Cj Bailey

Hormonal control of glucose homeostasis during development and ageing in mice

Age-related changes in the hormonal control of glucose homeostasis were examined in immature (5-wk-old), young adult (10-wk-old) and older adult (30 and 60-wk-old mice). In immature mice, basal plasma glucose and insulin concentrations were higher than young adult mice. Glucose tolerance was impaired in immature mice, although the plasma insulin response to glucose and other secretagogues (arginine and glucagon) was well developed, and the hypoglycaemic effect of exogenous insulin was not impaired. Glucagon and epinephrine evoked a greater acute hyperglycaemia in immature mice, suggesting that these hormones exert a stronger rapid glucose-raising effect in preadult life. Basal plasma glucose and insulin concentrations were lowest in young adult mice, and increased with advancing adult age. Glucose tolerance was best in young adult mice and deteriorated with age, while plasma insulin concentrations after administration of glucose, arginine and glucagon were lowest in young adult mice and increased with age. However, in response to these secretagogues, the percentage increase in plasma insulin above basal was reduced in older adult mice. This indicates a defect of stimulus-recognition-secretion-coupling in the B-cells of older adult mice. The raised plasma glucose concentrations of older adult mice could not be attributed to an increase in the acute hyperglycaemic action of glucagon or epinephrine. The hypoglycaemic response to exogenous insulin decreased with age, suggesting that tissue sensitivity to insulin was impaired. Treatment with growth hormone and cortisone for 5 days produced a greater antagonism of insulin in older mice than young adult or immature mice. Growth hormone impaired glucose tolerance at each age, but only produced a marked hyperinsulinaemia in older adult mice. In contrast, cortisone produced a marked hyperinsulinaemia at each age, but only impaired glucose tolerance in older adult mice.

Glucose and Insulin Response to Conditioned Feeding in Lean and Genetically Obese Hyperglycemic (ob/ob) Mice

The study reported here investigated the role of neuroendocrine reflexes in the stimulation of insulin secretion associated with feeding in lean and genetically obese hyperglycemic (ob/ob) mice. Twenty-week-old mice were conditioned over four weeks to restricted feeding periods of consecutively seven, four and two hours a day. Basal plasma glucose concentrations before feeding were raised in conditioned lean mice but lowered in conditioned ob/ob mice, with normalization of glycemia in ob/ob mice by four weeks. Conditioned mice consumed more food during the feeding period than control mice prefasted for the same time. Although the quantity of food consumed was less than the normal 24-hour intake of age-matched mice fed ad libitum, body weights were well maintained, indicating adaptations of metabolic efficiency or energy expenditure or both. During the feeding period, conditioned mice displayed a markedly enhanced plasma insulin response accompanied by a smaller increase in plasma glucose despite the consumption of more food. An anticipatory rise in plasma insulin was not evident when food was withheld during the prescribed two-hour feeding period after four weeks of conditioning. The results demonstrate that basal glucose concentrations were normalized in ob/ob mice but raised in lean mice by the restricted conditioned feeding procedure. Basal insulin concentrations and body weights were not significantly altered, but conditioning to expect food augmented the insulin response initiated by feeding in both lean and ob/ob mice.

Effects of ephedrine and atenolol on the development of obesity and diabetes in ob/ob mice.

To investigate the involvement of adrenergic mechanisms in the development of obesity, hyperglycaemia and hyperinsulinaemia in Aston ob/ob mice, the sympathomimetic agent ephedrine (12 mg/kg/day) and the predominantly beta 1-adrenergic antagonist atenolol (12 mg/kg/day) were administered alone and in combination to weanling ob/ob mice for 40 days. Excessive weight gain in ob/ob mice was reduced (15-20%) by ephedrine, exacerbated (8-10%) by atenolol, but not significantly altered by a combination of these agents. The effects of ephedrine and atenolol were lost rapidly (within 5 days) when these agents were withdrawn. Ephedrine slightly reduced the hyperphagia in ob/ob mice, and food intake was transiently increased above that of untreated ob/ob mice when this agent was withdrawn. The development of basal hyperglycaemia and hyperinsulinaemia was not significantly altered by any of the treatments studied. None of the treatments significantly altered body weight, food intake, plasma glucose or plasma insulin concentrations in lean (+/+) mice. The results indicate that a defective adrenergic mechanism involving beta 1-adrenergic receptors contributes to the development of obesity in ob/ob mice.

Effect of high fat and high carbohydrate cafeteria diets on the development of the obese hyperglycemic (ob/ob) syndrome in mice

Abstract The role of dietary fat and carbohydrate in the development of obesity, impaired glucose homeostasis and hyperinsulinemia was examined in young obese-hyperglycemic (ob/ob) mice. Palatable and varied high fat (HF) and high carbohydrate (HC) cafeteria diets were fed to ob/ob mice from 3 to 10 weeks of age. Mice fed the HF cafeteria diet consumed 15% more energy and gained 50% more in body weight than mice fed the HC cafeteria diet. Metabolic efficiency, as indicated by the ratio of body weight gain to energy intake was increased by 29% in mice fed the HF cafeteria diet. The latter mice also showed an earlier onset of hyperglycemia and a greater impairment of glucose tolerance. The development of hyperinsulinemia and the loss of an insulin response to parenterally administered glucose were similar in the two groups of mice. The results indicate a greater preference for HF than HC cafeteria diets, a greater retention of energy consumed as fat, and a greater impairment of glucose homeostasis in young ob/ob mice fed the HF cafeteria diet.