Risk factors: a) Obesity most important risk factor; increases peripheral resistance to insulin-mediated glucose uptake; especially visceral/abdominal

l adiposity; b) Genetics 40-80% of children with DM II have at least 1 affected parent; 1 affected parent 40% risk; 2 affected parents 60% risk c) Ethnicity -Native Americans Pima Indians have highest prevalence (51/1000) -blacks- several studies report that insulin resistance is greater in black children than in white children -Hispanics- reported to have lower insulin sensitivity and decreased pancreatic -cell function d) Gender girls 1.3-1.7x more likely than boys; related to insulin resistance in PCOS e) in-utero programming d/t: -prenatal undernutrition low birth weight associated with increased insulin resistance -gestational diabetes- high birth weight; Intrauterine exposure to hyperglycemia and hyperinsulinemia may affect the development of adipose tissue and pancreatic beta cells, leading to future obesity and altered glucose metabolism. f) Other insulin resistant states- most present at onset of puberty (~13.5; between 12-16) , a stage in devt when there is insulin sensitivity due to activity of GH and IGF-1 Pathogenesis: a) insulin resistance within muscles and adipose tissue (in the beginning)- obesity is associated with plasma levels of free fatty acids makes muscles more insulin resistant glucose uptake; simultaneously, in the liver, FFAs glucose production b) inadequate insulin production from cells to compensate in normal pts, the pancreas secretes more insulin in response to FFAs thus neutralizing the excess glucose; in DM II, FFAs fail to stimulate pancreatic insulin secretion no compensation hyperglycemia cells become desensitized to glucose insulin secretion c) also absolute mass of cells is decreased estimated that pts with type II have ~50% of their normal amount of cells; also have a gradual loss over time possibly due to the toxic effects of hyperglycemia on the cells d) elevated levels of proinsulin d/t impaired insulin processing- healthy pts have 2-4% of total circulating insulin as proinsulin, but diabetics have 10-20% (proinsulin has a effect for lowering blood glucose) e) Dysregulated Hepatic Glucose Metabolism In type 2 diabetes, hepatic glucose output is excessive in the fasting state and inadequately suppressed after meals. These are key components to the abnormal glycemic profile in diabetic patients, who have elevated glucose levels in the postabsorptive state and accentuated postprandial rises. Abnormal secretion of the islet hormones, both insufficient insulin and excessive glucagon, accounts for a significant portion of dysregulated hepatic glucose metabolism in type 2 diabetes. Increased concentrations of glucagon, especially in conjunction with hepatic insulin resistance, can lead to excessive hepatic gluconeogenesis and glycogenolysis and abnormally high fasting glucose concentrations. The liver is also resistant to insulin action in type 2 diabetes. This contributes to the reduced potency of insulin to suppress hepatic glucose production and promote hepatic glucose uptake and glycogen synthesis after meals. Despite ineffective insulin effects on hepatic glucose metabolism, the lipogenic effects of insulin in the liver are maintained and even accentuated

by fasting hyperinsulinemia. This contributes to hepatic steatosis and further worsening of insulin resistance.

-inappropriate glucose release from the liver (controlled by blood insulin levels glc) -increased breakdown of lipids within the adipocyte -resistance to and lack of incretin -high glucagon levels in the blood Genome wide association analysis has played an important role in identifying several new diabetes susceptibility loci. Some of these loci are in genes involved in pancreatic development and insulin synthesis. As an example, a genome wide association study to find genetic loci associated with type 2 diabetes in a French population confirmed the known association with the transcription factor 7-like 2 gene (TCF7L2) and identified four new loci associated with an increased risk of type 2 diabetes. These loci (SLC30A8, HHEX/IDE, and KCNJ11) are involved in beta cell development and insulin synthesis and appear to contribute substantially to type 2 diabetes risk.

MODY2 and MODY4 MODY is a rare cause of type 2 diabetes which has autosomal dominant transmission and features of both impaired insulin secretion and insulin resistance. One form, MODY2, appears to be due to mutations in the glucokinase gene on chromosome 7. Glucokinase, which phosphorylates glucose to glucose-6-phosphate, probably acts as the glucose sensor within pancreatic beta cells, and therefore, glucokinase defects likely result in decreased insulin secretion. Another form of MODY (MODY4) is associated with mutations in insulin promoter factor-1 (IPF-1/PDX-1), a pancreatic beta cell transcription factor [54]. These mutations result in decreased insulin secretion in response to glucose due to reduced binding of the protein to the insulin gene promoter [54,55] and perhaps by altering fibroblast growth factor signaling in beta cells Other genes that may affect susceptibility to type 2 diabetes are the genes for insulin-receptor substrates, the beta-3-adrenergic receptor, and peroxisome-proliferator-activated receptor gamma2.

Insulin Resistance The major insulin-responsive tissues are skeletal muscle, adipose tissue, and liver. Insulin resistance in muscle and fat is generally marked by a decrease in transport of glucose from the circulation. Hepatic insulin resistance generally refers to a blunted ability of insulin to suppress glucose production. Insulin resistance in adipocytes causes increased rates of lipolysis and release of fatty acids into the circulation, which can contribute to insulin resistance in liver and muscle, hepatic steatosis, and dyslipidemia. More generally the role of obesity in the etiology of type 2 diabetes is related to the insulin resistance in skeletal muscle and liver that comes with increased amounts of lipid storage, particularly in specific fat depots. The sensitivity of humans to the effects of insulin administration is inversely

related to the amount of fat stored in the abdominal cavity; more visceral adiposity leads to more insulin resistance. Similarly, intrahepatocyte or intramuscular fat, both commonly associated with obesity, are strongly linked to insulin resistance. Intracellular lipid or its byproducts may have direct effects to impede insulin signaling. Enlarged collections of adipose tissue, visceral or otherwise, is often infiltrated with macrophages and can become a site of chronic inflammation. Adipocytokines, secreted from adipocytes and immune cells, including TNF-, IL-6, resistin, and retinol-binding protein 4, can also cause systemic insulin resistance. Insulin resistance is even more severe in obese persons with type 2 diabetes who have further reductions of insulin-stimulated glucose uptake into skeletal muscle and relatively low rates of nonoxidative glucose metabolism (glycogen synthesis), and impaired suppression of hepatic glucose production and adipocyte lipolysis, despite insulin concentrations that are often elevated.