Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells.
Hyperinsulinemia (HI) is elevated plasma insulin at basal glucose. Impaired glucose tolerance is associated with HI, although the exact cause and effect relationship remains poorly defined. We tested the hypothesis that HI can result from an intrinsic response of the β-cell to chronic exposure to excess nutrients, involving a shift in the concentration dependence of glucose-stimulated insulin secretion. INS-1 (832/13) cells were cultured in either a physiological (4 mm) or high (11 mm) glucose concentration with or without concomitant exposure to oleate. Isolated rat islets were also cultured with or without oleate. A clear hypersensitivity to submaximal glucose concentrations was evident in INS-1 cells cultured in excess nutrients such that the 25% of maximal (S0.25) glucose-stimulated insulin secretion was significantly reduced in cells cultured in 11 mm glucose (S0.25 = 3.5 mm) and 4 mm glucose with oleate (S0.25 = 4.5 mm) compared with 4 mm glucose alone (S0.25 = 5.7 mm). The magnitude of the left shift was linearly correlated with intracellular lipid stores in INS-1 cells (r(2) = 0.97). We observed no significant differences in the dose responses for glucose stimulation of respiration, NAD(P)H autofluorescence, or Ca(2+) responses between left- and right-shifted β-cells. However, a left shift in the sensitivity of exocytosis to Ca(2+) was documented in permeabilized INS-1 cells cultured in 11 versus 4 mm glucose (S0.25 = 1.1 and 1.7 μm, respectively). Our results suggest that the sensitivity of exocytosis to triggering is modulated by a lipid component, the levels of which are influenced by the culture nutrient environment.
From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
Karel A
KA
Erion
From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
Charles A
CA
Berdan
From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
Nathan E
NE
Burritt
From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.
Barbara E
BE
Corkey
From the Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118 jdeeney@bu.edu.
Jude T
JT
Deeney
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D005947:Glucose; D002118:Calcium
beta cell (β-cell); calcium imaging; hyperinsulinemia; insulin secretion; lipid; metabolism; type 2 diabetes