A life without SCHAD: Novel implications for insulin-body weight interplay

The hormone insulin is important for correct regulation of the blood sugar level. The aim of this project is to obtain a better understanding of how insulin production is controlled in the body. We are studying a rare, inherited disease denoted congenital hyperinsulinism of infancy. Children with this condition produce too much insulin, tend to have high birth weights, and exhibit low blood sugar levels shortly after birth. If untreated, congenital hyperinsulinism can cause permanent brain damage or even be fatal. Due to increased insulin production and low blood sugar, hyperinsulinism may in several ways be considered as the "inverse" state of diabetes, a common disorder where the hallmark is chronically elevated blood sugar. A long-term goal of our project is therefore to gain new insights also in mechanisms involved in development of diabetes. We have been studying a particular type of congenital hyperinsulinism characterized by disruption of the SCHAD protein, which degrades fatty acids. A central finding of the project is that insulin-producing cells from mice with a non-functioning SCHAD gene can be transplanted into diabetic mice and make them healthy. A major aim of the project has been to create a novel mouse model for congenital hyperinsulinism, in which the SCHAD protein has been specifically inactivated in the insulin-producing beta-cells. These cells are located within the islets of Langerhans, cell groups found in the pancreas. The new model, denoted the b-SCHADKO mouse, has low blood sugar, but the animals are otherwise normal. Islets have been isolated from b-SCHADKO mice and have been compared with islets from normal mice. This resulted in the identification of a set of genes that are perturbed by the lack of SCHAD protein. Moreover, we have examined human DNA and identified rare variants of the SCHAD gene. The effects of these variants on the normal function of the SCHAD protein have been investigated in a new cellular model. Some of the variants make the protein very unstable whereas others have lost their enzyme activity. Taken together, the project has - based on findings in children with congenital hyperinsulinism - generated both an animal model and a cellular model for studies of mechanisms involved in persistently lowered blood sugar.

(1) Vi har laget en ny cellemodell for studier av varianter i SCHAD-genet. Ved å anvende disse cellene har vi oppnådd mer kunnskap om hvilken effekt genetiske SCHAD-varianter har og deres forekomst i befolkningen. (2) Vi har laget en ny musemodell hvor SCHAD-genet er ødelagt bare i de insulinproduserende cellene i bukspyttkjertelen. Denne modellen egner seg svært godt for mekanistiske studier av lavt blodsukker. (3) Gjennom den internasjonale delen av prosjektet har vi utviklet og forsterket forskningssamarbeidet med et verdensledende miljø ved Joslin Diabetes Center, Harvard Medical School, Boston. Dette samarbeidet vil være av stor verdi for vår videre forskning på medfødt hyperinsulinisme og diabetes.

Diabetes and obesity are chronic diseases representing some of the greatest health challenges in modern societies. We seek to obtain new knowledge about the regulation of insulin secretion and body weight by studying congenital hyperinsulinism of infancy (CHI). This inherited disease may be regarded as the 'reverse' condition of diabetes, as it is characterized by elevated insulin secretion/hypoglycemia and high birth weight. One type of CHI is caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a mitochondrial enzyme taking part in the degradation of fatty acids and with a suggested role in body weight control. Based on clinical observations and recent data from mouse studies, we hypothesize that SCHAD serves two functions in the body: one exerted in all or most cells (fatty acid oxidation and body weight control); the other being specific for the pancreatic beta-cell (regulation of insulin secretion). We therefore propose a project that has the potential to pinpoint a protein with a dual role in body weight control and insulin secretion, linking these processes in a so far unprecedented way. The disease will be mimicked by constructing tissue-specific SCHAD knockout mice followed by a comparison with the general knockout mouse already available. Moreover, we will produce induced pluripotent stem cells (iPSC) from patients with SCHAD deficiency and employ these cells in functional and molecular investigations. We will also mine an extensive data-set of whole-exomes from patients and controls for rare variants of the SCHAD gene, in order to explore its role in regulation of human glucose homeostasis and body weight. Hence, the disease will be analyzed by a variety of approaches, which involve extensive international collaboration. An elucidation of the mechanisms of SCHAD-CHI is likely to improve our understanding of insulin secretion in particular, and glucose metabolism and body weight control in general.