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Thouraya Baroudi Ouederni1, Ahmed Fadiel2,3, Nejla Stambouli1, Trudy J Scalize3, Hedi Ben Maiz4, Hafaona Kammoun Abid1, Rim Bouhaha1, Jose Sanchez-Corona5, Adel Hamza1,6*, Amel Benammar-Elgaaied1,*1Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, Tunis, Tunisia; 2New York University School of Medicine, NYU Medical Center, New York, NY, USA; 3Biomedical Informatics, OBGYN Department, Meharry Medical College, Nashville, TN, USA; 4Charles Nicolle Hospital, Internal Medicine A, Tunis, Tunisia; 5División de Medecina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano Del Seguro Social, Guadalajara, Jalisco, México; 6Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA; *These authors contributed equally to this work and are the corresponding authorsAbstract: Type 2 diabetes mellitus (T2DM) is characterized by three major metabolic abnormalities: impaired insulin-stimulated glucose uptake in muscle and adipose tissues, alterations in glucose-stimulated insulin secretion, and increased hepatic glucose production. Both genetic and environmental factors contribute to its development. The insulin gene (INS), insulin receptor gene (INSR), and insulin receptor substrate 1 gene (IRS1), identified by polymerase chain reaction and digestion with selected restriction enzymes PstI, NsiI, and BstnI, have been proposed as T2DM candidate genes. To determine the contribution of genetic and environmental factors on the occurrence of T2DM, we examined the frequency of T2DM among two ethnically diverse populations, Arabs and Berbers, who have shared the same environment, the island of Djerba, for thousands of years. Both populations have a high prevalence of obesity, T2DM, and a high consanguinity rate. A total of 162 T2DM men and women were matched to 110 healthy male and female controls. Results showed that the NsiI polymorphism in I