Hepatic Insulin Resistance Increases Risk of Gallstone Disease in Indigenous Americans in the Southwestern United States.

INTRODUCTION

Animal models indicate that hepatic insulin resistance (IR) promotes cholesterol gallstone disease (GSD). We sought to determine whether hepatic and whole-body IR is associated with incident GSD.

METHODS

At baseline, 450 Southwestern Indigenous American adults without GSD were included. Participants had a 2-step hyperinsulinemic-euglycemic clamp with glucose tracer at submaximal and maximal insulin stimulation (240 and 2,400 pmol/m 2 /min) for whole-body IR (M-low and M-high) and hepatic glucose production (HGP) before and during submaximal insulin infusion (HGP-basal and HGP-insulin). Incident GSD was identified during follow-up visits conducted at ∼2-year intervals. The associations of HGP (basal, insulin, and % suppression), M-low, and M-high with risk of GSD were assessed by Cox regression models adjusted for age, sex, body fat (%), glucose, and insulin.

RESULTS

Sixty participants (13%) developed GSD (median follow-up: 11.6 years). Participants who developed GSD were of similar age and whole-body IR as those who did not ( P 's > 0.07) but were more likely to be female; have higher body fat, higher HGP-basal, and HGP-insulin; and lower % suppression of HGP ( P 's < 0.02). In separate adjusted models, higher HGP-insulin and lower % suppression of HGP were associated with increased risk for GSD (hazard ratio [HR] per SD: HR 1.38, 95% CI 1.12-1.69, P = 0.002; HR 1.41, 95% CI 1.16-1.72, P = 0.0007). HGP-basal, M-low, and M-high were not associated with GSD in adjusted models ( P 's > 0.22).

DISCUSSION: Resistance to insulin suppression of HGP increases risk for GSD. Hepatic IR is a link between GSD and other conditions of the metabolic syndrome.