Sulfonylurea Drugs: Mechanism of Antidiabetic Action and Therapeutic Usefulness

Lebovitz, Harold E.; Feinglos, Mark N.

doi:10.2337/diacare.1.3.189

Cited by 92 publications

(35 citation statements)

References 23 publications

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“…Although these compounds can acutely stimulate insulin release if administered orally or intravenously, when given orally for a period of several months an improvement in glucose tolerance is often observed in the absence of any demonstrable increase in plasma insulin levels (6)(7)(8). This phenomenon is commonly referred to as the "extrapancreatic effect of the sulfonylureas" (6)(7)(8).…”

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Direct in vitro effect of a sulfonylurea to increase human fibroblast insulin receptors.

Prince¹,

Olefsky²

1980

J. Clin. Invest.

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A B S T R A C T We have studied the effects of the oral sulfonylurea agent glyburide to modulate insulin receptors on nontransformed human fibroblasts in tissue culture. When glyburide was added to monolayers of human fibroblasts, a dose-dependent increase in the number of cell surface receptors was observed with a maximum effect (19% increase) seen at 1 ,ug/ml glyburide. Insulin can induce a loss ofinsulin receptors in these cells, and when fibroblasts are exposed to 100 ng/ml insulin for 6 h, -60% of the initial complement of cell surface receptors are lost. When the process of insulin-induced receptor loss (or down regulation) was studied in the presence of glyburide, the drug exerted a marked inhibitory effect on this regulatory process. Thus, glyburide inhibited insulininduced receptor loss in a dose-dependent fashion, and the maximally effective drug concentration (1 ,ig/ml) inhibited 34% of the receptor loss. These studies demonstrate a direct in vitro effect of this oral hypoglycemic agent to increase the number of cell surface insulin receptors or prevent their loss, presumably by slowing the rate of receptor internalization. These findings may explain the well known extrapancreatic effect of sulfonylurea agents to improve insulinmediated tissue glucose metabolism. INTRODUCTION Insulin resistance is a widely described characteristic feature of adult onset, nonketotic, or type II diabetes mellitus (1), and this decrease in insulin effectiveness plays an important role in maintaining the hyperglycemic state. Insulin binding to receptors has been studied in this condition and several groups have reported that insulin receptors are decreased in type II diabetic patients (2-5). In subjects with chemical diabetes (3) there is a significant relationship between decreased insulin receptors and in vivo insulin resistance; however, this relationship is less clear in patients

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confidence: 99%

Direct in vitro effect of a sulfonylurea to increase human fibroblast insulin receptors.

Prince¹,

Olefsky²

1980

J. Clin. Invest.

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“…In diabetic patients not previously exposed to a sulphonylurea glibenclamide given 30 min before breakfast showed a (Jackson & Bressler, 1981). Lebovitz & Feinglos (1978) have suggested that amongst important extra-pancreatic actions of the drug there is induction of insulin receptors in the peripheral tissues. The net effect of its action will therefore depend on a balance between insulin production and enhanced peripheral action, and so the timing of the insulin peak in relation to food would still be important in the control of postprandial hyperglycaemia.…”

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confidence: 99%

Improved effect of tolbutamide when given before food in patients on long‐term therapy [letter]

Samanta¹,

Jones²,

Burden³

et al. 1984

Brit J Clinical Pharma

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“…Long term therapy may actually produce a decline in glucose stimulated insulin release, in spite of improved glucose tolerance (Jackson & Bressler, 1981). Lebovitz & Feinglos (1978) have suggested that amongst important extra-pancreatic actions of the drug there is induction of insulin receptors in the peripheral tissues. The net effect of its action will therefore depend on a balance between insulin production and enhanced peripheral action, and so the timing of the insulin peak in relation to food would still be important in the control of postprandial hyperglycaemia.…”

mentioning

confidence: 99%