Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion

Abstract

Aims: We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).

Methods: Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP).

Results: Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP.

Conclusions: A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.

Keywords: CDKN1c; Growth hormone; Guevara-Rosenbloom syndrome; Laron syndrome.

Figure 1.. Insulin and glucose levels following OGTT.

A 5-hour OGTT (1.5 g of glucose per kg of body weight) was performed. A) Insulin and B) glucose levels were measured every 30 minutes from all study subjects (LS n=19, GRS n=13, controls n=20). Kruskal-Wallis test was used to assess differences in insulin and glucose levels between groups at each timepoint. Dunn’s post hoc test was used to correct for multiple comparisons. C) Insulin and D) glucose levels were analyzed from a subset of age- and sex-matched subjects (LS n=6, GRS n=6, controls n=6). Friedman’s test was used to assess differences in insulin and glucose levels between matched subjects at each timepoint. Dunn’s post hoc test was used to correct for multiple comparisons. Adjusted P < 0.05 was considered significant. Data are represented as mean ± SEM. *Significant difference between LS and control groups. †Significant difference between GRS and control groups. ‡Significant difference between LS and GRS groups.

Figure 2:. Diminished insulin secretion and progressive glycation result in poor glucose handling, insulin resistance, and diabetes in GRS.

A 5-hour OGTT (1.5 g of glucose per kg of body weight) was performed. A) Insulin and B) glucose levels were measured every 30 minutes from GRS subjects (n=5), LS subjects (n=13), and controls (n=20) with HbA1c <6.2 and fructosamine <285 μmol/L. Unpaired t test with Welch’s correction was used to assess differences in insulin and glucose levels between GRS and control subjects at each timepoint. Data are represented as mean ± SEM. Adjusted P < 0.05 was considered significant. *Significant difference between GRS and control groups. C) Insulin and D) glucose were measured every 30 minutes from all GRS subjects (n=13, stratified according to HbA1c levels) and controls (n=20). Kruskal-Wallis test was used to assess differences in insulin and glucose levels between groups at each timepoint. Dunn’s post hoc test was used to correct for multiple comparisons. Adjusted P < 0.05 was considered significant. Data are represented as mean. *Significant difference between HbA1c >8 (black diamonds) and controls (black triangles). †Significant difference between HbA1c <6.2 (light grey squares) and HbA1c >8 (black diamonds) groups.

Figure 3:. Adipocytokines and growth factor levels according to clinical status.

Serum levels of A) leptin, B) total, and C) high molecular weight (HMW) adiponectin, D) IGF-I, E) IGF-II, and F) IGFBP3 in LS, GRS, and control subjects were compared. Data points represent individual subjects and mean ± SD are shown. Kruskal-Wallis test was used to assess differences in analyte means between groups. Dunn’s post hoc test was used to correct for multiple comparisons: *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 4:. IAPP levels following 5-hour OGTT according to clinical status.

A) Islet Amyloid Polypeptide (IAPP) levels were measured every 30 minutes following a 5-hour OGTT (1.5 g of glucose per kg of body weight) from a subset of age- and sex-matched subjects (LS=6, GRS=6, controls=6). B) IAPP AUC were compared among groups using one-way ANOVA and the Holm-Sidak test for multiple comparisons: *P < 0.05, **P < 0.01. Data are represented as mean ± SEM.