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Abstract
Clinical studies have revealed that testosterone supplementation had a positive effect on glucose homeostasis in type 2 diabetes mellitus (T2DM), but did not address how testosterone supplementation affected insulin responsiveness in the liver, a key glucose homeostatic organ. In this study, we aimed to study the effect of testosterone supplementation on hepatic insulin responsiveness and glucose homeostasis through liver in male high-fat diet-induced T2DM mice. Testosterone treatment to T2DM animals showed reduced hepatic glucose output. Testosterone inhibited the insulin signaling in liver, thus increased insulin resistance. However, testosterone treatment inactivated GSK3α independent of PI3K/AKT pathway and inhibited FOXO1 By interaction of androgen receptor to FOXO1 and downregulated PEPCK, causing repression of gluconeogenic pathway, which is otherwise upregulated in T2DM, resulted in better glucose homeostasis.
Highlights
Liver is one of the major organs involved in glucose homeostasis in the body
In type 2 diabetes mellitus (T2DM), the body is not able to effectively utilize insulin to maintain normoglycemic level, and the hepatic glucose output is not in the ambit of control of insulin and leads to hyperglycemia, which is reflected by higher fasting blood glucose level (BGL).[1,2,3]
Testosterone-deficient men, who had T2DM, when given androgen replacement therapy, showed improvement in glucose homeostasis parameters.[4,5]. These clinical studies did not show the effect of testosterone supplementation on the insulin responsiveness and gluconeogenesis in the liver, and on the serum levels of known regulators of glucose homeostasis, like insulin, glucagon, leptin, interleukin-6, and so on
Summary
Liver is one of the major organs involved in glucose homeostasis in the body. During extended fasting, the liver converts pyruvate to glucose, by a process called gluconeogenesis, to maintain normoglycemic level where phosphoenolpyruvate carboxykinase (PEPCK) being the rate-limiting enzyme. In type 2 diabetes mellitus (T2DM), the body is not able to effectively utilize insulin to maintain normoglycemic level, and the hepatic glucose output is not in the ambit of control of insulin and leads to hyperglycemia, which is reflected by higher fasting blood glucose level (BGL).[1,2,3] Clinical reports have shown that there is an association between testosterone levels and metabolic syndrome in men, and testosterone deficiency leads to T2DM In these studies, testosterone-deficient men, who had T2DM, when given androgen replacement therapy, showed improvement in glucose homeostasis parameters.[4,5] these clinical studies did not show the effect of testosterone supplementation on the insulin responsiveness and gluconeogenesis in the liver, and on the serum levels of known regulators of glucose homeostasis, like insulin, glucagon, leptin, interleukin-6, and so on.
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