Kalra Satya P
Department of Neuroscience and McKnight Brain Institute, University of Florida, Florida, USA.
Indian J Endocrinol Metab. 2013 Oct;17(Suppl 1):S23-4. doi: 10.4103/2230-8210.119496.
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.
过去十年积累的证据证实，下丘脑脂肪细胞瘦素不足是1型和2型糖尿病发病机制及相关代谢疾病的主要病因。瘦素不足会破坏下丘脑调节信息沿三条下行通路传递至外周器官，这些外周器官通常在一生中每分钟都参与维持葡萄糖稳态。在1型和2型糖尿病的各种动物模型中，通过全身或中枢注射恢复下丘脑的瘦素充足，或借助基因治疗在下丘脑中选择性提供瘦素，在整个治疗过程中消除了高血糖并稳定地使血糖正常化。在后续的临床试验中，对于患有先天性脂肪营养不良或获得性脂肪萎缩的瘦素缺乏和胰岛素缺乏的1型糖尿病患者以及瘦素缺乏和高胰岛素血症的2型糖尿病患者，每天两次注射瘦素在延长的治疗过程中使血糖正常化，且没有任何明显的不良反应。综上所述，这些发现充分证实了瘦素治疗在恢复胰岛素缺乏以及高胰岛素血症糖尿病患者葡萄糖稳态方面的疗效。因此，通过瘦素恢复最佳下丘脑信号以恢复葡萄糖稳态是一种非常合适的新治疗策略，可在一生中改善1型和2型糖尿病，并取代目前流行的胰岛素单一疗法。鉴于全球糖尿病流行带来的持续挑战和不断飙升的治疗成本，再加上基于恢复胰岛素信号疗法的众所周知的缺点，开展新的临床试验以确定能够安全维持终身稳定血糖水平的瘦素向下丘脑递送的合适剂量和途径至关重要且迫在眉睫。
