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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00085982 NCT00001987.

Keywords: A1c; Rabson-Mendenhall syndrome; growth hormone resistance; insulin receptor; leptin.

Published by Oxford University Press on behalf of the Endocrine Society 2021.

Figures

Figure 1.

Concomitant medications during follow-up. Diabetes medications were recorded for patients in the control and metreleptin groups at each visit throughout follow-up. A) Mean ± SEM insulin dose (units/day), B) Mean ± SEM metformin dose (mg/day), and C) Mean ± SEM metreleptin dose (mg/kg/day) are shown from 0 to 90 months in the control group (white squares) and metreleptin group (black circles). The number of patients with data available at each visit are provided. Patients who were never treated with insulin are included (as 0 units per day at all time points).

Figure 2.

Change from baseline in glycemic outcomes throughout follow-up. Mean change from baseline in A) mean A1c, B) individual patient A1c in the metreleptin-treated group and C) control group, D) 24-hour urine glucose excretion, E) fasting glucose, F) fasting insulin, (F) glucose AUC, H) insulin AUC, I) C-peptide AUC are shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. P values for comparison of mean change from baseline between groups across all time points are presented for each outcome. Using a mixed-model test, the metreleptin-treated group had greater improvements in A1c across all time points vs the control group (P = 0.007, least square mean [LSM] change in metreleptin group: −0.9%, LSM change in control group: +1.0%).

Figure 3.

Change from baseline in growth parameters throughout follow-up. Mean change from baseline in growth and growth axis parameters A) weight SDS, B) height SDS, C) BMI SDS, D) IGF-1 SDS, E) growth hormone are shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. P values for comparison of mean change from baseline between groups across all time points are presented for each outcome. Using a mixed-model test, the metreleptin-treated group had larger least square mean (LSM) changes from baseline across all time points compared to the control group in weight SDS (P = 0.03, LSM change in metreleptin group: −0.74, control group: 0), BMI SDS (P = 0.01, LSM change in metreleptin group: −1.03, control: 0.14), and growth hormone (P = 0.04, LSM change in metreleptin group: 4.77 ng/mL, control: −1.69 ng/mL).

Figure 4.

Change from baseline in kidney parameters throughout follow-up. Mean change from baseline in kidney function A) 24-hour urine protein, B) albumin excretion, C) eGFR is shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. Using a mixed-model test, there were no differences between the metreleptin-treated and control groups for changes from baseline across all time points.

Figure 5.

Proposed model for glycemic and growth observations in Rabson Mendenhall syndrome (RMS). The proposed model for the natural history of RMS is shown in white squares with gray arrows. RMS (1) is caused by pathogenic variants in the insulin receptor gene, leading to severe insulin resistance. Severe insulin resistance perpetuates uncontrolled glycemia (2), as glucose is not effectively transported from the blood into cells. Continuous uncontrolled glycemia leads to increased risk of neuropathy, nephropathy, retinopathy, and macrovascular complications (3). Uncontrolled glycemia also leads to cellular starvation (4), as glucose cannot enter cells. Growth hormone resistance develops in response to persistent cellular starvation (5). IGF-1 secretion is not stimulated by growth hormone (6), and growth hormone levels increase as a compensatory response (7). Changes in this pathway in response to metreleptin are shown in black squares with black arrows. Metreleptin use is associated with improved glycemia control (A). Improved glycemia is associated with increased IGF-1 SDS (B). Metreleptin use is also associated with decreased BMI, likely due to suppression of appetite (C). Decreased appetite with metreleptin treatment may exacerbate cellular starvation (D), thus worsening GH resistance and lowering IGF-1. The resultant decrease in IGF-1 is counterbalanced by increased IGF-1 from improved glycemia, leading to net zero change in IGF-1 after metreleptin.