Transient juvenile hypoglycemia in growth hormone receptor deficiency - mechanistic insights from Laron syndrome and tailored animal models

Abstract

The aim of the study is to find possible explanations for vanish ing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We review ed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of L aron 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 cohor t, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensiti vity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the difference s in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian c ohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and lea ds 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 pu berty 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 pro duction and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.