These results suggest that mutant GCK may lead to chronic hyperglycaemia by raising the threshold of circulating glucose level which induces insulin secretion.
These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment.
This nonradioactive SSCP technique may be useful to routinely diagnose glucokinase deficiency, which is an important cause of hyperglycemia among young type II diabetic patients.
Mutations in glucokinase are the primary cause of hyperglycemia in a substantial fraction of French patients with maturity-onset diabetes of the young and result in a relatively mild form of NIDDM that can be diagnosed in childhood.
Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency.
These results suggest that in addition to the altered beta cell function, abnormalities in liver glycogen metabolism play an important role in the pathogenesis of hyperglycemia in patients with glucokinase-deficient maturity onset diabetes of young.
Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.
Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50% of subjects have overt diabetes) and is evident during the early years of life.
Mutations in glucokinase/MODY2 result in mild chronic hyperglycaemia due to reduced pancreatic beta-cell responsiveness to glucose as well as decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis following meals.
Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications.
Mutations in MODY2/glucokinase result in mild chronic hyperglycaemia as a result of reduced pancreatic beta-cell responsiveness to glucose, and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis after meals.
Observations from other glucokinase families suggest that hyperglycaemia in this child is likely to be stable and will not require intensive medical follow up, whereas other forms of MODY (1, 3, and 4) might carry a different prognosis.
Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis.
The mutations co-segregate with hyperglycemia in the families of the three probands, whose biochemical and clinical phenotype is similar to other individuals with MODY 2 mutations.
Caucasian gestational diabetic subjects from the United Kingdom who had fasting hyperglycaemia in pregnancy but did not meet the diagnostic criteria for maturity-onset diabetes of the young (MODY) were selected for direct sequencing of the glucokinase gene if they fulfilled the following four criteria; (1) persisting fasting hyperglycaemia outside pregnancy (5.5-8 mmol/l) (2) a small increment (< 4.6 mmol/l) during a 2-h oral glucose tolerance test (3) insulin treatment during at least one pregnancy but subsequently controlled on diet and (4) a history of Type II (non-insulin-dependent) diabetes mellitus, gestational diabetes or fasting hyperglycaemia (> 5.5 mmol/l) in a first-degree relative.