Pathogenesis of prediabetes: role of the liver in isolated fasting hyperglycemia and combined fasting and postprandial hyperglycemia

Abstract

Context: People with prediabetes are at high risk of developing diabetes.

Objective: The objective of this study was to determine the pathogenesis of fasting and postprandial hyperglycemia in prediabetes.

Design: Glucose production, gluconeogenesis, glycogenolysis, and glucose disappearance were measured before and during a hyperinsulinemic clamp using [6,6-(2)H2]glucose and the deuterated water method corrected for transaldolase exchange.

Setting: The study was conducted at the Mayo Clinic Clinical Research Unit.

Participants: Subjects with impaired fasting glucose (IFG)/normal glucose tolerance (NGT) (n = 14), IFG/impaired glucose tolerance (IGT) (n = 18), and normal fasting glucose (NFG)/NGT (n = 16) were studied.

Intervention: A hyperinsulinemic clamp was used.

Outcome measures: Glucose production, glucose disappearance, gluconeogenesis, and glycogenolysis were measured.

Results: Fasting glucose production was higher (P < .0001) in subjects with IFG/NGT than in those with NFG/NGT because of increased rates of gluconeogenesis (P = .003). On the other hand, insulin-induced suppression of glucose production, gluconeogenesis, glycogenolysis, and stimulation of glucose disappearance all were normal. Although fasting glucose production also was increased (P = .0002) in subjects with IFG/IGT, insulin-induced suppression of glucose production, gluconeogenesis, and glycogenolysis and stimulation of glucose disappearance were impaired (P = .005).

Conclusions: Fasting hyperglycemia is due to excessive glucose production in people with either IFG/NGT or IFG/IGT. Both insulin action and postprandial glucose concentrations are normal in IFG/NGT but abnormal in IFG/IGT. This finding suggests that hepatic and extrahepatic insulin resistance causes or exacerbates postprandial glucose intolerance in IFG/IGT. Elevated gluconeogenesis in the fasting state in IFG/NGT and impaired insulin-induced suppression of both gluconeogenesis and glycogenolysis in IFG/IGT suggest that alteration in the regulation of these pathways occurs early in the evolution of type 2 diabetes.

Figure 1.

Plasma glucose, insulin, C-peptide, and glucagon concentrations observed before and during the clamp in the NFG/NGT (open diamonds), IFG/NGT (gray rectangles), and IFG/IGT (black triangles) subjects. An insulin infusion was started at time 0.

Figure 2.

Rates of glucose production and glucose disappearance observed in the subjects with NFG/NGT (white bars), IFG/NGT (gray bars), and IFG/IGT (black bars) before (basal) and during the insulin infusion (clamp). *P < .05; †P < .0001 vs NFG/NGT.

Figure 3.

Rates of gluconeogenesis and glycogenolysis observed in the subjects with NFG/NGT (white bars), IFG/NGT (gray bars), and IFG/IGT (black bars) before (basal) and during the insulin infusion (clamp). *P < .05; †P < .0001 vs NFG/NGT.