Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance.

CONTEXT: Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. OBJECTIVE: To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. METHODS: Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. RESULTS: Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone-binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. CONCLUSION: SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.

Effects of Metreleptin on Proteinuria in Patients With Lipodystrophy.

CONTEXT: Patients with lipodystrophy have high prevalence of proteinuria. OBJECTIVE: To assess kidney disease in patients with generalized (GLD) vs partial lipodystrophy (PLD), and the effects of metreleptin on proteinuria in patients with lipodystrophy. DESIGN, SETTING, PATIENTS, INTERVENTION: Prospective, open-label studies of metreleptin treatment in patients with GLD and PLD at the National Institutes of Health. OUTCOME MEASURES: The 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. RESULTS: At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared with patients with PLD. CrCl was above the normal range in 69% of patients with GLD and 39% with PLD (P = 0.02). With up to 24 months of metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during metreleptin treatment. CONCLUSIONS: Patients with GLD had significantly greater proteinuria than those with PLD, which improved with metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with metreleptin are not clear. Hyperfiltration was also more common in GLD vs PLD but did not change with metreleptin.

Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy.

PURPOSE: To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL). METHODS: Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs). RESULTS: Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea. CONCLUSIONS: In patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume.

Combined Immunosuppressive Therapy Induces Remission in Patients With Severe Type B Insulin Resistance: A Prospective Cohort Study.

OBJECTIVE: Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism, and a high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes. RESEARCH DESIGN AND METHODS: We performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, monitored for median 72 months (25th, 75th interquartile range 25, 88), and treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia. RESULTS: All data are given as median (25th, 75th interquartile range). Twenty-two patients aged 42 (25, 57) years, 86.4% women, fulfilled inclusion criteria. At baseline, fasting glucose was 307 (203, 398) mg/dL, HbA1c was 11.8% (9.7, 13.6), total testosterone (women) was 126 (57, 571) ng/dL (normal 8-60), and daily insulin requirement was 1,775 (863, 2,700) units. After 5 (4, 6.3) months, 86.4% (19 of 22) of patients achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 (76, 92) mg/dL, HbA1c of 5.5% (5.2, 6), and testosterone (women) of 28 (20, 47) ng/dL. During follow-up of 72 (25, 88) months, 13.6% (3 of 22) of patients developed disease recurrence, occurring 24 (22, 36) months after initial remission, which responded to repeated therapy. None of the patients died. CONCLUSIONS: Combined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes and, as such, should be recommended in patients with type B insulin resistance.

Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection.

PURPOSE: It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring. METHODS: A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l). RESULTS: Twelve patients (36%) developed hyperglycemia within 24 h (range 1-16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97-325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents. CONCLUSIONS: Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy.

BACKGROUND: Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy.

PURPOSE: The purpose of this study is to summarize the effectiveness and safety of metreleptin in patients with congenital or acquired generalized lipodystrophy. METHODS: Patients (n = 66) aged ≥6 months had lipodystrophy, low circulating leptin, and ≥1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10 mg/kg/day with a maximum of 0.24 mg/kg/day. Means and changes from baseline to month 12 were assessed for glycated hemoglobin (HbA1c), fasting triglycerides (TGs), and fasting plasma glucose (FPG). Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at months 4, 12, and 36, medication changes, and estimates of liver size. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Significant mean reductions from baseline were seen at month 12 for HbA1c (-2.2%, n = 59) and FPG (-3.0 mmol/L, n = 59) and mean percent change in fasting TGs (-32.1%, n = 57) (all p ≤ 0.001). Reductions from baseline over time in these parameters were also significant at month 36 (all p < 0.001, n = 14). At month 4, 34.8% of patients had a ≥1% reduction in HbA1c and 62.5% had a ≥30% reduction in fasting TGs; at month 12, 80% of patients had a ≥1% decrease in HbA1c or ≥30% decrease in TGs, and 66% had a decrease of ≥2% in HbA1c or ≥40% decrease in TGs. Of those on medications, 41%, 22%, and 24% discontinued insulin, oral antidiabetic medications, or lipid-lowering medications, respectively. Mean decrease in liver volume at month 12 was 33.8% (p < 0.001, n = 12). Most TEAEs were of mild/moderate severity. CONCLUSIONS: In patients with generalized lipodystrophy, long-term treatment with metreleptin was well tolerated and resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume.

Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy.

BACKGROUND: Reduced triglyceride clearance due to impaired lipoprotein lipase-mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. OBJECTIVE: To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. METHODS: Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of metreleptin therapy (16-32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. RESULTS: Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182-275] vs 174 ng/mL [160-189], P = .02) but not ANGPTL4 levels (55 [37-81] vs 44 ng/mL [37-52], P = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. After metreleptin, ANGPTL3 concentrations decreased significantly (223 [182-275] vs 175 ng/mL [144-214], P = .01) with no change in ANGPTL4 (55 [37-81] vs 48 ng/mL [32-73], P = .11). CONCLUSIONS: These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.

Effects of Metreleptin in Pediatric Patients With Lipodystrophy.

Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Objective: Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Design: Prospective, single-arm, open-label studies with continuous enrollment since 2000. Setting: National Institutes of Health, Bethesda, Maryland. Patients: Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia). Intervention: Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d). Main Outcome Measures: Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment. Results: After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty. Conclusion: Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Adipose-derived circulating miRNAs regulate gene expression in other tissues.

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

Type B Insulin Resistance Masquerading as Ovarian Hyperthecosis.

Context: Hyperinsulinemia can lead to pathologic ovarian growth and androgen production. Case Description: A 29-year-old woman developed an autoantibody to the insulin receptor (type B insulin resistance), causing extreme insulin resistance and hyperinsulinemia. Testosterone levels were elevated to the adult male range. Treatment with gonadotropin-releasing hormone (GnRH) analog led to normalization of testosterone, despite persistent extreme insulin resistance. Conclusions: This case demonstrates that gonadotropins are necessary for insulin to cause pathologic ovarian androgen production. Suppression of gonadotropins with GnRH analogs may be a useful therapeutic option in patients with severe hyperandrogenism or ovarian enlargement because of hyperinsulinemia.

Localization of Insulinoma Using 68Ga-DOTATATE PET/CT Scan.

Context: Reliable localization of insulinoma is critical for successful treatment. Objective: This study compared the accuracy of 68Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients: We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, 68Ga-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results: The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by 68Ga-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with 68Ga-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by 68Ga-DOTATATE in 1 out of 9 (11%). Conclusions: 68Ga-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned.

JCL roundtable: Diagnosis and clinical management of lipodystrophy.

Lipodystrophy comes in several forms, some involving the complete failure to develop adipose tissue and others with a partial absence in various bodily distributions. All appear to have a major genetic basis, and all involve a high frequency of lipoprotein disorders. High triglycerides and low high-density lipoprotein cholesterol are the usual findings that raise interesting questions as to how such abnormalities characteristic of obesity can be caused by genetic variants that produce a paucity of adiposity. We are learning to link some specific genetic variants that seem causal and to manage these disorders in more effective ways. We are joined by 3 experts who have been leaders in the study of the clinical presentation, genetics, abnormal physiology, and the management of lipodystrophy in recent years. They are Drs Abhimanyu Garg from the University of Texas Southwestern, Phillip Gorden of the National Institute of Diabetes, Digestive and Kidney Diseases, and Robert Shamburek of the National Heart, Lung and Blood Institute.

Insulinoma Due to Multiple Pancreatic Microadenoma Localized by Multimodal Imaging.

CONTEXT: Insulinomas are usually due to a solitary tumor, but they can be challenging to localize. CASE DESCRIPTION: A 66-year-old woman presented with a 1-year history of episodic neuroglycopenic hypoglycemia and was suspected of having an insulinoma. On a supervised fast, she was found to be hypoglycemic at 39 mg/dL, with an insulin of 40 µU/mL 26 hours into the fast and a proinsulin of 35 pmol/L. Contrast-enhanced computed tomography and magnetic resonance imaging did not localize a pancreatic lesion. Intra-arterial calcium stimulation testing showed a step-up of venous insulin levels at injection of the superior mesenteric artery and proximal and mid-splenic artery, and a 68Ga-DOTATATE positron emission tomography/computed tomography showed focal uptake in the neck of the pancreas with a standardized uptake value of 12. Despite negative intraoperative pancreatic palpation and ultrasound, the patient underwent an extended distal pancreatectomy with normalization of biochemical levels and resolution of her symptoms. Pathology showed four subcentimeter neuroendocrine tumors that were positive for insulin, consistent with a diagnosis of multiple microadenomas. CONCLUSIONS: Multiple microadenomas are a rare cause of hyperinsulinemic hypoglycemia and localization, and resection of these tumors may be facilitated by multimodal imaging.

Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy.

CONTEXT: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown. OBJECTIVE: The objective of the study was to test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII. DESIGN, SETTING, STUDY PARTICIPANTS, INTERVENTION, AND OUTCOME MEASURES: Using a post hoc cross-sectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n = 60) and age-, gender-, race-, and ethnicity-matched controls (n = 54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6­12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome. RESULTS: ApoCIII was higher in lipodystrophy patients (geometric mean [25th and 75th percentiles]) (23.9 mg/dL [14.6, 40.3]) compared with controls (14.9 mg/dL [12.3, 17.7]) (P < .0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R = 0.72, P < .0001) and healthy controls (R = 0.6, P < .0001). Leptin replacement (6­12 mo) did not significantly alter apoCIII (before leptin: 23.4 mg/dL [14.5, 40.1]; after leptin: 21.4 mg/dL [16.7, 28.3]; P = .34). CONCLUSIONS: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.

Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy.

OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014). PATIENTS: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS: Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS: Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients.

BACKGROUND: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. AIM: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. METHODS: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. RESULTS: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l-1 × min-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l-1 × 8 h-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. CONCLUSIONS: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreleptin.