Monogenic Causes of Diabetes : Glucokinase MODY
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page279-280
2025-12-14
34
Glucokinase catalyses the phosphorylation of glucose to glucose- 6- phosphate, the first and rate- limiting step in intracellular glucose metabolism in both β cells and hepatocytes (Figure 1). Owing to the unique catalytic properties of the enzyme, the rate of glucose phosphorylation is proportional to the glucose concentration, thus allowing β cells and hepatocytes to respond to changes in glycaemia. In the β cell, glucokinase acts as a glucose sensor, ensuring insulin release is appropriate to the glucose concentration. Heterozygous loss- of- function variants in GCK result in a shift of the dose–response curve to the right. Glycaemia is therefore regulated at a higher set- point, but remains tightly controlled. People with glucokinase variants are still able to stimulate their β cells maximally. Glucokinase is also present in the liver and as a result these individuals have reduced hepatic glycogen synthesis. Over 900 pathogenic variants have been identified that cause GCK MODY. Homozygous loss- of- function glucokinase variants are a rare cause of insulin requiring diabetes presenting in the neonatal period. Gain of- function variants cause congenital hyperinsulinism.
Fig1. Schematic of β- cell depicting key steps in glucose sensing and insulin secretion (brown boxes) and transcription factors, enzymes, organelles, and protein channels that may, if mutated, be a cause of monogenic diabetes (pale yellow boxes). ATP, adenosine triphosphate; GCK, glucokinase gene; MODY, maturity- onset diabetes of the young. Source: Adapted from Fajans et al..
Clinical features
People with GCK MODY, due to heterozygous loss- of- function variants, have mild fasting hyperglycaemia from birth, usually 5.4 8.3 mmol/l (97–149 mg/dl), and HbA1c results range between 40 and 60 mmol/mol (5.8–7.6%). There is only a minor increase in HbA1c with age, but this is also seen in older healthy people (Figure 2). People with GCK MODY do not typically have symptoms of hyperglycaemia. Post- meal glucose values are only mildly raised and there is frequently only a small increase (<3 mmol/l in 70% and <4.6 mmol/l in 90% of those with GCK MODY) seen at two hours on an oral glucose tolerance test, which may explain the near- normal HbA1c and rarity of complications. Glycated haemoglobin values above 60 mmol/mol (7.6%) would be suggestive of an alternative diagnosis and marked worsening of the glycaemia suggests the development of type 1 diabetes or type 2 diabetes in addition to GCK MODY. Microvascular and macrovascular complications are not seen, even when mild hyperglycaemia is present for 50 years. Almost all individuals with GCK will have an affected parent; however, as glucokinase MODY is asymptomatic there may be no known family history of diabetes, despite its autosomal dominant inheritance. Testing of apparently unaffected parents can reveal that one parent has mildly raised fasting plasma glucose.
Fig2. Variation of blood glucose concentration with age in people with glucokinase and transcription factor maturity- onset diabetes of the young. Source: Steele et al. and Hattersley.
Differentiating from type 1 diabetes and 2 diabetes
Diagnosis of glucokinase MODY is most important in young individuals who may otherwise be thought to have type 1 diabetes and treated with insulin. Unlike type 1 diabetes, hyperglycaemia remains mild and β- cell antibodies are expected to be negative; these individuals are only likely to be positive for antibodies in the same proportion as the normal population. Fasting C- peptide will remain detectable and the post- meal rise in glucose concentration will be far less than in type 1 diabetes. Differentiating glucokinase MODY from type 2 diabetes can be challenging, as both conditions can cause mild hyperglycaemia with a family history. Lack of obesity and absence of insulin resistance, a raised fasting glucose with a mild post- prandial rise, HbA1c 40–60 mmol/mol (5.8–7.6%), and non- progression over time all suggest glucokinase MODY.
Management
Outside pregnancy, anti- diabetes medication is not recommended as hyperglycaemia is mild, significant microvascular complications are not seen, and medication does not lower glucose because the homeostatic regulation of glycaemia is preserved. Once diagnosis is confirmed, all diabetes treatment should be discontinued and no follow- up is required; however, this should be done with caution as it is possible for type 1 diabetes or type 2 diabetes to coexist with a GCK variant.
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