Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Abstract

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m 2 ; female, 42 yr old, BMI 25.1 kg/m 2 ; female, 46 yr old, BMI 31.7 kg/m 2 ) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 Ϯ 3.27 vs. 8.16 Ϯ 2.77 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) ϭ 0.57 and P ϭ 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity. recombinant methionyl human leptin; euglycemic hyperinsulinemic clamp; homeostatic model assessment LEPTIN DEFICIENCY was the first described monogenic nonpleiotropic form of obesity. To date, 10 children (23,25,40,44,58) and three adults (46, 58) have been reported as leptin deficient in five families from Pakistan, one from Egypt, and one from Turkey. Leptin replacement decreases weight, fat mass, food intake, hyperinsulinemia, and serum lipid levels (22,23,25,46). We previously described a significant reduction in food intake (32-34, 61), resulting in substantial weight and fat loss, an increase in physical activity, and the resolution of hypogonadism and type 2 diabetes mellitus in leptin-treated adults (32). Moreover, leptin replacement altered the patients' brain structure and their response to food cues (2, 38).Although leptin and insulin have key metabolic roles, the interplay between both hormones is poorly understood. A majority of the studies suggest that leptin decreases insulin synthesis and secretion by pancreatic ␤-cells (9,12,29,54). It is speculated that the adipoinsular axis includes a leptinmediated inhibitory feedback loop on insulin secretion to decrease adipogenesi...

Leptin and insulin sensitivity: reply to Oral and Burant

“…(6), Elif A. Oral and Charles Burant discuss the findings of our paper recently published in AJP-Endocrinology and Metabolism, titled "Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients" (7). In that letter, they cite the DISCUSSION in our article and present data that support the hypothesis that the increase in insulin sensitivity, while off recombinant methionyl human leptin, can be attributed to the rapid expansion of the adipose tissue mass.…”

Changes in Satiety Hormones in Response to Leptin Treatment in a Patient with Leptin Deficiency

“…Leptin affects insulin sensitivity and might have fascillatory action on insulin secretion as in our subject during the early phase of leptin treatment sharp increases of insulin occurred in response to meals while at a later time point, insulin levels decreased. Although these seem like contradictory findings of leptin effects on insulin secretion and resistance, one needs to be aware that most of the interactions of leptin within the adipoinsular axis have been studied in vitro and in animal models [24]. Some animal studies showed that leptin increases insulin resistance [25, 26], other documented a decrease in insulin resistance [27, 28].…”

“…Indeed, our results are consistent with effects observed in clinical studies during which continued leptin replacement in leptin-deficient individuals was associated with reduced insulin levels. Similarly, the insulin-sensitizing effects of leptin replacement have been demonstrated in patients with lipodystrophy [24, 29, 30]. This suggests that relative hyperleptinemia during the early phase of leptin treatment may potentially contribute to increased insulin resistance [24] and plasma leptin may have an independent effect on insulin sensitivity which is not directly explained by adiposity or hyperinsulinemia [31].…”

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

“…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.…”

“…22,27,52 Similarly, lipoatrophy and leptin deficiency due to wasting inflicted by human immunodeficiency virus infection and treatment of human immunodeficiency virus-infected patients with antiretroviral treatment, are associated with insulin insensitivity and diabetes, both improved by daily leptin replacement. 25,52,[57][58][59] Importantly, these antidiabetic effects of daily leptin replacement manifesting independent of any discernible impact on appetite and weight, involved hypothalamic leptin responsive pathways because mice with conditional leptin receptor knockout in the hypothalamus were diabetic 60 and instillation of leptin receptors selectively in the hypothalamus repressed hyperinsulinemia in the diabetic, leptin receptor mutant rats. 61 Thus, both leptin deficit and leptinopenia-induced insufficient hypothalamic leptin signaling are associated with dysregulation of the glucose-insulin axis.…”