Pathophysiology of juvenile hypoglycemia in a porcine model for Laron syndrome

• Applicant: Dr. Arne Hinrichs
• Subject Area: Endocrinology, Diabetology, Metabolism ; Animal Breeding, Animal Nutrition, Animal Husbandry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441815498

The Laron syndrome is a hereditary disorder resulting from mutations of the growth hormone receptor (GHR) gene. Therefore, circulating growth hormone (GH) cannot be bound, diminishing insulin like growth factor 1 (IGF1) production. Besides growth retardation, affected patient show an increased accumulation of adipose tissue but preserved insulin sensitivity addressing Diabetes research. Severe hypoglycemia is reported from infants but adults show normoglycemia. By now, no profound explanation neither for the juvenile hypoglycemia nor the transiency to normoglycemia in adults has been found. We previously generated a porcine model for Laron syndrome (the GHR KO pig) and in line with observations in humans, animals at an age of three months show hypoglycemia while animals at an age of six months are normoglycemic. We will aim the following objectives by the investigation of GHR KO and control animals of the distinct age groups: 1. Determination of insulin sensitivity: An increased insulin sensitivity while absent GH action can cause the juvenile hypoglycemia. For the determination of whole body insulin sensitivity, we will perform hyperinsulinemic euglycemic clamp studies in animals from both age groups. Further we will determine the insulin sensitivity of liver, fat and muscle tissues by western blot. 2. Quantification of insulin production and hepatic extraction: To investigate differences in insulin production, we will quantify the mass of insulin producing beta cells by stereological examination of the pancreas in both age groups. Further we will calculate the ratio of insulin to C-peptide in circulation to clarify the extent of insulin extraction by the liver. 3. Investigation of the activity of gluconeogenesis: A reduced gluconeogenesis due to the lack of GH action can be expected to cause juvenile hypoglycemia and an increase can act as a counter regulatory mechanism increasing blood glucose in animals at an age of six months. To determine gluconeogenesis in vivo, we will evaluate the position of infused deuterium in in vivo produced glucose in the distinct age groups. The activity grade of gluconeogenesis will further be evaluated by western blot approaches. 4. Evaluation of the impact of puberty: Due to the simultaneous onset of normoglycemia and puberty observed in human patients, we will include the investigation of castrated GHR KO pigs in comparison to intact ones. We will provide the first coherent study in Laron syndrome comparing different age groups, investigating the distinct effects of lacking GH action on glucose homeostasis leading to preserved insulin sensitivity whilst fat accumulation in a suitable animal model.

• DFG Programme: Research Grants