Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats

Abstract

Male Zucker diabetic fatty (mZDF) rats spontaneously develop type 2 diabetes, whereas females only become diabetic when fed a diabetogenic high-fat diet (high-fat-fed female ZDF rat, HF-fZDF). The aim of this study was to investigate if differences in liver functions could provide clues to this sex difference. Non-diabetic obese fZDF rats were compared with either mZDF or HF-fZDF regarding hepatic molecular profiles, to single out those components that might be protective in the females. High-fat feeding in fZDF led to enhanced weight gain, increased blood glucose and insulin levels, reduced insulin sensitivity and a trend towards reduced glucose tolerance, indicative of a prediabetic state. mZDF rats were diabetic, with low levels of insulin, high levels of glucose, reduced insulin sensitivity and impaired glucose tolerance. Transcript profiling and capillary electrophoresis time-of-flight mass spectrometry were used to indentify hepatic transcripts and metabolites that might be related to this. Many diet-induced alterations in transcript and metabolite levels in female rats were towards a 'male-like' phenotype, including reduced lipogenesis, increased fatty acid (FA) oxidation and increased oxidative stress responses. Alterations detected at the level of hepatic metabolites, indicated lower capacity for glutathione (GSH) production in male rats, and higher GSH turnover in females. Taken together, this could be interpreted as if anabolic pathways involving lipogenesis and lipid output might limit the degree of FA oxidation and oxidative stress in female rats. Together with a greater capacity to produce GSH, these hepatic sex differences might contribute to the sex-different development of diabetes in ZDF rats.

Increased Oxidative Stress and Mitochondrial Dysfunction in Zucker Diabetic Rat Liver and Brain

“…Elderly ZDF rats have multiple energy metabolism-associated complications [2,3,22,][23]. It has been shown that prolonged exposure to insulin suppresses mitochondrial function which may lead to insulin resistance [11,12,24].…”

“…However, the precise molecular mechanisms of disease progression and complications in various tissues are still unclear. The Zucker diabetic fatty (ZDF, FA/FA) rat is a genetic experimental model of type 2 diabetes characterized by inherited insulin-resistance with progressive metabolic complications, hyperglycemia and hyperlipidemia [1,2]. While male rats develop spontaneous diabetes and metabolic complications, female rats become diabetic only after intake of high fat diet [2].…”

“…The Zucker diabetic fatty (ZDF, FA/FA) rat is a genetic experimental model of type 2 diabetes characterized by inherited insulin-resistance with progressive metabolic complications, hyperglycemia and hyperlipidemia [1,2]. While male rats develop spontaneous diabetes and metabolic complications, female rats become diabetic only after intake of high fat diet [2]. The ZDF rats exhibit progressive metabolic complications associated with increased insulin resistance, oxidative and nitrosative stress [3,4,5,6].…”

Increased Metabolic Stress in Zucker Diabetic Fatty Rat Kidney and Pancreas

“…The Zucker diabetic fatty (ZDF, FA/FA) rat is an experimental model of type 2 diabetes caused by an inherited insulin-resistant gene with progressive metabolic syndrome and hyperlipidemia [1,2]. While male rats develop spontaneous diabetes and associated metabolic complications, female rats become diabetic only after intake of high fat diet.…”

Cardiovascular risk and stress adaptation in metabolic diseases

“…The Zucker diabetic fatty rat with a point mutation in the leptin receptor is a recognized model of obesity, hyperlipidemia, hyperglycemia and hypertension [90][91][92]. In the present study, only male rats were used, since female ZDF rats are less prone to the development of metabolic syndrome [93,94]. Male ZDF rats develop an age-dependent obese and hyperglycemic phenotype at 10-12 weeks of age accompanied by a metabolic state of obesity, dyslipidemia, hyperinsulinemia and insulin resistance [95,96] which develops to a hyperglycemic insulin-deficient state [95].…”