Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants

Abstract

Context: Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear.

Objective: To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals.

Design: Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion.

Participants: Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study.

Main outcome measure: EGP.

Results: Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects.

Conclusion: Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Figure 1.

(A) Plasma insulin concentration and before and during the three insulin clamp steps performed before (baseline) and after 48 h of glucose infusion. (B) HGP during the three insulin clamp steps performed before and after 48 h of glucose infusion. (C) Basal hepatic insulin resistance index (basal HGP × fasting plasma insulin concentration) before (baseline) and after 48 h of glucose infusion.

Figure 2.

Insulin sensitivity (TGD/steady-state plasma insulin concentration) during the 40 mU/m²•min euglycemic insulin clamp performed before and after 48 h of glucose infusion. SSPI, steady-state plasma insulin.

Figure 3.

(A) Basal hepatic glucose production during the baseline study (black bars) and during the study performed after 48 h of glucose infusion (gray bars) in the FH+ and FH− participants. (B) Basal hepatic insulin resistance index (basal HGP × fasting plasma insulin concentration) before (black bars) and after 48 h of (gray bars) glucose infusion in the FH+ and FH− participants. dpm, disintegrations per minute; FPI, fasting plasma insulin.

Figure 4.

(A) Plasma glucagon concentration and (B) plasma FFA concentration before and after 48 h of glucose infusion.