Leptin as an adjunct of insulin therapy in insulin-deficient diabetes

Abstract

Aims/hypothesis. The purpose of this study was to assess the therapeutic implication of leptin in insulindeficient diabetes. Methods. Insulin-deficient diabetes was induced by streptozotocin (STZ) in transgenic skinny mice overexpressing leptin. Plasma concentrations of glucose, insulin, and leptin were measured. The effects on body weight, food intake, and hypothalamic gene expressions were analyzed. After diabetes was induced, graded doses of insulin ranging from 0.4 to 51.2 mU·g -1 ·day -1 were injected. Co-administration of leptin and insulin was also carried out using osmotic pumps. Results. After STZ injection, both transgenic and nontransgenic littermates developed marked hyperglycaemia as a result of severe hypoinsulinaemia [termed diabetic transgenic skinny mice overexpressing leptin (diabetic TGM) and diabetic non-transgenic littermates (diabetic WT) respectively], although diabetic TGM were more sensitive to exogenously administered insulin than diabetic WT. Diabetic WT were hypoleptinaemic and hyperphagic relative to non-diabetic WT, whereas diabetic TGM, which remained hyperleptinaemic, were less hyperphagic than diabetic WT. After STZ injection, hypothalamic expressions of orexigenic and anorexigenic peptide mRNAs were upregulated and down-regulated, respectively, in diabetic WT, whereas they were unchanged in diabetic TGM. Diabetic TGM became normoglycaemic, when treated with insulin at such doses that did not improve hyperglycaemia in diabetic WT. We found that a subthreshold dose of insulin that does not affect glucose homeostasis is effective in improving the diabetes in normal mice rendered diabetic by STZ injection, when combined with leptin. Conclusions/interpretation. This study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implication of leptin as an anti-diabetic agent. [Diabetologia (2003[Diabetologia ( ) 46:1329[Diabetologia ( -1337

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

“…Recently, we and others confirmed that leptin treatment effectively reduces food intake and improves hyperglycaemia, hypertriacylglycerolaemia and fatty liver in patients with lipoatrophic diabetes [13][14][15][16]. In addition, we demonstrated that leptin is useful as a glucose-lowering agent in a mouse model of insulin-deficient diabetes induced by high-dose streptozotocin (STZ) [11]. Leptin infusion reduced the dose of insulin required to improve hyperglycaemia by more than 90%, and prevented insulin-induced body weight gain in STZ-injected mice.…”

“…We previously generated transgenic skinny mice (LepTg) overexpressing leptin under the control of the liver-specific human serum amyloid P component promoter [6]. LepTg mice showed elevated plasma leptin levels comparable to those of obese human individuals, providing a unique experimental model to investigate various actions of leptin [6][7][8][9][10][11]. LepTg mice exhibited increased glucose metabolism and insulin sensitivity with augmented liver and skeletal muscle insulin receptor signalling [6].…”

“…The degree of beta cell destruction and insulin resistance can be adjusted by dosage, duration and condition of STZ injection and HFD feeding [11,24]. The effects of various glucose-lowering drugs (sulfonylurea, metformin, thiazolidinedione etc) have been examined in mice treated with low-dose STZ and HFD as a model of type 2 diabetes [22,23].…”

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.…”

“…De plus, la leptine restaurait également, dans ce modèle, la sensibilité hépatique et périphéri-que à l'insuline évaluée par le clamp Les animaux contrôles nourris de la même façon que ceux traités par la leptine perdaient du poids sans normaliser leur glycémie, montrant que la diminution de la prise alimentaire n'explique pas, à elle seule, l'effet de la leptine sur la normalisation glycémique chez les rongeurs insulinodéficients. En 2003, Miyanaga et al [16] ont montré, chez des souris rendues diabétiques après destruction des îlots bêta par la streptozotocine, que l'augmentation des concentrations circulantes de leptine, obtenue par transgenèse (surexpression du gène ob chez les « skinny mice ») ou par administration de leptine exogène par voie sous-cutanée, permettait de réduire significativement les besoins en insuline nécessaires à la normalisation des glycémies. Comme dans l'étude précédente, le rôle adjuvant de la leptine sur l'insulinothérapie n'était pas uniquement lié à son effet anorexigène, puisque l'hyperglycémie n'était pas diminuée par le contrôle identique 2 Le clamp euglycémique hyperinsulinémique consiste à perfuser de fortes doses d'insuline à débit constant tout en maintenant la normoglycémie grâce à une perfusion de glucose à débit variable.…”