Genetic and clinical characteristics of maturity‐onset diabetes of the young

Abstract

Genetic factors play an important role in various forms of diabetes mellitus (DM), but inheritance is complex and interacts with environmental factors. Although in most cases type 2 DM (T2DM) and T1DM are polygenic disorders, several monogenic forms have been identified. Among them, maturity-onset diabetes of the young (MODY) has been the most intensively investigated. MODY is a group of six different forms of monogenic diabetes, characterized by insulin secretion defects in pancreatic beta-cells, supposed to be responsible for 2-5% of all cases of diabetes. The most common are MODY2 and MODY3, caused by mutations in the genes encoding glucokinase and hepatocyte nuclear factor 1-alpha respectively. MODY2 is characterized by glucose sensing defects, leading to an increase in insulin secretion threshold. This causes lifelong sustained and mild hyperglycaemia from birth, most often in non-diabetic levels. Diagnosis is incidental in most cases. These patients are asymptomatic, seldom need treatment and rarely present chronic complications. MODY3 is characterized by a severe insulin secretion defect in response to glucose. Diagnosis is made usually in adolescence and early adulthood, often by osmotic symptoms. Hyperglycaemia is progressive, and patients frequently need treatment with oral drugs or insulin some time in their follow up. This group seems to have a marked sensitivity to sulphonylureas compared to other types of diabetes. The recognition of MODY as a monogenic disorder and a thorough understanding of its pathophysiology are important for correct diagnosis and treatment, with great impact on prognosis. Besides, the study of these forms of diabetes brings important contributions to the understanding of glucose homeostasis as a whole.

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

“…However, the average onset age is falling in humans and is becoming increasingly common among those aged ,30 years, including children and adolescents in various ethnic groups (15)(16)(17)(18). This early-onset diabetes is characterized by increased disease severity and pancreatic b-cell failure than is typical of type 2 diabetes (19)(20)(21). Data on the impact of earlyonset type 2 diabetes on human skeletal health are limited, although one report indicated that children with prediabetes with impaired glucose tolerance have low mineral content and low bone mass (22).…”

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β,

“…HeLa cells were transfected by use of Opti-MEM and LipofectAMINE 2000 reagent (Invitrogen) according to the manufacturer's recommendations. Briefly, a total of 50 ng of pCMV-SPORT6 HNF1β or mutants, 50 ng of pGL3-(β28) 3 and 5 ng of pRL-TK (control Renilla luciferase vector) were used for transfection of 1 × 10 5 cells seeded on a 24-well plate 1 day before transfection. Forty-eight hours after transfection, cells were washed with 1 × PBS and lysed with luciferase lysis buffer supplied with the luciferase assay kit (Promega).…”

“…Three copies of the HNF1β binding element from the β-fibrinogen promoter [pGL3-(β28) 3 ] were subcloned into the firefly luciferase reporter vector pGL3-Basis (Promega). The Quick Change Multi Site-Directed Mutagenesis kit (Stratagene) was used to create specific substitutions, and all sequences were verified.…”

More than kin, less than kind: one family and the many faces of diabetes in youth

“…Some subtypes of monogenic diabetes can be treated with sulfonylureas, like those caused by mutations in genes such as HNF1A and HNF4A (7), whereas others such as GCK-MODY may not need medical treatment at all (8). This is in contrast with type 1 diabetes, in which insulin therapy is required.…”