Gain of function of malate dehydrogenase 2 (MDH2) and familial hyperglycemia

Objective: We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. Methods: Existing Whole Exome Sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the US and Italy. Functional studies were carried out in vitro (transfected MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of two variants in the Malate Dehydrogenase 2 (MDH2) gene linked with hyperglycemia in two of the families. Results: A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in one family from the US. An infrequent MDH2 missense variant (p.Val160Met) also showed disease co-segregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio - a change known to affect insulin signaling and secretion. Stable expression of human wild type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. Conclusions: Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.