Functional Variants of the <emph type="ital">HMGA1</emph> Gene and Type 2 Diabetes Mellitus

Abstract

Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

Recent advances in the molecular genetics of type 2 diabetes mellitus

“…Analysis of cultured EBV-transformed lymphoblasts from patients with T2DM and the rs146052672 variant revealed that these cells had lower levels of HMGA1 and INSR protein than cells from either patients with wild-type T2DM or controls. Once again, in transformed lymphoblasts from the patients with the HMGA1 rs146052672 variant, restoration of HMGA1 protein expression by complementary DNA transfection (in the sense but not antisense direction) restored INSR protein expression and insulin binding to these cells [40] . Although not replicated in a heterogeneous French population [73] , the HMGA1 rs146052672 variant was significantly associated with T2DM among Chinese [41] and Hispanic-American [38] individuals.…”

“…In the context of these investigations, we later showed that four functional variants of the HMGA1 gene, leading to reduced INSR expression, were associated with insulin resistance and T2DM [40] . The most frequent functional HMGA1 variant, c.136-14_136-13insC (also designated rs146052672), was detected in 7%-8% of patients with diabetes in individuals of white European ancestry [40] .…”

“…However, certain patients with apparently normal INSR genes have reduced expression of both the INSR protein and INSR mRNA levels [13,18,19] . In these patients, it is possible that there are mutations in genes encoding transacting factors which regulate the level of INSR gene expression [40] . The mechanisms by which gene variants may impair insulin action in insulin target tissues are schematized in Figure 3.…”

“…The most frequent functional HMGA1 variant, c.136-14_136-13insC (also designated rs146052672), was detected in 7%-8% of patients with diabetes in individuals of white European ancestry [40] . Analysis of cultured EBV-transformed lymphoblasts from patients with T2DM and the rs146052672 variant revealed that these cells had lower levels of HMGA1 and INSR protein than cells from either patients with wild-type T2DM or controls.…”

Differential Genetic Advantages in Youth and in Aging, or How to Die Healthy

“…later, an unexpected relationship has been found between the levels of hMGA1 and a condition typical of middle age such as insulin resistance. namely, a number of polymorphisms in the hmga1 gene resulting in severe insulin resistance and pronounced hyperglycemia have been identified in animal models as well as in humans (18,31). hyperglycemia usually produces an increased level of oxidative stress and associated DnA damage in mitochondria (5), and, since the accumulation of unrepaired damage in DnA is considered a basic carcinogenic mechanism, it has been proposed that inherently low levels of hMGA1 expression (e.g.…”