Contribution of Elevated Free Fatty Acid Levels to the Lack of Glucose Effectiveness in Type 2 Diabetes

Meredith Hawkins, Julia Tonelli, Preeti Kishore, Daniel Stein, Enzo Ragucci, Alon Gitig, Kalpana Reddy

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate two-fold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA+) and without (NA-) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA1c = 10. 1 ± 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to -500 μmol/l blunted the ability of glucose to suppress endogenous glucose production (LIP- = -48% vs. LIP+ = -28%; P < 0.01) and increased glucose uptake (LIP- = 97% vs. LIP+ = 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA1c = 6.3 ± 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA- = -7% vs. NA+ = -41%; P < 0.001) and glucose uptake (NA- = 26% vs. NA+ = 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2748-2758
Number of pages11
JournalDiabetes
Volume52
Issue number11
DOIs
Publication statusPublished - Nov 1 2003

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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