202-LB: Reduced Glucose Effectiveness Exacerbates Impaired Glucose Tolerance in Prediabetic Dogs Free

The prodromal prediabetic state is characterized by glucose intolerance. Both insulin-dependent (sensitivity, secretion, clearance) and -independent factors (“glucose effectiveness”) contribute to glucose homeostasis. The relative importance of glucose effectiveness is not known. Healthy dogs (n=18) were tested at baseline (BL), after 6 wk on a high-fat diet (HFD), and 2 wk, after a sub-diabetogenic dose of streptozotocin (STZ, 18.5 mg/kg); HFD was continued. We performed intravenous glucose tolerance tests (IVGTTs)at 0, 6, and 8 wks. Minimal model analysis quantified insulin sensitivity (SI), acute insulin response to glucose (AIRg), disposition index (DI, = SI x AIRg), and glucose tolerance (KG). Glucose effectiveness (SG) was measured both by minimal model analysis and directly by multi-step hyperglycemic clamps at basal insulin in a subset of the dogs (n=5). Consumption of HFD induced 7.7±1.0% weight gain (P<0.001) and reduced SI (BL: 3.33±0.35; HFD: 2.01±0.38 x 10⁴ min^-1 per µU/ml; P=0.02). HFD elicited an increased AIRg (BL: 596±42; HFD: 1865±476 µU/ml, P=0.03) while maintaining KG (BL: 3.33±0.25; HFD: 3.67±0.33 min^-1, P=0.69) as well as β-cell function expressed as DI (BL: 1939±236; HFD: 1882±199, P=0.97). SG was not changed by fat feeding per se (P=0.88). Prediabetes (STZ) conserved fasting glucose, but KG deteriorated (-45% from HFD to STZ) due to sustained insulin resistance with compromised β-cell function (DI decreased by 45±8%, P<0.01). Additionally, minimal model-based SG declined 37±8% from HFD to STZ (0.044±0.003 vs. 0.027±0.003 min^-1, P<0.01), a result confirmed by glucose clamps (-30%). Impairments in both insulin-dependent and insulin-independent factors contribute to the glucose intolerance of experimental prediabetes. Rather than compensating for insulin resistance and beta-cell dysfunction, glucose effectiveness also declines, demonstrating that it exacerbates and contributes to glucose intolerance in the canine model of prediabetes.