SUN-562 - Insulin Modulates Central Regulation of Glucose Production

Introduction and

Objective:
Central nervous system (CNS) regulation of endogenous glucose production (EGP) via ATP-sensitive potassium (KATP) channels contributes to maintaining glucose homeostasis. Previous studies in human subjects demonstrated that pharmacologic activation of central KATP channels with diazoxide (DZX) suppressed EGP in healthy individuals but this was attenuated in type 2 diabetes (1). Since insulin is a key upstream activator of brain KATP signaling, central KATP-mediated regulation of EGP may require adequate insulin concentrations (2).

Methods:
To determine the impact of insulin on central regulation of EGP in humans, we recruited highly insulin sensitive participants to undergo similar studies. Eleven healthy, insulin sensitive subjects without diabetes (n=11 male; age 47.9 ± 10.7 years; BMI 28.4 ± 3.4 kg/m²; HbA1c 5.3 ± 0.3%; HOMA-IR 1.23 ± 0.69) underwent 7-hour normoglycemic ‘pancreatic clamp’ studies in which endogenous insulin secretion was inhibited with somatostatin (250 ug/hr). Insulin infusion rates (IIR) were established for each individual as the minimal rates required to maintain normoglycemia (∼90 mg/dL). Glucagon (1 ng/kg/min) and growth hormone (3 ng/kg/min) were infused to maintain fasting glucoregulatory hormone conditions. Subjects received DZX (4 mg/kg orally) or taste-matched placebo (PLC) in a randomized, double-blind fashion.

Results:
Under these low insulin conditions, DZX did not significantly alter EGP compared with PLC (n=11, DZX: 1.57 ± 0.22 mg/kg/min vs. PLC: 1.59 ± 0.29 mg/kg/min, p = 0.85). The IIR that were required to maintain normoglycemia in these insulin sensitive subjects were substantially lower than in previous studies (n=11, DZX: 0.10 ± 0.07 mU/kg/min and PLC: 0.12 ± 0.08 mU/kg/min, p=0.56, as compared to ~0.25 mU/kg/min in previous studies [1]) and the insulin levels measured during the clamp studies (n=8, DZX: 7.4 ± 4.5 μU/mL vs. PLC: 9.2 ± 6.0 μU/mL, p=0.51) were ~56% lower than those measured in previous studies (~20 μU/mL) (1).

Conclusions:
In healthy human subjects studied under low insulin clamp conditions, there was no additional suppression of EGP with DZX. These findings suggest that effective CNS KATP-mediated regulation of EGP requires adequate insulin levels for optimal transcription and action of KATP channels. Differences in insulin infusion rates across experimental models may explain discrepant findings in some prior animal studies. In normal human physiology, activation of central KATP pathways under conditions of adequate insulinization (i.e., non-fasting conditions) is more likely to play a significant role in the regulation of glucose metabolism.

References:
1. Diabetes 65:2569, 2016
2. Diabetes 60(12):3132, 2011

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