Mechanism of Insulin Resistance Induced by Sustained Levels of Cytosolic Free Calcium in Rat Adipocytes*

In freshly isolated individual rat adipocytes, cytosolic free Ca2+ concentration ([Ca2+]i) as measured with fura 2 slowly declined during incubation but was sustained, or even somewhat increased, by brief treatment with growth hormone (GH) at the beginning of a 3-h incubation period. GH-treated adipocytes were more permeable to Ca2+ than GH-deprived cells as indicated, using Mn2- as a surrogate and monitoring influx by the rate of quenching of fura 2 fluorescence. Blockage of Ca2- channels with 100 nM nimodipine lowered [Ca2+]i in GH-treated cells to the level seen in GH-deprived cells. Increases in [Ca2+]i or the rate of Mn2+ entry were twofold greater in GH-treated than in GH-deprived cells when extracellular K+ was increased to 30 mM. Similarly, the Ca2+ channel agonist BAY K 5552 or the diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol increased [Ca2+]i more in GH-treated than in GH-deprived adipocytes. Ca(2+)-ATPase activity was two times higher in plasma membranes isolated from GH-treated than from GH-deprived cells. Continued synthesis of Ca(2+)-ATPase may depend on [Ca2+]i, since the effects of GH on [Ca2+]i and Ca(2+)-ATPase were blocked by a cycloheximide or verapamil. We suggest that voltage-sensitive L-type Ca2+ channels regulate steady-state [Ca2+]i in rat adipocytes and that GH maintains the number or functional integrity of these channels.

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The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)47805-2 ◽

1987 ◽

Vol 262 (30) ◽

pp. 14385-14388

Author(s):

B Draznin ◽

K Sussman ◽

M Kao ◽

D Lewis ◽

N Sherman

Keyword(s):

Glucose Transport ◽

Free Calcium ◽

Optimal Range ◽

Cytosolic Free Calcium ◽

Rat Adipocytes

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Cellular ions in hypertension, insulin resistance, obesity, and diabetes: a unifying theme.

Journal of the American Society of Nephrology ◽

10.1681/asn.v34s78 ◽

1992 ◽

Vol 3 (4) ◽

pp. S78

Author(s):

L M Resnick

Keyword(s):

Insulin Resistance ◽

Essential Hypertension ◽

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Left Ventricular ◽

Insulin Dependent Diabetes ◽

Free Calcium ◽

Cytosolic Free Calcium ◽

Insulin Dependent ◽

Free Magnesium

The clinical linkage of hypertensive cardiovascular disease, left ventricular hypertrophy, and accelerated atherosclerosis with a spectrum of metabolic disturbances including peripheral insulin resistance, hyperinsulinemia, obesity, and frank non-insulin dependent diabetes mellitus, has been increasingly appreciated. However, the underlying biologic basis mediating this clinical association remains unclear. Nuclear magnetic resonance techniques have been used to measure various intracellular ion species in human erythrocytes and have found that common, shared intracellular abnormalities of cytosolic free calcium, free magnesium, and pH occur in each of these clinical syndromes. Specifically, essential hypertension is characterized by higher fasting free cytosolic calcium concentrations and reciprocally lower intracellular free magnesium and pH levels compared with those of normotensive control subjects. Furthermore, for all subjects, free calcium and free magnesium levels were closely related both to the left ventricular mass and to the degree of insulin resistance present. Moreover, these same intracellular ionic lesions were found in normotensive obese and/or non-insulin diabetic individuals. Last, evidence has recently been provided that the cardiovascular consequences of increased dietary sugar and salt intake may well be determined by their concurrent influence on cellular ion metabolism. These data led to a hypothesis for a central role for altered cellular ion homeostasis in mediating the clinical linkage of cardiovascular and metabolic disease. According to this ionic hypothesis, essential hypertension, non-insulin dependent diabetes, and their frequently associated features of obesity, left ventricular hypertrophy, and accelerated atherosclerosis all derive from and reflect different clinical manifestations of the same underlying cellular lesion, characterized at least in part by elevated cytosolic free calcium and suppressed free magnesium levels.

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