Resistance to Adenovirally Induced Hyperleptinemia in Rats

Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the effect of adenovirally induced hyperleptinemia on food intake, body weight, and islet fat content in ventromedial hypothalamic-lesioned (VMHL) rats, shamlesioned (SL) controls, and Zucker Diabetic Fatty (ZDF) rats in which the leptin receptor is mutated. Infusion with recombinant adenovirus containing the rat leptin cDNA increased plasma leptin by z 20 ng/ml in VMHL and ZDF rats but had no effect on their food intake, body weight, or fat tissue weight. Caloric matching of hyperphagic VMHL rats to SL controls did not reduce their resistance to hyperleptinemia. Whereas prediabetic ZDF rats had a fourfold elevation in islet fat, in VMHL rats islet fat was normal and none of them became diabetic. Isolated islets from ZDF rats were completely resistant to the lipopenic action of leptin, while VMHL islets exhibited 50% of the normal response; caloric matching of VMHL rats to SL controls increased leptin responsiveness of their islets to 92% of controls. We conclude that leptin regulation of adipocyte fat requires an intact VMH but that islet fat content is regulated independently of the VMH. ( J. Clin. Invest. 1998. 102:728–733.

Resistance to Adenovirally Induced Hyperleptinemia in Rats

Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the effect of adenovirally induced hyperleptinemia on food intake, body weight, and islet fat content in ventromedial hypothalamic-lesioned (VMHL) rats, shamlesioned (SL) controls, and Zucker Diabetic Fatty (ZDF) rats in which the leptin receptor is mutated. Infusion with recombinant adenovirus containing the rat leptin cDNA increased plasma leptin by z 20 ng/ml in VMHL and ZDF rats but had no effect on their food intake, body weight, or fat tissue weight. Caloric matching of hyperphagic VMHL rats to SL controls did not reduce their resistance to hyperleptinemia. Whereas prediabetic ZDF rats had a fourfold elevation in islet fat, in VMHL rats islet fat was normal and none of them became diabetic. Isolated islets from ZDF rats were completely resistant to the lipopenic action of leptin, while VMHL islets exhibited 50% of the normal response; caloric matching of VMHL rats to SL controls increased leptin responsiveness of their islets to 92% of controls. We conclude that leptin regulation of adipocyte fat requires an intact VMH but that islet fat content is regulated independently of the VMH. ( J. Clin. Invest. 1998. 102:728–733.

Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable glycemia for lifetime

Comparison of the effect of intravenous dexmedetomidine and lignocaine spray instilled into the endotracheal tube on extubation response in patients undergoing spine surgery

Background: In spine surgery rapid emergence and extubation with haemodynamic stability is crucial for early neurological examination. Here, we have studied the effect of α2 agonist – dexmedetomidine intravenous (IV) and lignocaine spray instilled into the endotracheal tube at the end of the procedure to attenuate the extubation responses. Methods: A total of 45 patients undergoing spine surgery were randomly allocated in three groups. After the return of spontaneous respiration, Group-D: Dexmedetomidine 0.3 mcg/kg IV, Group-L: 10% lignocaine spray 1.5 mg/kg through endotracheal route and Group-P: Normal saline IV given over 60 s. Haemodynamic responses (systolic blood pressure, diastolic blood pressure, mean arterial pressure [MAP], heart rate [HR] and SpO2) were recorded before and after administration of drugs and also duration of emergence, extubation, quality of extubation and post-operative sedation level were evaluated. Results: The increase in MAP and HR during extubation was significantly less in Group-D than Group-L and Group-P, 2 min after administration of the respective drugs (P < 0.05). There were no significant differences in the grade of a cough after extubation and post-operative sedation level. Conclusion: Dexmedetomidine (0.3 mcg/kg) attenuates haemodynamic response better than lignocaine spray (1.5 mg/kg) during emergence and extubation. It also provides smooth extubation and easy recovery without any post-operative sedative effect