1799-P: Lipotoxicity Impairs Central Regulation of Endogenous Glucose Production (EGP) in Type 2 Diabetes (T2D)

Brain signals are integral to maintaining normal glucose homeostasis. Activation of hypothalamic K_ATP channels with diazoxide (DZX) reduces EGP in nondiabetic rodents and humans, but not in T2D. High fatty acids levels, typical of T2D, can increase endoplasmic reticulum (ER) stress and thereby impair glucose sensing by hypothalamic neurons.

We thus hypothesized that lowering fatty acids with nicotinic acid (NA) could restore suppression of EGP by central K_ATP channels in T2D. We performed 4-h euglycemic 'pancreatic clamp' studies (somatostatin with replacement of basal insulin, glucagon and growth hormone) in n=15 T2D subjects (11M, 50±2 years, BMI=30±1 kg/m², HbA1c=9.7±0.5%) under 4 conditions: placebo (PL) vs. DZX (6 mg/kg, n=8) vs. DZX with 16-h NA infusion (DZX+NA; 0.01 mg/kg/min; n=5) vs. NA alone (n=7) (Figure 1a). DZX failed to suppress EGP; the response of EGP to DZX was restored by adding NA (Figure 1b). Confirming our hypothesis that diabetes impacts hypothalamic ER stress and K_ATP channels, several markers of ER stress were increased while expression of the Kir6.2 subunit of the K_ATP channel trended lower in hypothalamic wedges of Zucker Diabetic Fatty (ZDF) vs. nondiabetic rats (Figure 1c).

Hypothalamic ER stress and altered K_ATP channel expression may contribute to the loss of central regulation of EGP in T2D. Regulation of EGP may be normalized by reducing fatty acid levels, thus improving glycemic control.

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