Acute Hypoglycemia in Healthy Humans Impairs Insulin-Stimulated Glucose Uptake and Glycogen Synthase in Skeletal Muscle: A Randomized Clinical Study

Diabetes. 2017 Sep;66(9):2483-2494. doi: 10.2337/db16-1559. Epub 2017 Jun 8.

Abstract

Hypoglycemia is the leading limiting factor in glycemic management of insulin-treated diabetes. Skeletal muscle is the predominant site of insulin-mediated glucose disposal. Our study used a crossover design to test to what extent insulin-induced hypoglycemia affects glucose uptake in skeletal muscle and whether hypoglycemia counterregulation modulates insulin and catecholamine signaling and glycogen synthase activity in skeletal muscle. Nine healthy volunteers were examined on three randomized study days: 1) hyperinsulinemic hypoglycemia (bolus insulin), 2) hyperinsulinemic euglycemia (bolus insulin and glucose infusion), and 3) saline control with skeletal muscle biopsies taken just before, 30 min after, and 75 min after insulin/saline injection. During hypoglycemia, glucose levels reached a nadir of ∼2.0 mmol/L, and epinephrine rose to ∼900 pg/mL. Hypoglycemia impaired insulin-stimulated glucose disposal and glucose clearance in skeletal muscle, whereas insulin signaling in glucose transport was unaffected by hypoglycemia. Insulin-stimulated glycogen synthase activity was completely ablated during hyperinsulinemic hypoglycemia, and catecholamine signaling via cAMP-dependent protein kinase and phosphorylation of inhibiting sites on glycogen synthase all increased.

Trial registration: ClinicalTrials.gov NCT01919788.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Cross-Over Studies
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Glycogen Synthase / genetics
  • Glycogen Synthase / metabolism*
  • Humans
  • Hypoglycemia / etiology
  • Hypoglycemia / metabolism*
  • Insulin / adverse effects*
  • Male
  • Muscle, Skeletal / enzymology*
  • Phosphorylation
  • Young Adult

Substances

  • Glucose Transporter Type 4
  • Insulin
  • SLC2A4 protein, human
  • Glycogen Synthase
  • Glucose

Associated data

  • ClinicalTrials.gov/NCT01919788