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Arne Hinrichs, Simone Renner, Martin Bidlingmaier, John J Kopchick, and Eckhard Wolf

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 in two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provide 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, increasing glucose levels with age. In 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 or 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 the 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.