Efficacy and Safety of Leptin-Replacement Therapy and Possible Mechanisms of Leptin Actions in Patients with Generalized Lipodystrophy

Ebihara, Ken; Kusakabe, Toru; Hirata, Masakazu; Masuzaki, Hiroaki; Miyanaga, Fumiko; Kobayashi, Nozomi; Tanaka, Tomohiro; Chusho, Hideki; Miyazawa, Takashi; Hayashi, Tatsuya; Hosoda, Kiminori; Ogawa, Yoshihiro; DePaoli, Alex M.; Fukushima, Masanori; Nakao, Kazuwa

doi:10.1210/jc.2006-1546

Cited by 218 publications

(176 citation statements)

References 39 publications

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“…1a), which can be seen in human obese individuals. In our clinical research on leptin-replacement therapy in patients with generalised lipodystrophy, the peak plasma leptin levels of the 400% dose under the protocol of once-daily injections was 34.5± 2.1 (mean±SE) ng/ml, and the therapy was well tolerated without any adverse effects for about 5 years [15]. In addition, higher leptin levels were obtained in the obese human clinical trial [33].…”

Section: Discussionmentioning

confidence: 81%

“…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].…”

Section: Introductionmentioning

confidence: 77%

“…The effectiveness of leptin treatment in diabetes has been reported in patients with leptin deficiency and lipodystrophy and in amenorrhoea in patients with hypothalamic hypogonadism caused by low body weight [5,[13][14][15][16]27]. These patients are in hypoleptinaemic states, and hypoleptinaemia is involved in the pathophysiology of their diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with type 2 diabetes often exhibit dyslipidaemia and an increase of triacylglycerol content in the liver and skeletal muscle [18,19]. Furthermore, in contrast to patients with lipoatrophic diabetes and insulin-deficient diabetes who are in hypoleptinaemic states [13][14][15][16]20], patients with type 2 diabetes often have increased adiposity and elevated leptin levels.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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Aims/hypothesisWe have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity. Methods To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 μg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight] −1 h −1 ) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined. Results Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of α2 AMPK activity in skeletal muscle. Pairfeeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction. Conclusions/interpretation This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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“…This is corroborated by recent clinical and animal investigations that excess as well as complete absence of fat in the body are concomitant with hyperinsulinemia, insulin insensitivity and diabetes. 7,[22][23][24][25][26][27][28] The discovery of insulin in 1922 and the subsequent development of insulin analogs have been the life-saving treatments of hyperglycemia and in delaying or preventing the array of chronic complications of diabetes mellitus. 2,13,[29][30][31] Diabetes, therefore, has traditionally been viewed as an affliction of either lack of or incomplete use of insulin and, consequently, conventional research has focused entirely on improving ways to deliver insulin for precision in attaining glycemic control to simulate the physiological range of blood glucose, necessary to combat the comorbidity cluster of this chronic malady.…”

Section: Introductionmentioning

confidence: 99%

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

Kalra

2011

Gene Ther

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The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

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Monogenic Causes of Diabetes

Misra

Hattersley

2016

Textbook of Diabetes

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Efficacy and Safety of Leptin-Replacement Therapy and Possible Mechanisms of Leptin Actions in Patients with Generalized Lipodystrophy

Abstract: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

Cited by 218 publications

References 39 publications

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

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

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

Monogenic Causes of Diabetes

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