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		Literature Compendium

Current Concepts in Type 2 Diabetes

Volume 1
Overview of Type 2 Diabetes Pathogenesis, Complications, Risk Reduction, and Lifestyle Intervention

Chapter 1
Type 2 Diabetes: The Principles of Its Pathogenesis and Progression

Fasting plasma glucose (FPG) concentration is tightly controlled within a narrow range. In people with Type 2 diabetes, both insulin secretion and insulin action are impaired, and chronic hyperglycaemia is a characteristic feature. The 3 reports included in this chapter highlight the physiological mechanisms that maintain glucose homeostasis in the post-absorptive state; discuss the metabolic derangements that lead to impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and Type 2 diabetes; and provide the therapeutic rationale for both fasting and postprandial glycaemic control in the prevention and management of Type 2 diabetes.

In their review, Abdul-Ghani and colleagues¹ discuss the epidemiology and metabolic characterization of IGT and IFG—the 2 metabolic states that define pre-diabetes—and provide a therapeutic rationale based on an understanding of the differences between IFG and IGT in the site and pattern of insulin resistance.

Insulin resistance and impaired β-cell function—the primary physiological defects in Type 2 diabetes—can be detected both in persons with IGT and in those with IFG. However, numerous clinical investigations suggest that the site of insulin resistance varies between the 2 disorders. In persons with IGT, there is typically marked insulin resistance in muscle and mild insulin resistance in the liver, whereas persons with IFG typically have normal or near-normal insulin sensitivity in muscle and marked insulin resistance in the liver. The pattern of impaired insulin secretion also differs between persons with IGT and those with IFG. Early-phase insulin secretion is reduced in both states, whereas late-phase insulin secretion is impaired only in IGT. Based on the differences between IGT and IFG with regard to the site and pattern of insulin resistance, it is possible to predict which individuals might benefit from particular agents.

Ceriello and colleagues² provide a brief review of recent evidence suggesting that postprandial plasma glucose (PPG) concentration may be as important as FPG concentration and HbA_1c level as indicators for disease management in individuals with Type 2 diabetes. The authors cite 2 studies—a classic landmark study and a recent trial—that support the relationship between postprandial glucose regulation and improved outcome in individuals with diabetes. The results of these studies confirm that PPG is an independent risk factor for cardiovascular disease in individuals with Type 2 diabetes in the clinical setting. Numerous intervention trials have also shown that treating postprandial hyperglycaemia may reduce the incidence of new cardiovascular events. The authors provide a convincing case for adding control of postprandial hyperglycaemia to maintenance of FPG and HbA_1c within target ranges as a primary therapeutic strategy in the management of Type 2 diabetes.

Woerle and colleagues³ performed a prospective intervention trial to determine the relative importance of controlling FPG and PPG in achieving overall glycaemic control. A total of 164 individuals (mean age, 62.4 years) with baseline HbA_1c ≥7.5% were enrolled in the trial and given an intensified treatment regimen aimed at achieving an FPG concentration of <100 mg/dl. HbA_1c was assessed 3 months after initial therapy modification. At study end, HbA_1c, FPG, PPG, and daylong hyperglycaemia (defined as the average of pre-meal, postprandial, and bedtime plasma glucose concentration, excluding FPG) decreased significantly from baseline levels. The decrease in PPG was the primary determinant of HbA_1c. This important trial provides evidence that control of fasting hyperglycaemia alone may be insufficient to achieve target HbA_1c levels in individuals with suboptimal glycaemic control and that control of postprandial hyperglycaemia is an essential component of management.

References 

1. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130-1139.

2. Ceriello A, Davidson J, Hanefeld M, et al, for the International Prandial Glucose Regulation (PGR) Study Group. Postprandial hyperglycaemia and cardiovascular complications of diabetes: an update. Nutr Metab Cardiovasc Dis. 2006;16:453-456.

3. Woerle HJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes: importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract. 2007;77:280-285.

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The Literature Compendium is funded by an educational grant from Pfizer Inc.

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