Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.

Abstract

Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

“…The direct effects of leptin on glucose metabolism and insulin signaling have not yet been fully elucidated. However, in vivo studies have shown that leptin improves insulin sensitivity (Ebihara et al, 2001;Lin et al, 2002;Ogawa et al, 1999;Yamauchi et al, 2001) and normalize glucose metabolism in rodents (Chinookoswong et al, 1999;Masuzaki et al, 1999). Transgenic expression of neuron-specific leptin receptor in receptor-deficient mice leads to amelioration of diabetes (de Luca et al, 2005).…”

La leptine, nouvelle perspective thérapeutique dans le traitement du diabète ?

“…Plusieurs études chez des rongeurs insulinodéficients ont suggéré que l'administration de leptine pourrait traiter le diabète ou améliorer l'effet de l'insuline [14][15][16][17]. La première étude, publiée en 1999 [15], a pris pour modèle des rats traités par la streptozotocine, et a montré que l'infusion sous-cutanée de leptine, en l'absence d'insulinothéra-pie, pouvait normaliser les glycémies.…”

“…La première étude, publiée en 1999 [15], a pris pour modèle des rats traités par la streptozotocine, et a montré que l'infusion sous-cutanée de leptine, en l'absence d'insulinothéra-pie, pouvait normaliser les glycémies. Ces résultats sont en faveur d'un rôle insulino-indépendant de la leptine sur le métabolisme glucidique, permettant à la fois de diminuer la production hépatique de glucose et d'augmenter son utilisation périphérique en l'absence d'insuline.…”

Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

“…2,8,10,15,23,33,34 In this context, recent attention has been devoted to the disclosure that dynamic physiological fluctuations in circulating titers of leptin, a hormone produced primarily by white adipose tissue under the direction of insulin, have a critical role in conferring glucose homeostasis indirectly through the central nervous system. 10,16,[35][36][37][38][39][40][41][42] The goals of this review are to collate major contributions emanating from research conducted with the aid of gene transfer technology in unraveling the neural etiology of this chronic disease of hyperglycemia, which is correctable by leptin gene therapy confined selectively to the hypothalamus, and that this neurotherapy can be gainfully employed to forestall the pathogenesis of diabetes and varied attendant comorbidities.…”