Volume 1 number 1 Summer 2003
Special issue for the abstracts of the 7th Pan Arab Conference on Diabetes
PACD7 , 25 – 28 March 2003 Cairo

Abstract Number : 37
Pathogenesis of Type 2 Diabetes: Implications for Therapy

Robert Rizza, USA

People with type 2 diabetes have both fasting and Postprandial hyperglycemia. Multiple factors contribute to these abnormalities. In the fasting state, glucose production is excessive resulting in a progressive rise in glucose concentration, which, through mass action, increases glucose uptake. The rise in glucose concentration continues until production again equals uptake. Following food ingestion, glucose enters the systemic circulation having passed through the portal venous system. While the absolute rates of systemic meal glucose appearance do not differ in diabetic and non-diabetic humans, Postprandial hepatic glucose uptake is not appropriate for the degree of hyperglycemia. Furthermore, suppression of endogenous glucose production is delayed, resulting in excessive amounts of glucose entering the systemic circulation following food ingestion. While the absolute rates of glucose uptake by peripheral tissues are either normal or elevated in people with diabetes, they also are not appropriate for the prevailing glucose levels. 

Alterations in both insulin secretion and insulin action contribute to fasting and postprandial hyperglycemia. People with diabetes have both a decrease and a delay in insulin secretion. This results in a mismatch between the rate of appearance of the ingested glucose and the rate of rise in insulin. The delay in insulin secretion also contributes to delay suppression of glucose production. Insulin resistance becomes particularly important several hours after meal ingestion when an increase in glucose uptake in peripheral tissues is required to restore glucose concentrations to preprandial levels. Glucose effectiveness, defined as the ability that glucose suppresses own production and stimulate its own uptake is impaired in type 2 diabetes. Alterations in glucose effectiveness can account for a 30-50 mg/dL increment in the Postprandial glucose concentration. Finally, whereas glucagon promptly suppresses in non-diabetic humans after carbohydrate ingestion, it either does not suppress or paradoxically increases in people with diabetes. 

New and existing therapies are directed toward correcting these abnormalities. Insulin secretagogues such as sulfonylureas increase total insulin secretion. Shorter acting secretagogues such as repaglinide and nateglinide increase early postprandial insulin secretion. Incretins, incretin analogues, and inhibitors of incretin degradation such as GLP-1, exendin-4, and DPP IV increase insulin secretion, decrease glucagon secretion, and delay gastric emptying. Other analogues of islet peptides such as pramlintide also delay gastric emptying and inhibit glucagon secretion. Agents that improve insulin action such as thiazolidinediones increase both muscle and fat glucose uptake. On the other hand, biguanides such as metformin decrease hepatic glucose production. Used alone or in combination, these or newer therapeutic agents have the potential of normalizing fasting and Postprandial glucose concentrations in people with type 2 diabetes mellitus. 

References for Background Reading Material

1. Basu A, Alzaid A, Dinneen S, Caumo A, Cobelli C, Rizza RA: Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing ° of insulin resistance. J Clin Invest 97:2351-2361, 1996.

2. Dinneen S, Gerich J, Rizza RA: Carbohydrate metabolism in non-diabetic and diabetic humans: physiology and pathophysiology. N Engl J Med. 327:707-713, 1992. 

3. Basu A, Basu R, Shah P, Vella A, Johnson CM, Nair KS, Jensen MD, Schwenk WF, Rizza RA: Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. Diabetes 49:272-283, 2000.

4. Basu A, Caumo A, Bettini F, Gelisio A, Alzaid A, Cobelli C, RizzaRA: Impaired basal glucose effectiveness in NIDDM: contribution of defects in glucose disappearance and production, measured using an optimized minimal model independent protocol. Diabetes 46:421-432, 1997.

OnlineDiabetes Journal, All rights reserved