Characterization of Stages in Development of Obesity-Diabetes Syndrome in Sand Rat (Psammomys obesus)

Sand rats (Psammomys obesus) maintained on a diet providing a free choice between laboratory chow and salt bush (Atriplex halimus) were classified into four groups differing in extent of the diabetic syndrome: A, normoglycemic-normoinsulinemic; B, normoglycemichyperinsulinemic; C, hyperglycemic-hyperinsulinemic; or D, hyperglycemic with reduced insulin levels. The metabolic pattern of these groups was characterized by measuring 1) the uptake of fatty acid-labeled, very-lowdensity lipoprotein-borne triglycerides (VLDL-TG) and [³H]%-2-deoxyglucose (2-DOG) into muscle and adipose tissues; 2) incorporation of [¹⁴C]alanine into glycogen in vivo; 3) gluconeogenesis from lactate, pyruvate, and alanine in hepatocytes; 4) the effect of insulin on glycogen synthesis from glucose; 5) the oxidation of albumin-bound [1-¹⁴C]palmitate and [¹⁴C]glucose in strips of soleus muscle; 6) activities of muscle and adipose tissue lipoprotein lipase; and 7) activities of rate-limiting enzymes of glycolysis, gluconeogenesis, and fatty acid synthesis in liver. In group A, uptake of VLDL-TG and activity of lipoprotein lipase were higher in adipose tissue and lower in muscle than in albino rats. In the liver, gluconeogenesis and the activity of phosphoenolpyruvate carboxykinase, as well as lipid synthesis and the activity of NAOP-malate dehydrogenase,were higher than in albino rats, whereas activity of pyruvate kinase was lower. In group B, uptake of VLDL-TG by adipose tissue and muscle and lipoprotein lipase activity were similar or higher than in group A. Uptake of 2-DOG by muscle and adipose tissue and activity of liver phosphoenolpyruvate carboxykinase were lower than in group A. In groups C and D, uptake of VLDL-TG and lipoprotein lipase activity in muscle were further increased. In adipose tissue a progressive decrease in VLDL-TG uptake and lipoprotein lipase activity was found, and uptake of 2-DOG by muscle and adipose tissue was further reduced. In the liver, gluconeogenesis was increased, and activity of phosphoenolpyruvate carboxykinase reached a maximum in group D. These results suggest that in the hyperinsulinemic stage (group B), uptake of glucose by muscle and adipose tissue is reduced, but insulin suppresses gluconeogenesis and stimulates hepatic synthesis and adipose tissue uptake of TG. Hyperglycemia manifests itself when insulin resistance results in increased gluconeogenesis and a further reduction in peripheral glucose uptake. These characteristics can be regarded as a model for the development of type II diabetes in humans evoked by nutritional affluence.