Adipose tissue insulin deficiency

Il.f.l.1. Insulins. Insulin is the most effective of diabetes medications. Insulin has profound effects on carbohydrate, protein, fat metabolism and electrolytes. It has anabolic and anticatabolic actions. In a state of insulin deficiency, glycogenesis, glucose transport, protein synthesis, triglyceride synthesis, LPL activity in adipose tissue, cellular potassium uptake all decrease on the other hand, gluconeogene-sis, glycogenolysis, protein degradation, ketogene-sis, lipolysis increase. 

The metabolic abnormalities of diabetes mellitus result from a deficiency of insulin and a relative excess of glucagon. These aberrant hormonal levels most profoundly affect metabolism in three tissues liver, muscle, and adipose tissue (Figure 25.3). 

In the -in vivo situation, the ketogenic action of glucagon is most prominent in states of insulin deficiency. This can be explained because insulin normally suppresses the effect of glucagon on hepatic cAMP levels [170] and inhibits the action of the hormone on lipolysis, i.e., fatty acid release in adipose tissue [171]. 

MTP-1403 (91) and MTP-1307 (92) are able to improve glucose tolerance in normal rats and in insulin-resistant mice and lower fasting plasma glucose in rats but not in insulin-deficient diabetic animals. In rats, the hypogly-caemic effect is accompanied by an increase in insulin levels, more pronounced with MTP-1307 than with MTP-1403. The mechanism of action is unknown. In vitro MTP-1307 inhibits gluconeogenesis in hepatocytes and glucose oxidation in adipose tissue, at 0.1 to 3 mM [397]. 

High blood glucose levels occur because of either a deficiency of insulin (insulin-dependent diabetes mellitus, IDDM) or the inability of tissues such as adipose and muscle to take up glucose in the presence of normal amounts of insulin (insulin resistance or noninsulin-dependent diabetes mellitus [NIDDM]). If insulin-deficiency diabetes mellitus is untreated, the body responds as if it is starving. Fuel stores are degraded in the face of high blood glucose, and ketoacidosis may occur. Many metabolic pathways are affected. 

In diabetes mellitus, blood glucose homoeostasis and rate of lipolysis in adipose tissue appear to be associated. This relationship is most apparent in an insulin-deficient state, where glucose homoeostasis is maintained at the expense of other fuel sources, mainly FFA. Insulin deficiency initiates lipolysis. The increase in fatty acid oxidation further favours hepatic gluconeogenesis. 

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