Clinical Complexity of Type 2 Diabetes
Clinically, one can distinguish three states—normal, impaired glucose tolerance, and overt diabetes—characterized by specific cut-offs of blood glucose levels either while fasting or after an oral glucose load. However, T2D is a clinically heterogeneous disease often associated with complicating features of the metabolic syndrome such as obesity, dyslipidemia, hypertension, insulin resistance, and/or hyperinsulinemia. These physiological abnormalities may have overlapping molecular and genetic causes to further complicate diagnosis and treatment options. Many but not all patients develop comorbidities, including retinopathy, nephropathy, neuropathies, and cardiovascular disease. The potential for these unpredictable manifestations of the disease cannot be assessed during initial management, potentially leading to sub-optimal clinical care.2
Today, a physician may choose from a panel of seven drug classes, roughly grouped into four areas of action: increase of insulin secretion by the pancreas (sulfonylurea, meglitinides, exenatide, dipeptidyl peptidase-4 inhibitors), decreased glucose absorption by the intestines (α-glucosidase inhibitors), inhibition of glucose production in the liver (biguanide), and enhanced insulin sensitivity in adipose and peripheral tissues (thiazolidinediones). Thus, current medical management of T2D can be a lengthy and costly trial-and-error method before good glucose homeostasis is achieved.
Genetic Complexity of Type 2 Diabetes
Genetic factors are known to play an important part in the development of T2D, as exemplified by rare monogenic subtypes, the high prevalence in particular ethnic groups, and its modification by genetic admixture and the difference in concordance rates between monozygotic and dizygotic twins.3
Monogenic forms of T2D account for up to ~5% of T2D, but most cases of T2D do not show clear, Mendelian inheritance patterns. The extent to which multiple genes and the environment impact disease susceptibility and progression is still a subject of research. New technologies now facilitate this task. These include genome-wide linkage scans, which explore the co-segregation of genetic segments in affected members of the same family. Over 50 family-based linkage studies on a variety of populations have been reported. The availability of high-density singlenucleotide (SNP) arrays now allows researchers to perform genome-wide case-control association scans. Association studies investigate the relationship between disease and a genetic marker or a set of markers, comparing a population of affected individuals with a population of nonaffected subjects.
Monogenic Forms of Type 2 Diabetes
Maturity-onset Diabetes of the Young
Classically, maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, a diagnosis of T2D before the age of 25 years, and a primary defect of insulin secretion. Six MODY genes have been identified to date. Most frequently, MODY is due to either mutations in the gene for the beta-cell glucose-sensing hexokinase glucokinase (MODY2) or mutations in hepatocyte nuclear factor-1alpha (TCF1, MODY3). Most of the remaining MODY sub-types are associated with mutations in genes for transcription factors expressed in the pancreatic beta cells: hepatocyte nuclear factor 4alpha (MODY1), insulin promoter factor-1 (MODY4), hepatocyte nuclear factor-1beta (MODY5), and NeuroD/Beta2 (MODY6). About 10% of MODY cannot currently be explained through mutations in any of these genes.
Importantly, mutations in particular genes show distinct clinical characteristics in view of severity, the prognosis for disease development, and the risk of complications. Patients with MODY2 present with mild and stable hyperglycemia that is present from birth. Microvascular complications are rare and pharmacological treatment of hyperglycemia is usually not required. In contrast, MODY3 patients show severe hyperglycemia, usually after puberty, which may lead to the diagnosis of type 1 diabetes. Despite the progression of insulin secretion defects, MODY3 patients are quite sensitive to sulfonylurea treatment. Risk of diabetic retinopathy and nephropathy are high in MODY3, making frequent follow-up mandatory. In contrast, the frequency of cardiovascular disease seems not to be increased in MODY patients. In patients with MODY5, due to mutations in hepatocyte nuclear factor-1beta, diabetes is associated with pancreatic atrophy, renal morphological and functional abnormalities, and genital tract and liver test abnormalities. It is also noteworthy that, although MODY is predominantly inherited, penetrance or expression of the disease may vary and a family history of diabetes is not always present.
Advances in the Genetics of Type 2 Diabetes Mellitus in the Light of Personalized Healthcare
Diabetes is a chronic disorder of glucose homeostasis that affects >170 million people worldwide, and this figure is expected to double in the next 20 years. The majority of diabetes (~90%) is type 2 diabetes (T2D), caused by a combination of impaired insulin secretion from pancreatic beta cells and insulin resistance of the peripheral target tissues, especially muscle and liver. Historically, T2D has been considered a disease of late-adulthood onset, rarely observed in individuals under the age of 50. However, recent years have seen a steep increase in disease prevalence among children and adolescents, which has mainly betaen attributed to the unprecedentedly high levels of obesity in these groups.1
Clinical Complexity of Type 2 Diabetes
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