MODY (Maturity-Onset Diabetes of Young)
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MODY (Maturity-Onset Diabetes of Young)
Diabetes mellitus is a chronic disease characterized by high blood glucose levels that requires long-term medical attention both to limit the development of its devastating complications and to manage them when they do occur. The pancreatic Beta-cell and its secretory product Insulin are central in the pathophysiology of diabetes. There are two main types of diabetes, Type-I, which is Insulin dependent, and Type-II, which is non-insulin dependent. Type-II diabetes is a complex and heterogeneous disease caused by both environmental and genetic factors. It maybe of various forms each of which is characterized by variable degrees of Insulin resistance and Beta-cell dysfunction, and which together lead to hyperglycemia. At each end of this spectrum are single gene disorders that affect the ability of the pancreatic Beta-cell to secrete Insulin or the ability of muscle, fat and liver cells to respond to Insulins actions (Ref.1). The pathophysiology of the common polygenic form of Type-II (late-onset) diabetes results from early-onset Insulin resistance coupled with functional defects in Insulin secretion by pancreatic islet Beta-cells. In contrast, the monogenic form of diabetes, MODY (Maturity-Onset Diabetes of Young)--primarily results from defects that affect the functioning of islet Beta-cells and the pancreas does not produce enough Insulin. This in turn leads to hyperglycemia, or high blood sugar, which can cause the body to become resistant to Insulin. The impaired secretion of Insulin seen in MODY is similar to the deficiency found in Type-I diabetes. Yet, unlike Type-I diabetes, MODY develops slowly and does not completely destroy the ability of the pancreas to secrete Insulin. Rather, it impairs Insulin secretion so that the body cannot adequately control blood glucose levels from one moment to the next (Ref.4).

Molecular defects in six different genes have been currently identified in MODY patients. All of these genes encode proteins involved in the glucose homeostasis of the pancreatic Beta-cell. The Glucokinase gene (associated with MODY2) encodes an enzyme of the glycolytic pathway, which can modulate Insulin secretion in response to glycemic variations. The other five genes encode nuclear proteins that control the appropriate expression of Beta-cell genes. HNF1Alpha (Hepatocyte Nuclear Factor-Alpha associated with MODY3) and HNF1Beta (MODY5) are atypical homeodomain proteins. IPF1 (Insulin Promoter Factor-1/MODY4) encodes a homeodomain-containing protein, while HNF4Alpha is a steroid nuclear receptor family member and (Neurogenic Differentiation-1), or BETA2 (Beta-cell E-box Transactivator-2 [MODY6]) is a basic helix-loop-helix transcription factor (Ref.6). HNF4Alpha activates the expression of genes involved in the transport and metabolism of many nutrients including lipids and glucose. HNF4Alpha expression is in turn controlled by HNF3Alpha and HNF3Beta and is required for normal hepatic function and directly activates the Insulin gene promoter and is also required for glucose-induced Insulin secretion. It also plays an important role in pancreatic Beta-cells. The glycolytic enzyme Glucokinase which is expressed at highest levels in the pancreatic Beta-cell catalyzes the transfer of phosphate from ATP to glucose to form Glucose-6-phosphate. Glucose is transported into the Beta-cell by a specific GLUT2 (Glucose-transporter protein) on the cell surface. By means of this reaction, Glucokinase functions as the glucose sensor of the Beta-cell. The generation of ATP by glycolysis and the Krebs cycle leads to inhibition and closure of the ATP-sensitive K+ channels (the target of sulfonylurea drugs), depolarization of the plasma membrane, opening of the Voltage-dependent Ca2+ channels , and influx of extracellular Ca2+ and mobilization of Ca2+ from intracellular stores (Ref.3). These activities lead to the fusion of Insulin-containing secretory granules with the plasma membrane and the release of Insulin into the circulation. A mutation in one of the alleles of the genes encoding HNF4Alpha, Glucokinase, HNF1Alpha, IPF1, HNF1Beta, and NeuroD1 leads to a reduction in Beta-cell Glucokinase activity, resulting in decreased glucose phosphorylation in the Beta-cell and glucose-stimulated Insulin release at any blood glucose concentration (Ref.2). MODY4 and MODY6 are also caused by mutations in genes encoding PDX1 (Pancreatic Homeodomain) transcription factor which is activated by inductive signal that acts via the Insulin Receptor and/or the IGF1R (Insulin-Like Growth Factor-1 Receptor).

Genetic influences are important in the etiology of diabetes. The most common clinical presentation of MODY is mild, asymptomatic hyperglycemia in nonobese children, adolescents, and young adults who have a prominent family history of diabetes, often in successive generations. Some patients have mild fasting hyperglycemia for many years, whereas others have varying degrees of glucose intolerance for several years before the onset of persistent fasting hyperglycemia (Ref.4). Since mild hyperglycemia may not cause the classic symptoms of diabetes, the diagnosis may not be made until adulthood. In some patients, there may be rapid progression to overt asymptomatic or symptomatic hyperglycemia, necessitating therapy with an oral hypoglycemic drug or Insulin. Non-genetic factors that affect Insulin sensitivity such as infection, puberty, pregnancy and, rarely, obesity may trigger the onset of diabetes and also affect the severity of hyperglycemia in MODY. In addition to mutations in the nuclear genome, abnormal mitochondrial function resulting from mutations in the mitochondrial genome can lead to diabetes. According to current estimates, MODY may account for 1 to 5 percent of all cases of diabetes in the United States and other industrialized countries (Ref.5 & 6). MODY is treated very much like Type-II diabetes with diet and exercise, often in combination with oral pills, insulin, or both. A better understanding of the causes and pathophysiology of MODY is emerging from genetic, molecular biology, and physiological studies of this disorder. Probably this knowledge will lead to new therapeutic approaches and agents that will prevent, correct, or at least delay the decline in pancreatic Beta-cell function that characterizes not only MODY but also Type-II diabetes.