Familial Hyperglycemia Due to Mutations in Glucokinase -- Definition of a Subtype of Diabetes Mellitus

TLDR

Non‑insulin‑dependent diabetes mellitus is genetically heterogeneous, and maturity‑onset diabetes of the young—an autosomal dominant, early‑onset form of NIDDM—can arise from glucokinase mutations that regulate glucose metabolism in β‑cells and liver. The study aimed to determine the frequency and clinical characteristics of glucokinase mutations in 32 French MODY families and 21 late‑onset NIDDM families. Researchers assessed metabolic status via fasting glucose and OGTT, isolated DNA from lymphocytes, performed linkage analysis, amplified glucokinase exons by PCR, and screened for mutations using conformation‑dependent polymorphism analysis and sequencing.

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is a genetically heterogeneous disorder. Maturity-onset diabetes of the young, a form of NIDDM with an early age of onset and autosomal dominant inheritance, can result from mutations in glucokinase, a key enzyme of glucose metabolism in beta cells and the liver. We studied 32 French families with maturity-onset diabetes of the young as well as 21 families with late-onset NIDDM to determine the frequency and clinical features of mutations of glucokinase. Fasting plasma glucose concentrations and oral glucose-tolerance tests were used to determine metabolic status. DNA was isolated from lymphocytes, and DNA polymorphisms in the glucokinase gene were tested for linkage with diabetes. Individual exons of the glucokinase gene from one affected member in each family were amplified by the polymerase chain reaction and screened for mutations by analysis of the conformation-dependent polymorphisms of single-stranded DNA and by DNA sequencing.