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Alex M DePaoli

Publications and source records attributed to Alex M DePaoli.

18 recordsLinked to original sources
PubMed2006

Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.

BACKGROUND: Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy; however, the efficacy, safety, and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear. METHODS: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiological replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months. RESULTS: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P < 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P < 0.05) within 1 wk. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and microalbuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed antileptin antibodies but not neutralizing antibodies. The therapy was well tolerated, and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure, or reduction of bone mineral density. CONCLUSIONS: 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.

Adolescent↗
PubMed2005

Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy.

CONTEXT: We conducted this study to understand the role of leptin therapy in immunomodulation. OBJECTIVE: Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml). DESIGN AND SETTING: We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health. PATIENTS: Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied. INTERVENTION: Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months. RESULTS: Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline. CONCLUSION: These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.

Adolescent↗
PubMed2005

Recombinant osteoprotegerin for juvenile Paget's disease.

Juvenile Paget's disease, a genetic bone disease characterized by accelerated bone turnover, results from inactivating mutations in the gene encoding osteoprotegerin--a key regulator of osteoclastogenesis. The effects of recombinant osteoprotegerin were investigated in two adult siblings with juvenile Paget's disease. Bone resorption (assessed by N-telopeptide excretion) was suppressed by once-weekly subcutaneous doses of 0.3 to 0.4 mg per kilogram of body weight. After 15 months of treatment, radial bone mass increased in one patient by 9 percent and in the other by 30 percent, skeletal bisphosphonate retention decreased by 37 percent and 55 percent, respectively, and there was radiographic improvement. Apart from mild hypocalcemia and hypophosphatemia, no apparent adverse events occurred.

Adult↗
PubMed2005

Effect of leptin replacement on brain structure in genetically leptin-deficient adults.

The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.

Adult↗
PubMed2005

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

Adolescent↗
PubMed2004

Recombinant human leptin in women with hypothalamic amenorrhea.

BACKGROUND: Disruptions in hypothalamic-gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalamic amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea. METHODS: Eight women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean (+/-SD) of 8.5+/-8.1 months. RESULTS: Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of three months. Three patients had an ovulatory menstrual cycle (P<0.05 for the comparison with an expected rate of spontaneous ovulation of 10 percent); two others had preovulatory follicular development and withdrawal bleeding during treatment (P<0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corticotropin, or urinary N-telopeptide. CONCLUSIONS: Leptin administration for the relative leptin deficiency in women with hypothalamic amenorrhea appears to improve reproductive, thyroid, and growth hormone axes and markers of bone formation, suggesting that leptin, a peripheral signal reflecting the adequacy of energy stores, is required for normal reproductive and neuroendocrine function.

Adult↗
PubMed2004

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

Adult↗
PubMed2004

A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.

UNLABELLED: The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis. INTRODUCTION: RANKL is an essential osteoclastic differentiation and activation factor. MATERIALS AND METHODS: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers. RESULTS AND CONCLUSIONS: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of -81% in the 3.0 mg/kg AMG 162 group compared with -10% in the placebo group; serum NTX changes were -56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to approximately 3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.

Aged↗
PubMed2004

Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency.

To examine leptin's role in human appetite regulation, we studied recombinant methionyl human leptin's effects on satiation and satiety in a model of leptin insufficiency, lipodystrophy. Eight females with hypoleptinemia and lipodystrophy were given sc injections of A-100 (maximal dose, 200% of that predicted to normalize serum leptin) for 4 months. Satiation and satiety were determined before and again during leptin treatment. Satiation was measured as the time to voluntary cessation of eating from a standardized food array after a 12-h fast. Satiety was determined as the time to hunger sufficient to consume a full meal after consumption of a standardized preload. During leptin treatment, satiation time decreased (41.2 +/- 18.2 to 19.5 +/- 10.6 min; P = 0.01), satiety time increased (62.9 +/- 64.8 to 137.8 +/- 91.6 min; P = 0.04), energy consumed to produce satiation decreased (2034 +/- 405 to 1135 +/- 432 kcal or 8.5 +/- 1.7 to 4.7 +/- 1.8 MJ; P < 0.01), and the amount of food desired in the postabsorptive state decreased (P < 0.02). Ghrelin concentrations also decreased during leptin administration (284.3 +/- 127.9 to 140.6 +/- 104.5 pmol/liter; P < 0.002). We conclude that increased leptin in patients with lipodystrophy results in less caloric, shorter, more satiating meals and longer-lived satiety. These data support the hypothesis that leptin plays an important, permissive role in human appetite regulation.

Adolescent↗
PubMed2004

Leptin hormonal kinetics in the fed state: effects of adiposity, age, and gender on endogenous leptin production and clearance rates.

Leptin is an adipocyte-secreted hormone that regulates energy homeostasis and neuroendocrine function. Replacement therapy with recombinant methionyl human leptin (r-metHuLeptin) improves obesity, insulin resistance, hyperlipidemia, and neuroendocrine dysfunction associated with low-leptin states. We administered three doses of r-metHuLeptin (0.1, 0.3, and 1.0 mg/kg) to healthy subjects to determine r-metHuLeptin pharmacokinetics in the fed state, to determine endogenous leptin production and clearance rates, and to study the effects of age, body mass index, gender, and race on r-metHuLeptin pharmacokinetics. We detected no dose-dependent effects on elimination half-life (t(1/2)), dose-normalized area under the curve (nAUC(0- infinity)), total body clearance (CL), or volume of distribution at steady state. The mean t(1/2), CL, and volume of distribution at steady state of r-metHuLeptin are 3.4 +/- 1.5 h, 79 +/- 16 ml/kg.h, and 150 +/- 39 ml/kg, respectively. Older subjects have a higher nAUC(0- infinity) (P = 0.003) and tend to have a decreased leptin production rate (Rsyn) and CL (P = 0.01). Increased body mass index is associated with higher baseline endogenous leptin levels (P < 0.0001), higher Rsyn (P < 0.0001), and longer t(1/2) (P = 0.008). Females have significantly greater baseline endogenous leptin levels and Rsyn than males (P < 0.0001). In summary, the leptin production rate is increased in females and with increasing adiposity, whereas leptin clearance is decreased with increasing adiposity, and nAUC(0- infinity) is increased with age. Elucidation of leptin pharmacokinetic parameters allows the accurate calculation of exogenous leptin replacement doses for humans in the fed state.

Adipose Tissue↗
PubMed2004

Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy.

Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.

Adolescent↗
PubMed2004

Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy.

Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.

Body Composition↗
PubMed2003

The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.

To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone-IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity.

Adult↗
PubMed2003

Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy.

OBJECTIVE: To investigate whether leptin-induced improvements in glycemic control, hyperlipidemia, and insulin sensitivity in hypoleptinemic patients with generalized lipodystrophies are accompanied by reduction in intrahepatic and intramyocellular lipid (IMCL) accumulation. RESEARCH DESIGN AND METHODS: We examined the effects 8-10 months of subcutaneous leptin replacement therapy on insulin sensitivity, IMCL, and intrahepatic lipid content in two patients with acquired generalized lipodystrophy and one patient with congenital generalized lipodystrophy. All patients had extreme lack of body fat, low plasma leptin levels, and elevated serum triglycerides, but only two had diabetes. Insulin sensitivity was measured by a high-dose (0.2 IU/kg) insulin tolerance test, as well as by hyperinsulinemic-euglycemic glucose clamp studies in two patients. IMCL and intrahepatic lipid content were measured by (1)H magnetic resonance spectroscopy. All measurements were obtained before and during 2-10 months of leptin therapy. RESULTS: Glycemic control and lipoprotein levels markedly improved with leptin therapy in the two diabetic patients, and a slight improvement in lipoprotein levels was seen in the nondiabetic patients. Insulin stimulated glucose uptake during 60-120 min of the euglycemic clamp studies, and the rate of glucose disappearance during the insulin tolerance test nearly doubled with leptin therapy. As compared with the baseline period, after 8-10 months of leptin therapy, the mean intrahepatic lipid content was reduced by approximately 80% and the IMCL content was reduced by approximately 42%. CONCLUSIONS: Reduction in IMCL and intrahepatic lipid content may partly explain leptin-induced improvement in insulin sensitivity in patients with generalized lipodystrophy.

Adolescent↗
PubMed2002

Leptin-replacement therapy for lipodystrophy.

BACKGROUND: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. METHODS: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. RESULTS: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. CONCLUSIONS: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.

Adolescent↗
PubMed2002

Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Adult↗
PubMed2002

Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.

Animals↗