Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy.

CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Clinical outcome in a series of pediatric patients with congenital generalized lipodystrophies treated with dietary therapy.

BACKGROUND: Congenital generalized lipodystrophy (CGL) produces clinical features with severe metabolic consequences. Research has focused on measuring the response to the drugs. Nevertheless, there are no studies on the response to dietary therapy. The aim of this study was to show the clinical response to early nutritional intervention to modify or reverse metabolic effects in pediatric patients with CGL. METHODS: A retrospective study was conducted on patients with CGL followed up between January 2003 and June 2017. After diagnosis, patients were indicated a diet with a total calorie intake according to the reference daily intake (RDI), without fast sugars. Clinical feature and laboratory tests (insulin, glucose, A1C, lipid panel, liver and kidney function tests), and complementary studies (abdominal ultrasonography, echocardiogram), at the first visit and during follow-up were recorded. Statistics, version 10, was used for analysis. RESULTS: Eight patients were included. The median age at the first visit was 1.1 years (range, 0.28-9.9 years) and the median time of follow-up was 3.9 years (range, 0.4-9.47 years). The median initial triglyceride level was 516 mg/dL (range, 327-3590 mg/dL) p=0.014; median low-density lipoprotein (LDL) was 157 mg/dL (range, 94-370 mg/dL) p=0.03; median glycemia was 84 mg/dL (range, 63-126 mg/dL) p=0.02; median insulin was 28.84 µUI/mL (range, 3.9-116); median homeostatic model assessment-insulin resistance (HOMA-IR) was 5.3 (range, 1.21-23.2). After 3-6 months of diet, the median percentage of triglyceride decrease was 79.5% (range, 47-97%), LDL 44% (range, 20.5-59%), glycemia 8.8% (range, 0-53.1%), insulin 67.8% (range, 0-92.8%) p=0.02 and HOMA-IR was 81.5% (range, 50-98%) p=0.05. As of the last follow-up visit, in none of the patients, liver ultrasonography or echocardiogram had deteriorated. CONCLUSIONS: In these pediatric patients with CGL, a diet adjusted to RDI with restriction of fast sugars led to a marked improvement in metabolic parameters.

Effect of diet intervention and oral zinc supplementation on metabolic control in Berardinelli-Seip syndrome.

BACKGROUND/AIMS: Berardinelli-Seip syndrome (BSS), also termed congenital generalized lipodystrophy or congenital generalized lipoatropic diabetes, is a rare autosomal recessive disease characterized by the nearly complete absence of metabolically active adipose tissue from birth, extreme insulin resistance, diabetes mellitus, and hepatomegaly. The aim of this study was to evaluate the effect of diet intervention and oral zinc supplementation on the metabolic control of BSS patients. METHODS: During a 3-month period, 10 BSS patients received individualized diets and oral zinc supplementation. Food intake, clinical laboratory parameters, serum zinc and leptin, and plasma C-peptide concentrations were evaluated at the beginning of the study and after 3 months. RESULTS: At the beginning of the study, all patients had elevated energy, protein, total fat, carbohydrate, calcium, iron, and zinc intakes. After 3 months, all of these parameters had decreased. Total fiber intakes remained low before and after diet intervention and oral zinc supplementation, and plasma levels of fasting glucose remained high. In contrast, glycated hemoglobin decreased significantly. Plasma leptin, C-peptide, and serum zinc levels increased during venous zinc tolerance testing, but there were no significant differences between the 2 curves obtained before and after diet intervention and oral zinc supplementation. CONCLUSIONS: Diet intervention and oral zinc supplementation were effective at controlling energy consumption, macronutrients, and glycated hemoglobin. Zinc likely acts as an adjunct therapy, thereby improving the effectiveness of leptin.

Early course of Berardinelli-Seip congenital lipodystrophy (BSCL).

Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare autosomal recessive disease. In the described patient diagnostic relevant symptoms developed at 3 week age.