Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency. Hepatocyte Nuclear Factor 1 alpha (HNF1A) encodes for a transcription factor expressed in liver, kidney, intestine and pancreas. Mutations in this gene lead to Maturity Onset Diabetes of the Young type 3 (MODY3) 1. This genetic defect represents the most prevalent form of monogenic diabetes 2. HNF1alpha-deficiency leads to an insulin secretion defect that is characterized by a significant phenotypic variability 3. Indeed, even in the same kindred, patients carrying the very same mutation may develop diabetes during childhood whereas other members of the family may develop hyperglycemia only after 50 years of age 3. It has been postulated that this variability may be ascribed to the effect of modifier genes. In support of this hypothesis, a genome scan on different MODY3 families has demonstrated the existence of loci in linkage with the age of onset of the disease 4. One of the limitations of human genetics approach is represented by the complexity of the interaction between the nature of the mutation and the phenotype 5. These limitations prevented the identification of the genetic variations responsible for these effects. To circumvent this problem we took advantage of mouse genetics and in particular of a mouse model that recapitulates the main phenotypic traits of MODY3. It has been previously shown that Hnf1a −/− mice tend to have smaller Langerhans islets and exhibit a profound defect in glucose-dependent insulin secretion that is comparable to that presented by MODY3 patients 6,7. In the kidney, a specific set of sodium dependent co-transporters including Slc5a2 is defectively expressed leading to renal Fanconi syndrome characterized by massive glucose, phosphate and amino acid urinary wasting 8. In a similar way, MODY3 patients suffer from a reduced maximal renal reabsorption capacity for glucose 8. It has been shown that Hnf1a-deficiency leads to a reduced nutrient secretagogue-induced insulin release that is linked to impaired glycolysis 9 and uncou-pling of mitochondrial oxidative phosphorylation 10 in beta islets. Hnf1a-deficiency leads to the significant loss