Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy

Abstract

The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

FIG. 1.

Glucose (upper panel), insulin (middle panel), and glucagon (lower panel) concentrations observed in people who did not have diabetes, had mild type 2 diabetes or had severe type 2 diabetes. Fifty grams of glucose was ingested at time zero (1).

FIG. 2.

Simplified portrayal of glucose metabolism in the postabsorptive (upper panel) and postprandial (lower panel) states (9).

FIG. 3.

Rates of total body glucose appearance (upper panel), meal-derived glucose appearance (middle panel), and endogenous glucose production (lower panel) observed in people with or without type 2 diabetes. Fifty grams of glucose was ingested at time zero (10).

FIG. 4.

Rates of total body glucose disappearance and forearm glucose uptake observed in people with or without type 2 diabetes. Fifty grams of glucose was ingested at time zero (10).

FIG. 5.

Plasma glucose (upper panel) and insulin (lower panel) concentrations observed in people with or without type 2 diabetes. Infusions of glucose, insulin, somatostatin, glucagon, and growth hormone started at time zero (15).

FIG. 6.

Rates of endogenous glucose production (upper panel) and total body glucose disappearance (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (15). *P < 0.05 vs. no diabetes.

FIG. 7.

A schematic portrayal of the splanchnic catheterization method. HA, hepatic artery; HV, hepatic vein; PV, hepatic vein (16).

FIG. 8.

SGP. Rates of SGP observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.

FIG. 9.

Rates of SGU (upper panel) and leg glucose uptake (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.

FIG. 10.

Schematic portrayal of glucose metabolism in the blood, liver, and urine when labeled glucose and galactose are infused intravenously and acetaminophen is given by mouth in order to sample UDP-glucuronide in the urine (16). * and ** represent respectively labeled glucose and galactose.

FIG. 11.

The contribution of extracellular and intracellular glucose to the hepatic UDP-glucose pool when glucose is clamped at ∼145 mg/dl and insulin at ∼300 pmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.

FIG. 12.

Plasma glucose and insulin concentrations observed in people without diabetes, people with mild type 2 diabetes and people with severe type 2 diabetes. Infusions of glucose, insulin, somatostatin, glucagon, and growth hormone started at time zero (28).

FIG. 13.

Rates of endogenous glucose production observed in people who did not have diabetes, had mild diabetes, or had severe diabetes either before (basal) or during a hyperglycemic clamp (28). *P < 0.05 vs. no diabetes.

FIG. 14.

Rates of gluconeogenesis (upper panel) and glycogenolysis (lower panel) observed in people who did not have diabetes, had mild diabetes, or had severe diabetes either before (basal) or during a hyperglycemic clamp (28). *P < 0.05 vs. no diabetes.

FIG. 15.

Postprandial insulin profile. Plasma insulin concentrations observed in people with and without type 2 diabetes following ingestion of a meal at time zero (34).

FIG. 16.

Plasma insulin concentrations observed in lean nondiabetic subjects (upper panel), obese nondiabetic subjects (middle panel), and obese people with type 2 diabetes (lower panel) in the presence of either a nondiabetic or diabetic insulin profile. A prandial glucose infusion and infusions of somatostatin, insulin, glucagon, and growth hormone were started at time zero (34).

FIG. 17.

Glucose concentrations observed in lean nondiabetic subjects (upper panel), obese nondiabetic subjects (middle panel), and obese people with type 2 diabetes (lower panel) in the presence of either a nondiabetic or diabetic insulin profile. A prandial glucose infusion and infusions of somatostatin, insulin, glucagon, and growth hormone were started at time zero (34).

FIG. 18.

Glucose concentrations observed in lean nondiabetic subjects, obese nondiabetic subjects, and obese people with type 2 diabetes in the presence of either a nondiabetic insulin profile (upper panel) or diabetic insulin profile (lower panel). A prandial glucose infusion and infusions of somatostatin, glucagon, and growth hormone also were started at time zero (34).

FIG. 19.

Rates of glucose clearance observed in lean nondiabetic subjects, obese nondiabetic subjects, and obese people with type 2 diabetes in the presence of either a nondiabetic insulin profile (upper panel) or diabetic insulin profile (lower panel). A prandial glucose infusion and infusions of somatostatin, glucagon, and growth hormone also were started at time zero (34).

FIG. 20.

Rates of endogenous glucose production observed in lean nondiabetic subjects, obese nondiabetic subjects, and obese people with type 2 diabetes in the presence of either a nondiabetic insulin profile (upper panel) or diabetic insulin profile (lower panel). A prandial glucose infusion and infusions of somatostatin, insulin, glucagon, and growth hormone also were started at time zero (34).

FIG. 21.

Plasma insulin concentrations observed during nondiabetic (upper panel) or diabetic (lower panel) insulin profiles when glucagon concentrations were either maintained constant by glucagon infusion started at time zero (nonsuppressed study day) or permitted to decrease by delaying the glucagon infusion until 120 min. A prandial glucose infusion and infusions of somatostatin and growth hormone also were started at time zero (36).

FIG. 22.

Plasma glucagon concentrations observed during nondiabetic (upper panel) or diabetic (lower panel) insulin profiles when glucagon concentrations were either maintained constant by glucagon infusion started at time zero (nonsuppressed study day) or permitted to decrease by delaying the glucagon infusion until 120 min. A prandial glucose infusion and infusions of somatostatin and growth hormone also were started at time zero (36).

FIG. 23.

Plasma glucose concentrations observed during nondiabetic (upper panel) or diabetic (lower panel) insulin profiles when glucagon concentrations were either maintained constant by glucagon infusion started at time zero (nonsuppressed study day) or permitted to decrease by delaying the glucagon infusion until 120 min. A prandial glucose infusion and infusions of somatostatin and growth hormone also were started at time zero (36).

FIG. 24.

Schematic summary of alterations in glucose metabolism observed in people with type 2 diabetes. An arrow pointing up indicates an increase and an arrow pointing down indicates a decrease in flux.