the three filament model accurately predicts history-dependent force generation in half sarcomeres for eccentric and concentric contractions, and predicts the activation-dependent forces for stretches beyond actin-myosin filament overlap

Effects of GI vs content of cereal fibre of the evening meal on glucose tolerance at a subsequent standardized breakfast

&lt;p&gt;Objective: To investigate if the improved glucose tolerance previously observed at breakfast following an evening meal with boiled barley kernels derives from colonic events related to the fermentation of the elevated amounts of indigestible carbohydrates present and/or from the low-GI features.&lt;/p&gt; &lt;p&gt;Subjects/Methods: Twenty healthy volunteers aged 19–30 years.&lt;/p&gt; &lt;p&gt;Design: High-GI white wheat bread (WWB), WWB+barley dietary fibre (DF) corresponding to the DF content of barley kernels, low-GI spaghetti+ barley DF, spaghetti+double amounts of barley DF (2*DF), spaghetti+oat DF, or whole grain barley flour porridge, were provided as late evening meals. At a subsequent standardised WWB breakfast, B-glucose, s-insulin, p-SCFA, p-FFA, and breath hydrogen (H&lt;sub&gt;2&lt;/sub&gt;) were measured.&lt;/p&gt; &lt;p&gt;Results: The B-glucose response (incremental areas under the curves (IAUC) 0–120 min and total areas under the curves 0–180 min) to the standardized breakfast was significantly lower after consuming spaghetti+2*DF in the evening compared with barley porridge (&lt;i&gt;P&lt;/i&gt;=0.012). The spaghetti+2*DF meal also resulted in the highest breath H2 excretion (&lt;i&gt;P&lt;/i&gt;&#60;0.02). The glucose IAUC (0–120 min) after the standardized breakfast was positively correlated to fasting p-FFA (&lt;i&gt;r&lt;/i&gt;=0.29, &lt;i&gt;P&lt;/i&gt;&#60;0.02), and the total glucose area (0–180 min) was negatively correlated to the p-propionate level (0–30 min) (&lt;i&gt;r&lt;/i&gt;=−0.24, &lt;i&gt;P&lt;/i&gt;&#60;0.02).&lt;/p&gt; &lt;p&gt;Conclusions: The prolonged digestive and absorptive phase per se, like with a low-glycaemic index (GI) spaghetti evening meal, did not induce overnight benefits on glucose tolerance. Addition of barley DF in high amounts (2*DF) was required to improve overnight glucose tolerance. The correlations observed between glycaemia and p-propionate implicate colonic fermentation as a modulator of glucose tolerance through a mechanism leading to suppressed free fatty acids levels. It is proposed that the overnight benefits on glucose tolerance previously reported for boiled barley kernels is mediated through colonic fermentation of the prebiotic carbohydrates present in this product.&lt;/p&gt

Effects of GI and content of indigestible carbohydrates of cereal-based evening meals on glucose tolerance at a subsequent standardised breakfast

&lt;b&gt;Objective:&lt;/b&gt; To evaluate the impact of four low-glycaemic index (GI) and one high-GI cereal-based evening meals on glucose tolerance at a subsequent standardised breakfast.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Design:&lt;/b&gt; Wheat kernels, barley kernels, spaghetti, spaghetti with added wheat bran and white wheat bread (WWB) were consumed in the evening in a random order at five different occasions. At the subsequent breakfast, blood glucose, serum insulin, plasma short chain fatty acid, plasma free fatty acid (FFA) and breath hydrogen were measured.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Setting:&lt;/b&gt; The study was performed at Applied Nutrition and Food Chemistry, Lund University, Sweden.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Subjects:&lt;/b&gt; Fifteen healthy volunteers were recruited. One subject was later excluded owing to abnormal blood glucose values.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results:&lt;/b&gt; The blood glucose response (0–120 min) to the standardised breakfast was significantly lower after consuming barley kernels in the evening compared with evening meals with WWB (P=0.019) or spaghetti+wheat bran (P=0.046). There were no significant differences in insulin concentrations at breakfast. Breath hydrogen excretion at breakfast was significantly higher after an evening meal with barley kernels compared with WWB, wheat kernels or spaghetti (P=0.026, 0.026 and 0.015, respectively), and the concentration of plasma propionate at breakfast was significantly higher following an evening meal with barley kernels compared with an evening meal with WWB (P=0.041). In parallel, FFA concentrations were significantly lower after barley kernels compared with WWB (P=0.042) or spaghetti evening meals (P=0.019).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The improved glucose tolerance at breakfast, following an evening meal with barley kernels appeared to emanate from suppression of FFA levels, mediated by colonic fermentation of the specific indigestible carbohydrates present in this product, or, to the combination of the low-GI features and colonic fermentation.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Sponsorship:&lt;/b&gt; European Commission QLK1-2001-00431 (EUROSTARCH)