Lifetime congenital isolated GH deficiency does not protect from the development of diabetes

Abstract

ObjectivesAdult subjects with untreated, lifetime, isolated GH deficiency (IGHD) due to a homozygous GHRH receptor gene mutation (MUT/MUT) residing in Itabaianinha, Brazil, present with lower BMI, higher prevalence of impaired glucose tolerance (IGT), increased insulin sensitivity (IS), and reduced β-cell function (βCF) when compared with non-BMI-matched homozygous normal controls. However, the prevalence of diabetes mellitus (DM) in this cohort is unknown. Comparing their IS and βCF with BMI-matched individuals heterozygous for the same mutation (MUT/N) may be useful to elucidate the role of the GH–IGF1 axis in IS and βCF. The purposes of this work were to verify the prevalence of IGT and DM in adult MUT/MUT subjects from this kindred and to compare IS and βCF in MUT/MUT and MUT/N.DesignCross-sectional study.MethodsWe studied most (51) of the living IGHD adults of this kindred who are GH naive. The oral glucose tolerance test (OGTT) could be performed in 34 subjects, fasting glucose was measured in 15, while two had a previous diagnosis of DM. The OGTT results of 24 MUT/MUT subjects were compared with those of 25 BMI-matched MUT/N subjects. IS was assessed by homeostatic model assessment of insulin resistance (HOMA–IR), quantitative IS check index, and oral glucose IS index for 2 and 3 h. βCF was assayed by HOMA-β, insulinogenic index, and the area under the curve of insulin:glucose ratio.ResultsThe prevalence of DM and IGT in IGHD was 15.68 and 38.23% respectively. IS was increased and βCF was reduced in MUT/MUT in comparison with MUT/N.ConclusionsLifetime, untreated IGHD increases IS, impairs βCF, and does not provide protection from diabetes.

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

“…Because we have previously reported that ␤-cell mass and in vitro glucose-stimulated insulin release is not altered in HF-fed AOiGHD mice (7), the current findings suggest AOiGHD-related impairment of insulin-dependent suppression of HGP may contribute to impaired glucose tolerance observed when caloric intake is in excess (22). Glucose intolerance with improved insulin sensitivity is also observed in 6-to 12-mo-old GH receptor antagonist transgenic mice (13), GHRH knockout mice (7), GH receptor knockout mice (11), and in patients with isolated GHD due to inactivating mutations in the GHRH receptor gene (27,32). Interestingly, the opposite phenotype (improved glucose tolerance with normal/impaired insulin sensitivity) is observed in HiGH mice (10) and in mice expressing the bovine GH transgene (6).…”

“…Glucose intolerance, with improved systemic insulin sensitivity [as measured by insulin tolerance tests (ITT)], is also observed in mouse models with GHD (7) and growth hormone (GH) resistance (11,13). Notably, the opposite metabolic phenotype (improved glucose tolerance with normal/reduced insulin sensitivity) is observed in mice with elevated heterologous (6) or endogenous (10) GH levels.The disconnect between systemic insulin sensitivity and glucose tolerance observed in mouse model systems and humans with isolated changes in GH production and signaling (6,7,10,13,15,22,27,32) suggests GH might differentially alter tissue-specific insulin sensitivity and/or change ␤-cell function/ mass. To differentiate between these possibilities, we have performed studies using mice with adult-onset, isolated GHD [AOiGHD (22)] and mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors [HiGH (10)].…”

“…HUMANS WITH LONG-TERM adult-onset growth hormone deficiency (AOGHD) have been reported to have impaired glucose tolerance (5,27,32), systemic insulin resistance, and increased hepatic glucose production [HGP; (12,16,24)], with a higher prevalence of diabetes (1). However, the direct impact of growth hormone deficiency (GHD) on insulin-mediated glucose homeostasis is not clear cut.…”

“…In fact, insulin sensitivity was shown to be improved in AOGHD subjects compared with age-, sex-, and body mass index (BMI)-matched controls (28). Also, subjects with congenital isolated GHD resulting from an inactivating mutation in the growth hormone-releasing hormone (GHRH) receptor are more insulin sensitive compared with their unaffected relatives despite increased visceral adiposity and glucose intolerance (27,32). Glucose intolerance, with improved systemic insulin sensitivity [as measured by insulin tolerance tests (ITT)], is also observed in mouse models with GHD (7) and growth hormone (GH) resistance (11,13).…”

“…The disconnect between systemic insulin sensitivity and glucose tolerance observed in mouse model systems and humans with isolated changes in GH production and signaling (6,7,10,13,15,22,27,32) suggests GH might differentially alter tissue-specific insulin sensitivity and/or change ␤-cell function/ mass. To differentiate between these possibilities, we have performed studies using mice with adult-onset, isolated GHD [AOiGHD (22)] and mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors [HiGH (10)].…”