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The dietary effects of hyperglycemia increasingly result in type 2 diabetes in humans. Two species, the spiny mice (Acomys cahirinus) and the desert gerbil (Psammomys obesus), which have different metabolic responses to such effects, are discussed. Spiny mice exemplify a pathway that leads to diabetes without marked insulin resistance due to low supply of insulin on abundant nutrition, possibly characteristic of a desert animal. They respond with obesity and glucose intolerance, beta-cell hyperplasia, and hypertrophy on a standard rodent diet supplemented with fat-rich seeds. The accompanying hyperglycemia and hyperinsulinemia are mild and intermittent but after a few months, the enlarged pancreatic islets suddenly collapse, resulting in loss of insulin and ketosis. Glucose and other secretagogues produce only limited insulin release in vivo and in vitro, pointing to the inherent disability of the beta-cells to respond with proper insulin secretion despite their ample insulin content. On a 50% sucrose diet there is marked lipogenesis with hyperlipidemia without obesity or diabetes, although beta-cell hypertrophy is evident.

P. obesus is characterized by muscle insulin resistance and the inability of insulin to activate the insulin signaling on a high-energy (HE) diet. Insulin resistance imposes a vicious cycle of hyperglycemia and compensatory hyperinsulinemia, leading to beta-cell failure and increased secretion of proinsulin. Ultrastructural studies reveal gradual disappearance of beta-cell glucokinase, GLUT 2 transporter, and insulin, followed by apoptosis of beta-cells. Studies using the non-insulin-resistant HE diet-fed animals maintained as a control group are discussed. The insulin resistance that is evident to date in the normoglycemic state on a low-energy diet indicates sparing of glucose fuel in muscles of a desert-adapted animal for the benefit of glucose obligatory tissues. Also discussed are the effect of Psammomys age on the diabetogenicity of the HE diet; the impaired function of several components of the insulin signal transduction pathway in muscles, which reduces the availability of GLUT4 transporter; the testing of several antidiabetic modalities for the prevention of nutritional diabetes in Psammomys; and various complications related to the diabetic condition.