Time-dependent effects of free fatty acids on glucose effectiveness in type 2 diabetes.
Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.
Kishore
Preeti
P
Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. pkishore@aecom.yu.edu
Tonelli
Julia
J
Koppaka
Sudha
S
Fratila
Corina
C
Bose
Anita
A
Lee
Do-Eun
DE
Reddy
Kalpana
K
Hawkins
Meredith
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism* / Q000502:physiology; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008875:Middle Aged; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D009525:Niacin; D012965:Sodium Chloride; D005990:Glycerol