Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes.
Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (approximately 1,500-4,000 micromol/l). However, plasma FFA levels >1,000 micromol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (approximately 600-800 micromol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA approximately 1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.
Kashyap
Sangeeta R
SR
Diabetes Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Belfort
Renata
R
Berria
Rachele
R
Suraamornkul
Swangjit
S
Pratipranawatr
Thongchai
T
Finlayson
Jean
J
Barrentine
Andrea
A
Bajaj
Mandeep
M
Mandarino
Lawrence
L
DeFronzo
Ralph
R
Cusi
Kenneth
K
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D006728:Hormones / Q000097:blood; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D006728:Hormones; D007328:Insulin