Effects of Metreleptin in Patients with Generalized Lipodystrophy Before vs After the Onset of Severe Metabolic Disease.

CONTEXT: Leptin replacement therapy with metreleptin improves metabolic abnormalities in patients with generalized lipodystrophy (GLD). OBJECTIVE: Determine how timing of metreleptin initiation in the clinical course of GLD affects long-term metabolic health. METHODS: Retrospective analysis of patients ≥ 6 months old with congenital (n=47) or acquired (n=16) GLD treated with metreleptin at the National Institutes of Health since 2001. Least squares means (LSM) for HbA1c, insulin area under the curve (AUC) from oral glucose tolerance tests, triglycerides, urine protein excretion, platelets, transaminases, and aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) for early and late treatment groups, defined by baseline metabolic health, were analyzed during median 72 (24, 108) months follow-up. RESULTS: Compared to late groups, early groups based on metabolic status had higher mean±SEM insulin AUC (20831±1 vs 11948±1), lower HbA1c (5.3±0.3 vs 6.8±0.3%), triglycerides (101±1 vs 193±1 mg/dL), urine protein excretion (85±1.5 vs 404±1.4 mg/24 hr), ALT (30±1 vs 53±1 U/L), AST (23±1 vs 40±1 U/L), and APRI (0.22±1.3 vs 0.78±1.3), and higher platelets (257±24 vs 152±28 K/µL) during follow-up (P<0.05). Compared to patients ≥6 years old at baseline, patients <6 years had lower HbA1c (4.5±0.5 vs 6.4±0.2%) and higher AST (40±1vs 23±1 U/L) during follow (P<0.05). CONCLUSION: Patients with GLD who initiated metreleptin before the onset of severe metabolic complications had better long-term control of diabetes, proteinuria, and hypertriglyceridemia. Early treatment may also result is less severe progression of liver fibrosis, but further histological studies are needed to determine the effects of metreleptin therapy on liver disease.

Insulin Signaling Through the Insulin Receptor Increases Linear Growth Through Effects on Bone and the GH-IGF-1 Axis.

CONTEXT: Childhood overnutrition is associated with increased growth and bone mineral density (BMD) vs the opposite for undernutrition. The role of insulin receptor (InsR) signaling in these phenotypes is unclear. Rare disease patients with hyperinsulinemia and impaired InsR function (homozygous [-/-] or heterozygous [+/-] INSR pathogenic variants, type B insulin resistance [TBIR]) model increased InsR signaling, while patients with intact InsR function (congenital generalized lipodystrophy, CGL) model decreased InsR signaling. OBJECTIVE: This work aimed to understand mechanisms whereby InsR signaling influences growth. METHODS: A cross-sectional comparison was conducted of CGL (N = 23), INSR-/- (N = 13), INSR+/- (N = 17), and TBIR (N = 8) at the National Institutes of Health. Main outcome measures included SD scores (SDS) for height, body mass index, insulin-like growth factor (IGF)-1, and BMD, and IGF binding proteins (IGFBP)-1 and -3. RESULTS: INSR-/- vs CGL had higher insulin (median 266 [222-457] vs 33 [15-55] mcU/mL), higher IGFBP-1 (72 350 [55 571-103 107] vs 6453 [1634-26 674] pg/mL), lower BMI SDS (-0.7 ± 1.1 vs 0.5 ± 0.9), lower height SDS (-1.9[-4.3 to -1.3] vs 1.1 [0.5-2.5]), lower BMD SDS (-1.9 ± 1.4 vs 1.9 ± 0.7), and lower IGFBP-3 (0.37 [0.19-1.05] vs 2.00 [1.45-2.67] µg/mL) (P < .05 for all). INSR +/- were variable. Remission of TBIR lowered insulin and IGFBP-1, and increased IGF-1 and IGFBP-3 (P < .05). CONCLUSION: Patients with hyperinsulinemia and impaired InsR function exhibit impaired growth and lower BMD, whereas elevated InsR signaling (CGL) causes accelerated growth and higher BMD. These patients demonstrate that insulin action through the InsR stimulates direct anabolic effects in bone and indirect actions through the growth hormone (GH)-IGF-1 axis. TBIR patients exhibit abnormalities in the GH axis that resolve when InsR signaling is restored, supporting a causal relationship between InsR and GH axis signaling.

Clinical Effects of Sodium-Glucose Transporter Type 2 Inhibitors in Patients With Partial Lipodystrophy.

OBJECTIVE: Severe insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy. METHODS: A retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment. RESULTS: The hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections. CONCLUSION: SGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.

Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function.

CONTEXT: Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. OBJECTIVE: This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. METHODS: We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate. RESULTS: Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1. CONCLUSION: Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.

Effects of metreleptin in patients with lipodystrophy with and without baseline concomitant medication use.

OBJECTIVE: To evaluate the effects of metreleptin in distinct subgroups of patients with generalized lipodystrophy (GL) and partial lipodystrophy (PL), using multivariate linear regression modeling to account for the role of patients' baseline usage of concomitant glucose and lipid-lowering medications and other covariates on their outcomes. MATERIALS AND METHODS: A post-hoc statistical analysis of two published single-arm, interventional, phase 2 clinical trials at NIH was conducted. Concomitant medication use was assessed for the clinical trial population using prescription fill data, measured at baseline and the post-one year following metreleptin initiation. Pre-specified co-primary efficacy endpoints measured were change from baseline in HbA1c at month 12, and the percent change from baseline in fasting serum triglycerides (TG) at month 12. Descriptive and statistical analyses were conducted for the overall population, the separate populations with GL and PL, and additional PL subgroups defined by baseline metabolic markers of elevated HbA1c and elevated fasting TG. RESULTS: As previously reported, improvement in HbA1c and fasting TG from baseline to 12 months on metreleptin were observed in the overall population (mean change -1.57 percentage points and median change -37.9%, respectively) and subgroups. For both HbA1c and TG, baseline levels were significant predictors of changes after metreleptin. After considering baseline characteristics such as disease type, age, sex, and baseline HbA1c, baseline insulin use was not found to be a significant predictor of HbA1c improvement following metreleptin initiation. Similar results were seen for TG levels, with the use of any lipid-lowering medications at baseline not found to be a significant predictor of reductions in fasting TG levels. CONCLUSIONS: Patients treated with metreleptin experienced statistically significant improvement in metabolic markers of glycemic and hypertriglyceridemic control-e.g. HbA1c and triglyceride levels-across various subgroups after controlling for baseline characteristics and concomitant medication usage.

Effects of Metreleptin on Patient Outcomes and Quality of Life in Generalized and Partial Lipodystrophy.

Generalized and partial lipodystrophy are rare and complex diseases with progressive clinical and humanistic burdens stemming from selective absence of subcutaneous adipose tissue, which causes reduced energy storage capacity and a deficiency of adipokines such as leptin. Treatment options were limited before leptin replacement therapy (metreleptin) became available. This retrospective study evaluates both clinical and humanistic consequences of the disease and treatment. Chart data were abstracted from a cohort of metreleptin-treated patients with generalized and partial lipodystrophy (n = 112) treated at the US National Institutes of Health. To quantify the quality-of-life consequences of the lipodystrophy disease attributes recorded in chart data, a discrete choice experiment was completed in 6 countries (US, n = 250; EU, n = 750). Resulting utility decrements were used to estimate the quality-adjusted life-year consequences of changes in lipodystrophy attribute prevalence before and after metreleptin. In addition to metabolic impairment, patients with generalized and partial lipodystrophy experienced a range of lipodystrophy consequences, including liver abnormality (94%), hyperphagia (79%), impaired physical appearance (77%), kidney abnormality (63%), reproductive dysfunction (80% of females of reproductive age), and pancreatitis (39%). Improvement was observed in these attributes following initiation of metreleptin. Quality-adjusted life-year gains associated with 12 months of treatment with metreleptin were estimated at 0.313 for generalized and 0.117 for partial lipodystrophy, reducing the gap in quality of life between untreated lipodystrophy and perfect health by approximately 59% and 31%, respectively. This study demonstrates that metreleptin is associated with meaningful clinical and quality-of-life improvements.

Leptin decreases de novo lipogenesis in patients with lipodystrophy.

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study.

CONTEXT: Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. OBJECTIVE: We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. DESIGN/SETTING/PATIENTS: We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. OUTCOME MEASURES: Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. RESULTS: Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). CONCLUSIONS: This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants.

CONTEXT: Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group. OBJECTIVE: To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. DESIGN: Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides. INTERVENTION: Metreleptin (0.08 to 0.16 mg/kg) for 12 months. OUTCOME: Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. RESULTS: Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%. CONCLUSION: Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.

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.

Thyroid Abnormalities in Patients With Extreme Insulin Resistance Syndromes.

CONTEXT: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia. OBJECTIVE: The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population. DESIGN: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin. RESULTS: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin. CONCLUSION: Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.

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.

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.

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation.

Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

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.

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.