Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes.
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 twofold 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 (HbA(1c) = 10.1 +/- 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to approximately 500 micro mol/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 (HbA(1c) = 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.
Hawkins
Meredith
M
Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. hawkins@aecom.yu.edu
Tonelli
Julia
J
Kishore
Preeti
P
Stein
Daniel
D
Ragucci
Enzo
E
Gitig
Alon
A
Reddy
Kalpana
K
D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004655:Emulsions; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D009525:Niacin / Q000494:pharmacology; D012016:Reference Values; D013997:Time Factors
D015415:Biomarkers; D001786:Blood Glucose; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D006442:Glycated Hemoglobin; D009525:Niacin