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.

Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota.

Intestinal microbiota, diet, and physical activity are inextricably linked to inflammation occurring in the presence of tumor progression and declining neurocognition. This study aimed to explore how fecal microbiota, inflammatory biomarkers, and neurocognitive behavior are influenced by voluntary exercise and surplus dietary protein and folic acid which are common health choices. Dietary treatments provided over 8 weeks to C57BL/CJ male mice (N = 76) were: Folic Acid (FA) Protein (P) Control (FPC, 17.9% P; 2 mgFA/kg); Folic Acid Deficient (FAD); Folic Acid Supplemented (FAS; 8 mgFA/kg); Low Protein Diet (LPD, 6% P); and High Protein Diet (HPD, 48% P). FAS mice had decreased plasma HCys (p < 0.05), therefore confirming consumption of FA. Objectives included examining influence of exercise using Voluntary Wheel Running (VWR) upon fecal microbiota, inflammatory biomarkers C - reactive protein (CRP), Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), nuclear factor kappa ß subunit (NF-κßp65), Caspase-3 (CASP3), Tumor Necrosis Factor-alpha (TNF-α), and neurocognitive behavior. CRP remained stable, while a significant exercise and dietary effect was notable with decreased VEGF (p < 0.05) and increased CASP3 (p < 0.05) for exercised HPD mice. Consumption of FAS did significantly increase (p < 0.05) muscle TNF-α and the ability to build a nest (p < 0.05) was significantly decreased for both FAD and LPD exercised mice. Rearing behavior was significantly increased (p < 0.05) in mice fed HPD. An emerging pattern with increased dietary protein intake revealed more distance explored in Open Field Testing. At week 1, both weighted and unweighted UniFrac principal coordinates analysis yielded significant clustering (permanova, p ≤ 0.05) associated with the specific diets. Consumption of a HPD diet resulted in the most distinct fecal microbiota composition. At the phylum level-comparing week 1 to week 8-we report a general increase in the Firmicutes/Bacteroidetes ratio, characterized by an outgrowth of Firmicutes by week 8 in all groups except the HPD. MaAsLin2 analysis corroborates this finding and emphasizes an apparent inversion of the microbiome composition at week 8 after HPD. Explicit modification of oncogenic inflammatory biomarkers and fecal microbiome post high FA and protein intake along with voluntary exercise contributed to current underlying evidence that this diet and exercise relationship has broader effects on human health and disease-perhaps importantly as a practical modulation of cancer progression and declining neurocognition.