PPM1-0102-160028

Insulin deficiency and/or resistance to insulin action are the main pathophysiologic features of all type diabetes, which lead to inability to efficiently metabolize glucose, hyperglycemia, short and long term complications of diabetes. In type 1 diabetes (T1D), auto-immune destruction of the insulin-secreting β cells in the pancreas results in severe insulin deficiency and rapid development of hyperglycemia, polyuria, polydipsia and diabetic ketoacidosis. The pathogenesis of the auto-immune insult to the β cells is not well understood, environmental factors, such as viruses, toxins and stress, may play a role in addition to the genetic background. In type 2 diabetes (T2D), insulin resistance develops very early; the β cells compensate by increasing insulin secretion; glucose levels remain normal for a longtime. When theβcells fail to sustain the increasing demand for insulin, hyperglycemia develops slowly and over a long period of time. Initially the patient may have “pre-diabetes”, a condition in which glucose levels during an oral glucose challenge or after 8 hours of fasting are below the diagnostic threshold for diabetes but are above normal. Frank hyperglycemia and full-blown T2D develop when insulin secretion declines significantly. Several of the mutations causing monogenic diabetes, MODY, and most of the genes associated with T2D, are transcription factors or enzymes that regulate insulin secretion and β cell function. Only few genes are associated with insulin resistance were discovered so far. Insulin resistance, or the declining sensitivity of the different target tissues to insulin actions, has a complex pathogenesis, resulting from the interaction of genetic predisposition, lifestyle and environmental factors. Obesity, particularly visceral obesity associated with fatty liver, results in insulin resistance; the sedentary lifestyle contributes to decreased muscle mass and decreased glucose uptake by muscles. Thus both type 1 and type 2 diabetes have a genetic background characterized by susceptibility genes, which if present, the environmental insults readily result in diabetes. The prevalence of diabetes in Qatar is about 17% of adults (about 85,000 patients in Qatar); most of them are T2D, the prevalence of T1D is ~ 1% of the population with a yearly incidence of about 11 per 100,000. However, in clinical practice we encounter Qatari families having 30-100% of siblings with diabetes. High clustering of diabetes in certain families cannot be random! It is not clear if shared genetic, lifestyle or environmental factors is/are responsible for high prevalence of diabetes in these families. We therefore propose to perform a systematic genetic analysis of affected and un-affected members of these families to deduce possible shared diabetes-predisposing genes. We shall develop inter-institutional collaboration between HMC, QBRI, QBB and Qatar Genome to achieve the following objectives: 1. Develop a registry for families with high prevalence of diabetes; 2. Analyze the clinical phenotype of diabetic and non-diabetic members of the families for obesity, insulin resistance, insulin secretion, dietary habits, daily exercise levels; 3. Perform whole genome sequencing of genomic DNA from affected and unaffected members of the families; 4. Analyze the data to deduce role of genes, lifestyle and environment in the clustering of diabetes in these families. The inclusion criteria include prevalence of T2D in more than 1/3 of siblings or presence of T1D in at least 2 siblings. We shall phenotype the members in term of family history, dietary habits and physical activity, weight, BMI, If time and fund allows, we shall do detailed metabolic studies, using euglycemic hyperinsulinemic clamp and hyperglycemic clamp to quantify insulin resistance and β cell functions in diabetic and non-diabetic members of selected families to further understand the pathogenesis of diabetes in such a particular family. For example we have few families in whom most siblings are affected with T2D or T1D, which suggest an autosomal dominant inheritance, for such a family, it will be important to learn if they have insulin deficiency or extreme insulin resistance. In such families we shall recruit both affected and un-affected family members for the detailed metabolic study. Studying the genes contributing to the clustering of diabetes in certain Qatari families will lead to multiple benefits: 1) potential for personalized treatment, particularly if a MODY gene is discovered, 2) potential novel physiology and novel drug target if a new diabetes causing gene is discovered, 3) understanding the role of gene-gene interactions in causing diabetes (inheritance of multiple risk genes that potentiate each other effects, due to inter-cousin marriage, etc.) or gene-environment-lifestyle interaction.