Effect of Very Small Concentrations of Insulin on Forearm Metabolism. Persistence of Its Action on Potassium and Free Fatty Acids without Its Effect on Glucose*

Zierler, Kenneth L.; Rabinowitz, D.

doi:10.1172/jci104981

Cited by 309 publications

(81 citation statements)

References 21 publications

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“…Furthermore, we show for the first time that the re-esterification process is partly mediated via a PI 3-kinase dependent process. The antilipolytic effect of insulin is considered to be the most sensitive of its metabolic actions [32]. Our data support this notion.…”

Section: Discussionsupporting

confidence: 82%

Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway

et al. 1998

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The intracellular mechanism responsible for insulin receptor-mediated stimulation of glucose transport is partly understood [1±4]. In contrast, much less is known about the signalling pathways that couple the insulin receptor to lipid metabolism. In fat cells, insulin inhibits the mobilization of non-esterified fatty acids (NEFA) in two synergistic ways [5]. Firstly, insulin decreases the rate of lipolysis (i. e. activates antilipolysis). Secondly, insulin increases the rate of re-synthesis of triglycerides from the NEFA that are formed by lipolysis, i. e. the re-esterfication effect.Although the intracellular signalling cascade which regulates antilipolysis has not been studied to the same degree as glucose transport or mitogenesis, similar early steps in the insulin receptor signalling cascade are likely to be involved. The insulin receptor is activated by binding of insulin, which causes the receptor to undergo autophosphorylation on tyrosine residues [1±4]. Autophosphorylation activates the tyrosine kinase of the receptor and allows the receptor Diabetologia (1998) Summary Increased mobilization of non-esterified fatty acids (NEFA) from visceral as opposed to peripheral fat depots can lead to metabolic disturbances because of the direct portal link between visceral fat and the liver. Compared with peripheral fat, visceral fat shows a decreased response to insulin. The mechanisms behind these site variations were investigated by comparing insulin action on NEFA metabolism with insulin receptor signal transduction through the insulin receptor substrate-1 (IRS-1) pathway in omental (visceral) and subcutaneous human fat obtained during elective surgery. Insulin inhibited lipolysis and stimulated NEFA re-esterification. This was counteracted by wortmannin, an inhibitor of phosphaditylinositol (PI) 3-kinase. The effects of insulin on antilipolysis and NEFA re-esterification were greatly reduced in omental fat cells. Insulin receptor binding capacity, mRNA and protein expression did not differ between the cell types. Insulin was four times more effective in stimulating tyrosine phosporylation of the insulin receptor in subcutaneous fat cells (p < 0.001). Similarly, insulin was two to three times more effective in stimulating tyrosine phosphorylation of IRS-1 in subcutaneous fat cells (p < 0.01). This finding could be explained by finding that IRS-1 protein expression was reduced by 50 ± 8 % in omental fat cells (p < 0.01). In omental fat cells, maximum insulin-stimulated association of the p85 kDa subunit of PI 3-kinase to phosphotyrosine proteins and phosphotyrosine associated PI 3-kinase activity were both reduced by 50 % (p < 0.05 or better). Thus, the ability of insulin to induce antilipolysis and stimulate NEFA re-esterification is reduced in visceral adipocytes. This reduction can be explained by reduced insulin receptor autophosphorylation and signal transduction through an IRS-1 associated PI 3-kinase pathway in visceral adipocytes. [Diabetologia (1998 Keywords Tyrosine kinase, insulin receptor substrate...

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Section: Discussionsupporting

confidence: 82%

Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway

et al. 1998

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“…Potassium and sodium movement in the isolated diaphragm in response to insulin occurs in the absence of glucose (27). There is temporal separation of potassium and glucose uptake (28,29), and insulin stimulates potassium uptake in doses at which there is no appreciable glucose flux (30). Rats fed a high-fat diet developed slower uptake of glucose and potassium, creating an apparent view of concordant regulation (31).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin stimulates potassium cellular uptake by elevation and increased sensitivity to intracellular sodium, translocation and activation Na ϩ /K ϩ -ATPase, and inhibition of potassium efflux (30,(37)(38)(39)(40)(41)(42)(43). The mechanism of insulin-stimulated phosphate uptake is unknown.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Insulin Action on Glucose versus Potassium Uptake in Humans

Nguyen¹,

Maalouf²,

Sakhaee³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Insulin has several physiologic actions that include stimulation of cellular glucose and potassium uptake. The ability of insulin to induce glucose uptake by cells is impaired in type 2 diabetes mellitus, but whether potassium uptake is similarly impaired is not known. This study examines whether the cellular uptake of these molecules is regulated in concert or independently.Design, setting, participants, & measurements Thirty-two nondiabetic and 13 type 2 diabetic subjects with normal GFR were given a similar, constant metabolic diet for 8 days. On day 9, they were subjected to a hyperinsulinemic euglycemic clamp for 2 hours. Serum and urinary chemistry were obtained before and during the clamp. Glucose disposal rate was calculated from glucose infusion rate during hyperinsulinemic euglycemia. Intracellular potassium and phosphate uptake were calculated by the reduction of extracellular potassium or phosphate content corrected for urinary excretion.Results Although glucose disposal rate tended to be lower in type 2 diabetics, cellular potassium uptake was similar between diabetics and nondiabetics. Additionally, although glucose disposal rate was lower with increasing body mass index (R 2 ϭ 0.362), cellular potassium (R 2 ϭ 0.052), and phosphate (R 2 ϭ 0.002), uptake rates did not correlate with body mass index. There was also no correlation between glucose disposal rate and potassium (R 2 ϭ 0.016) or phosphate uptake (R 2 ϭ 0.053).Conclusions Insulin-stimulated intracellular uptake of glucose and potassium are independent of each other. In type 2 diabetes, potassium uptake is preserved despite impaired glucose disposal.

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“…Thus following the rapid intravenous injection of glucose in normal dogs, there is a small rise, if any, in leg lymph insulin [17]. Moreover in the human forearm preparation [2, 21,22] or in the perfused rat adipose tissue [18], a transient and physiological rise in arterial serum insulin does not increase the cell glucose uptake. In some of these experiments, the arterial and venous concentrations of serum insulin were measured, and insulin was cleared by the perfused tissues.…”

Section: Discussionmentioning

confidence: 99%

The displacement of insulin from blood capillaries

Rasio¹

1969

Diabetologia

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Summary. Normal anaesthetized bull-dogs were perfused with constant amounts of 125I bovine insulin. During the control period, steady state arterio-venous gradients and lymph levels were achieved. Positive arterio-venous differences were observed across the bind limbs and the head. Lower levels of 12aI-insulin were found in cervical and leg lymph than in corresponding venous plasma. The rapid intravascular injection of unlabelled insulin resulted in an almost immediate reversal of the arterio-venous gradients of x~sI-insulin in the head and the hind limb. The injection of small amounts of glucose into the lower abdominal aorta induced a very rapid diminution of the arterio-venous gradient across the hind quarters ; the effect was not mediated by the release of endogenous insulin. In both experiments, the lymph levels of 12sT-insulin remained relatively constant.The data indicate that the vascular pole of the capillary endothelial cells can adsorb labelled insulin and either exchange it with unlabelled insulin or release it under the direct influence of glucose.

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Effect of Very Small Concentrations of Insulin on Forearm Metabolism. Persistence of Its Action on Potassium and Free Fatty Acids without Its Effect on Glucose*

Cited by 309 publications

References 21 publications

Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway

Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway

Comparison of Insulin Action on Glucose versus Potassium Uptake in Humans

The displacement of insulin from blood capillaries

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