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Transient Juvenile Hypoglycemia in Growth Hormone Receptor Deficiency – Mechanistic Insights from Laron Syndrome and Tailored Animal Models

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Transient Juvenile Hypoglycemia in Growth Hormone Receptor Deficiency – Mechanistic Insights from Laron Syndrome and Tailored Animal Models 2 185 A Hinrichs and others Transient hypoglycemia in GHR 185:2 R35–R47 Review deficiency MECHANISMS IN ENDOCRINOLOGY Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models Arne Hinrichs1,2 , Simone Renner1,2,3 , Martin Bidlingmaier4 , John J Kopchick5 and Eckhard Wolf 1,2,3,6 1Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany, 2Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleißheim, Germany, 3German Center for Diabetes Research (DZD), Neuherberg, Germany , 4Endocrine Laboratory, Medizinische Klinik Correspondence und Poliklinik IV, Klinikum der Universität München, Munich, Germany, 5Edison Biotechnology Institute Heritage should be addressed College of Osteopathic Medicine and Molecular and Cellular Biology Program, Department of Biomedical Sciences, to A Hinrichs Ohio University, Athens, Ohio, USA, and 6Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Email Munich, Munich, Germany [email protected]. uni-muenchen.de Abstract The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In European Journal of Endocrinology the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals. European Journal of Endocrinology (2021) 185, R35–R47 Introduction low serum levels of insulin-like growth factor 1 (IGF1) and elevated levels of GH. Phenotypically they have a small Growth hormone receptor deficiency (GHRD) – the stature and are somewhat obese (1). In the Israeli cohort of human Laron syndrome (LS) – is a hereditary disorder LS patients (2), several inactivating mutations of the GHR leading to diminished growth hormone (GH) binding gene have been reported (1), while a cohort in Ecuador is and intracellular signal transduction. LS patients have more uniform with only one inactivating GHR mutation https://eje.bioscientifica.com © 2021 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-21-0013 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 08:54:59PM via free access -21-0013 Review A Hinrichs and others Transient hypoglycemia in GHR 185:2 R36 deficiency (3). In total, just 350 LS patients are estimated worldwide, (Table 1). Hypoglycemic glucose levels of 3040 mg/dL were of which the Ecuadorian cohort is the largest in numbers, reported (8), leading to heavy sweating, pallor, headache, with approximately 100 affected individuals (4, 5). A seizures, and loss of consciousness (12, 13). In the Israeli mouse model for LS – the Ghr-KO mouse – was produced by cohort, glucose values were found to vary widely but were disruption of Ghr exon 4 (6). A porcine LS model has been always lower than in controls during childhood, although established by inducing a frameshift mutation in GHR exon statistical significance disappeared at age 5 years (1, 10). 3 (7). Similar to human LS patients, these animal models Fasting glucose levels tend to normalize at puberty (10), show the characteristic phenotype of postnatal growth and even occasional cases of hyperglycemia have been retardation and increased accumulation of adipose tissue. observed in patients aged 40 years and older (8). Young Juvenile hypoglycemia is commonly observed as a key adult Ecuadorian LS patients (age < 20 years) revealed symptom of LS but vanishes when the patients get adult normal fasting glucose levels (9, 14). In contrast to the (1, 8, 9). Nevertheless, differences in glucose homeostasis Israeli cohort, hyperglycemic values were not reported, and between various cohorts of LS patients have been described a lifelong increased insulin sensitivity was assumed (9). – ranging from insulin resistance (10) to a metabolically Under physiological conditions, insulin levels healthy phenotype with increased insulin sensitivity increase at puberty, earlier in females than in males, even in obese LS patients (9). This review summarizes the and decrease in adulthood (15). A similar age-dependent alterations of glucose homeostasis in different cohorts peak was observed in LS patients of the Israeli cohort, of LS patients and in rodent and pig models with GHRD. and their insulin levels were always higher than in Mechanisms potentially involved in the phenomenon of age-matched control subjects. The difference appeared transient juvenile hypoglycemia are discussed. earlier in females than males and was more pronounced from age 6 to 10 years than from age 11 to 22 years. Thus, the degree of hyperinsulinemia decreased with age, and in adult patients, a trend of relative insulinopenia Glucose homeostasis in growth hormone was observed (8, 10, 16). Studies of insulin levels in the receptor deficiency Ecuadorian LS cohort did not focus on a comparison of different ages; in adult LS patients, insulin levels in Laron syndrome patients the range of one-third of those of control siblings and Juvenile hypoglycemia is a major symptom in LS patients relatives were reported (9, 14). from both cohorts (8, 11 ) and has clinical implications In Israeli LS patients, a high incidence of glucose European Journal of Endocrinology in infants and children after longer periods of fasting intolerance was revealed by oral (17) and intravenous (18) Table 1 Parameters of glucose metabolism in distinct age groups. Age groups are divided according to glycemic status. In human LS patients (Israeli and Ecuadorian cohort), prepubertal, hypoglycemic patients are referred to as young, after puberty, reaching normoglycemia as adult. In Ghr-KO mice, animals up to an age of 9.5 months, exhibiting hypoglycemia are referred to as young according to (36), starting from 11 months of age, reaching normoglycemia according to (37), animals are referred to as adults. GHR-KO pigs are referred as young at the age of 3 months and adults at puberty with 6 months of age. Israeli cohort Ecuadorian cohort Ghr-KO mouse GHR-KO pig (7) Young Adult Young Adult Young Adult Young Adult Glucose ↓ (1) ↓↔↑ (8) ↓ (11) ↔ (9) ↓ (35, 36) ↔ (37, 38); ↑ (36) ↓ ↔ Insulin ↑↑ (10) ↑↔ (8, 10, 16) ↓ (9, 14) ↓ (36, 37); ↔ (35) ↓ (35, 36, 37) ↔ ↓ ↔ ↓ GTT Glucose response EN – NO (10, 17) EN (10, 17) NO (9) EN (39, 40) EN (41) NO NO Insulin response IM (10, 18) IM (10); NO – EN IM (9) IM (39) IM IM (17, 19) Caloric intake ↔ (8) ↔ (53) ↑ (37, 56) ↑ (37, 57) Energy expenditure ↑ (53) ↑ (55) ↑ (57) HOMA-IR ↑(8) ↑ ↔ (8) ↓ (9) ↓ (36) ↓ (36) ↔ ↓ ↔ ↑ ITT Glucose response IM (10, 19) NO (10, 19) IM (35, 64) IM (41, 74) Beta-cell mass ↓ (10) ↓ (9) ↓ (35, 39) EN, enhanced; IM, impaired; NO, normal. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 10/01/2021 08:54:59PM via free access Review A Hinrichs and others Transient hypoglycemia in GHR 185:2 R37 deficiency glucose tolerance tests (GTTs) (10). Glucose intolerance was rhIGF1 for a limited time showed a reduction of fat mass first observed at early puberty, and the incidence increased and hyperlipidemia, which reversed upon discontinuation with age (19). The amplitude of insulin response following of treatment (28). Long-term rhIGF1 replacement therapy glucose load was commonly lower in LS patients compared reversed insulin resistance and improved glucose tolerance to controls (10, 18) and decreased with age, that is, was lower in the Israeli LS cohort (10). Glucose levels were reported to in young adults (23–30 years) than in pubertal patients stabilize as patients were more likely able to tolerate fasting (11–22 years) (8). However, cases of hyperinsulinemic episodes without hypoglycemic episodes and insulin levels peaks (17) and rising insulin levels with age in LS patients persistently decreased (29). In the Ecuadorian cohort of presenting with insulin-resistant diabetes were reported LS patients, rhIGF1 replacement therapy has been used (19), highlighting the broad variability among patients in clinical trials and showed that a reduced dosage could in this cohort (8). Comparing Ecuadorian
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