Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM ; acarbose, metformin, and the thiazolidinediones prevent or delay type 2 DM, but are not approved for this purpose . When administered to nondiabetic individuals for other reasons (cardiac, cholesterol lowering, etc.), two pharmacologic agents (ramipril, pravastatin) reduced the number of new cases of diabetes.
Individuals with a strong family history, those at high risk for developing DM or those with IFG or IGT should be strongly encouraged to maintain normal body mass index (BMI) and engage in regular physical activity.
– Genetically Defined, Monogenic Forms of Diabetes Mellitus
Several monogenic forms of DM have so far been identified. Five different variants of MODY, caused by mutations in genes encoding islet cell transcription factors or glucokinase (Fig . 323-3), have been identified so far, and all are transmitted as autosomal dominant disorders (Table 323-1).
MODY 2 is the result of mutations in the glucokinase gene that lead to mild-to-moderate hyperglycemia. Glucokinase catalyzes the formation of glucose-6-phosphate from glucose, a reaction that is important for glucose sensing by the beta cells and for glucose utilization by the liver.
As a result of glucokinase mutations, higher glucose levels are required to elicit insulin secretory responses, thus altering the set point for insulin secretion. Homozygous mutations in glucokinase cause severe, neonatal diabetes . MODY 1, MODY 3, and MODY 5 are caused by mutations in the hepatocyte nuclear transcription factors (HNF) 4a, HNF-la, and HNF-10, respectively. As their names imply, these transcription factors are expressed in the liver but also in other tissues, including the pancreatic islets and kidney (as a result, patients may also have renal absorption abnormalities and renal cysts).
The mechanisms by which such mutations lead to DM is not well understood, but it is likely that these factors affect islet development or the transcription of genes that are important in stimulating insulin secretion . MODY 1 and 3 begin with mild hyperglycemia, but progressive impairment of insulin secretion requires treatment with oral agents or insulin.
MODY 4 is a rare variant caused by mutations in the insulin promoter factor (IPF) 1, which is a transcription factor that regulates pancreatic development and insulin gene transcription.
Homozygous inactivating mutations cause pancreatic agenesis, whereas heterozygous mutations result in DM . Studies of populations with type 2 DM suggest that mutations in the glucokinase gene and various islet cell transcription factors are very rare in ordinary type 2 DM.
