Castration-induced testosterone deficiency increases fasting glucose associated with hepatic and extra-hepatic insulin resistance in adult male rats

Abstract

BackgroundTestosterone deficiency is associated with insulin resistance. However, how testosterone deficiency affects insulin actions remains unclear. The aim of this study was to investigate the influence of castration-induced testosterone deficiency on the metabolic kinetics of glucose and to evaluate the hepatic and extra-hepatic insulin sensitivity, in advanced-age male Sprague–Dawley (SD) rats.MethodsTen-week-old male SD rats were randomly divided into three groups: (1) a control group (n = 10) in which the rats underwent sham castration (2) a castrated group (TD group for testosterone deficiency, n = 10) in which the rats underwent bilateral orchidectomy surgery and (3) a castrated group given testosterone propionate via intraperitoneal injection (25 mg/kg/day) to supplement androgen (TD + TP group, n = 10). At ten weeks after castration in the noted groups, all rats were subjected to an oral glucose tolerance test (OGTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Twenty weeks following that treatment, all rats underwent a hyperinsulinemic-euglycemic clamp procedure in conjunction with isotope--labeled glucose and glycerol tracer infusions. The rate of appearance (Ra) of glucose, glycerol and gluconeogenesis (GNG), hepatic glucose production and the rate of glucose disappearance (Rd) were assessed. Glucose uptake was determined by measuring the 2-deoxy-D-14C-glucose in the gastrocnemius muscles.ResultsTen weeks after castration in the TD group, the fasting blood glucose and insulin levels were significantly increased (p < 0.01), the glucose-- induced insulin secretion was impaired and ITT revealed a temporarily increased whole body insulin sensitivity compared with the control group; 30 weeks after castration, the Ra of glucose, Ra of glycerol, as well as the HGP and GNG were also increased (p < 0.01), while the exogenous glucose infusion rate and uptake glucose in the muscle markedly decreased (p < 0.01).ConclusionsCastration-induced testosterone deficiency primarily increases fasting blood glucose levels. The clamp experiments revealed a clear insulin resistance both at the hepatic and extra-hepatic levels.

Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies

“…Ten weeks after castration, the β-cell mass was reduced to 30% of that observed in control rats and an excessive rise in glucose levels was observed 30 min after glucose injection [103]. This type of glucose intolerance reflects impairment of β-cell function [166], and castration has been shown to decrease insulin levels following a glucose load in male rats [162]. Testosterone also increases insulin expression [169] and suppresses the β-cell death induced by streptozotocin in male rats [170,171].…”

“…Non-obese castrated rats show exacerbated hepatic and extra-hepatic (including muscle) insulin resistance, which increases the fasting glucose level [162]. Obese AR-KO or castrated mice showed a decreased [95,125,140] or unchanged [111,126] insulin sensitivity.…”

Gender and Sex Differences in Adipose Tissue

“…Castration studies have been conflicted showing decreased weight [35], improved glucose tolerance [36], increased insulin sensitivity [37], and improved triglycerides [38] even with increased fat mass, with other studies showing that castration impairs glucose tolerance and insulin resistance [39•]. AR-KO mice also show increased adiposity [40] and improved insulin sensitivity consistent with a deleterious role for androgens in adipose tissue [41].…”

Male Hypogonadism Causes Obesity Associated with Impairment of Hepatic Gluconeogenesis in Mice

“…15) In addition, several studies have suggested that hypogonadism induces abnormal hepatic regulation of glucose homeostasis. 10,14,15,24) Hence, unlike in ARKO mice, surgical castration may induce obesity mainly via involvement of hepatic gluconeogenesis rather than adipocyte lipid metabolism. However, more information is needed about the profiles of genes which are highly regulated by androgens as well as HSL in Cast mice.…”

“…For example, in male rats, castration induces insulin resistance with fasting hyperglycemia or hepatic steatosis. 14,15) In male mice, castration increases plasma adiponectin levels and induces glucose uptake into white adipose tissue (WAT). [16][17][18] In terms of fat accumulation in WAT, Floryk et al 19) reported that soon after surgical castration (i.e., within 14 d), WAT mass is reduced in male mice, even though androgen-depressive therapies clearly induce obesity in human clinical cases.…”