Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog

Abstract

Objective: Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions.

Methods: Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP ) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively).

Results: SICLAMP was highly variable (5.9-75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight-fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT.

Conclusions: These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.

Figure 1. Variability in adiposity and body weight in normal dogs

(A) dogs ranked by total adiposity (height of stacked bars), with respective visceral (solid) and subcutaneous (hatched) fat mass. (B) Body weight for dogs ranked by total fat. Note that variability of total and subcutaneous fat greatly exceeds that of body weight.

Figure 2. Correlation between clamp-based insulin sensitivity and fasting insulin under baseline conditions

Fasting insulin was inversely correlated with SI_CLAMP, which confirms that insulinemia may well contribute to the prevailing degree of insulin sensitivity, even in the absence of dietary or pharmacologic perturbation.

Figure 3. Strong correlation between insulin sensitivity and metabolic clearance rate of insulin using indices derived from (A) euglycemic hyperinsulinemic clamp and (B) IVGTT

Regardless of experimental methodology, a lower degree of insulin sensitivity was associated with low insulin clearance, which contributes to the hyperinsulinemia required as compensation for insulin resistance.