The grey zone between type 1 and type 2 diabetes : genetic aspects of diabetes in adults
Year: 2012
Type: dissertation
Study design: Observational Study
Abstract: In the last decades the prevalence of diabetes has increased dramatically. Diabetes is a complex disease often subdivided into type 1 diabetes, characterized by autoimmune destruction of the insulin-producing beta-cells, and type 2 diabetes, characterized by insulin resistance and some degree of reduced insulin secretion. However, type 1 diabetes-associated autoantibodies are present in up to 11% of European patients diagnosed with type 2 diabetes. This autoimmune subtype of adult-onset diabetes is termed latent autoimmune diabetes in adults (LADA). For childhood-onset type 1 and type 2 diabetes several disease-associated genetic regions have been identified, whereas much less is known about the genetic predisposition to LADA and adult-onset type 1 diabetes. The aims were to compare LADA and type 1 diabetes patients diagnosed at >35 years, focusing on gene variants predisposing to type 1 or type 2 diabetes and zinc transporter type 8 autoantibodies (ZnT8A), as well as to assess genetic heterogeneity in LADA. Moreover, phenotypic associations of type 1 diabetes risk variants were assessed in LADA patients and in non-diabetic adults. LADA shared a genetic predisposition with both type 1 (HLA-DQB1, PTPN22, and CTLA4) and type 2 diabetes (SLC30A8 and TCF7L2). Compared with adult-onset type 1 diabetes LADA differed genetically, with respect to both type 1 and type 2 diabetes-risk variants, and immunologically, with respect to prevalence and persistence of ZnT8A. Genetic heterogeneity in LADA was attributed to both GADA reactivity and family history of type 1 diabetes. GADA reactivity was associated with higher frequencies of the type 1 diabetes-risk variants (HLA-DQB1, PTPN22, and CTLA4) and lower frequency of the type 2 diabetes-risk variants (SLC30A8 and FTO). Family history of type 1 diabetes was associated with increased frequencies of HLA-DQB1-risk genotypes and reduced frequencies of TCF7L2-risk genotypes. In non-diabetic adults, HLA-DQ and PTPN22 were associated with GADA positivity. Even though the type 1 diabetes-risk genotypes were not associated with progression to non-insulin-dependent diabetes in these individuals, those individuals carrying a higher number of type 1 diabetes-risk genotypes were unable to increase the insulin secretion to a level similar to carriers of a lower number of risk genotypes in response to reduced insulin sensitivity over time. Furthermore, in both LADA and type 2 diabetes patients type 1 diabetes-risk variants were associated with reduced insulin secretion. Our data suggest that LADA is a slowly progressive form of autoimmune diabetes distinct from type 1 diabetes, and that type 1 diabetes-risk variants signify a mild reduction in beta-cell function in non-diabetic adults as well as in LADA and type 2 diabetes patients.
Source: Työväentutkimus Vuosikirja
Author: Mette K. Andersen
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2255564723