MODY due to glucokinase mutations

Glucokinase plays a central role in carbohydrate metabolism. A member of the hexokinase family, it catalyses the first reaction of the glycolytic pathway, the conversion of glucose to glucose 6-phosphate. Pancreatic beta cells express the GLUT 2 receptor, which has a high glucose transport capacity and is unaffected by insulin. Beta cells also express glucokinase, and the flux of glucose through the pathway it catalyses allows it to act as a glucose sensor for the beta cell. Individuals with mutations within the GCK gene (GCK-MODY) have an abnormality of glucose sensing, which leads to an elevated threshold for initiation of glucose-stimulated insulin secretion. This results in stable mild hyperglycaemia, which does not predispose to complications of diabetes, and is thus unique among the various forms of dysglycaemia.

Background

Early descriptions of MODY noted its relative freedom from long-term complications of diabetes. This was later identified as specific to GCK-MODY. Glucokinase was an obvious candidate gene for diabetes because of its role in glucose sensing in the beta cell, and mutations in this gene were the first to be detected in MODY in 1992 when studies in MODY pedigrees showed linkage to the glucokinase gene region on chromosome 7p.[1][2]

Glucokinase

Glucokinase is a member of the hexokinase family that is expressed in hepatocytes and pancreatic beta cells. It differs from other members of the hexokinase family in that it has a high transport capacity (Km) for glucose, and is not inhibited by its product, glucose 6-phosphate, at physiological levels. When paired with the GLUT2 receptor, as in the liver and beta cell, it thus permits rapid insulin-independent entry and metabolism of glucose. This enables the liver to act as a 'sink' for circulating glucose, and the same system acts as a glucose sensing mechanism for the beta cell.

Glucokinase mutations

Not surprisingly, any mutation affecting the expression of glucokinase in the beta cell has readily detectable consequences. Heterozygous inactivating mutations cause mild fasting hyperglycaemia, the hallmark of GCK-MODY; homozygous inactivating mutations result in more severe hyperglycaemia presenting as permanent neonatal diabetes mellitus (PNDM). Other GCK mutations result in over-secretion of insulin and present with hyperinsulinemic hypoglycaemia.

Heterozygous inactivating mutations in GCK lead to a resetting of the normal threshold for glucose-stimulated insulin secretion.[3] Importantly, insulin secretion remains regulated. This leads to a consistent phenotype of fasting hyperglycaemia (fasting plasma glucose 5.5–8 mmol/l) with a low postprandial rise in glucose level and a HbA1c generally below 8%.[4][5] In contrast to other forms of diabetes, hyperglycaemia does not deteriorate with age.[6]

A characteristic feature of glucokinase diabetes, as shown in the oral glucose tolerance test, is raised fasting glycaemia with a small increment between the fasting and 2 hour values (2.1±2.3 mmol/l).[4] This distinguishes it from HNF1A-MODY, where the mean increment is 5.2±3.9 mmol/l.[4]

Clinical features and Management

Patients are typically asymptomatic and detected on routine screening, e.g. during incidental hospital admissions, in pregnancy, or as part of a routine health assessment. They may not meet formal diagnostic criteria for diabetes, or they may be classified as gestational diabetes, impaired fasting glycaemia, MODY or type 2 diabetes according to the circumstances that led to testing.

In GCK-MODY the defect is present from birth, and diagnosis may be delayed for many decades. This being the case, many glucokinase families do not meet classical MODY criteria with a diagnosis under the age of 25 years.

Evidence from observational studies (including a study of 99 GCK-MODY subjects exposed to hyperglycaemia for an average of 48.6 years) indicates that GCK-MODY patients do not develop microvascular diabetes-related complications, consistent with the near-normal levels of glycaemia.[7] [8] GCK-MODY patients typically have favourable cardiovascular risk factor profiles and prevalence of macrovascular outcomes comparable to unaffected population.[8][9] No change in HbA1c was seen in a small observational study of 20 GCK-MODY subjects after pharmacological therapy was discontinued following genetic diagnosis,[10] suggesting that treatment with oral hypoglycaemic agents or insulin does not affect diabetes control. It is recommended that anti-diabetic therapies can be stopped in most individuals with GCK-MODY (although insulin is often used in pregnancy). Annual monitoring of HbA1c is recommended to identify any individuals who develop worsening of hyperglycaemia because of concomitant obesity/insulin resistance. In this situation a rising HbA1c should be managed with metformin. Secondary care follow-up of patients is probably not warranted, so long as clear information is given to both the patient and their primary care provider.

References

  1. ^ Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356(6365):162–4

  2. ^ Hattersley AT, Turner RC, Permutt MA et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992;339(8805):1307–10

  3. ^ Byrne MM, Sturis J, Clement K, et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994;93(3):1120–30

  4. ^ Stride A, Vaxillaire M, Tuomi T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 2002;45(3):427–35

  5. ^ Martin D, Bellanne-Chantelot C, Deschamps I, et al. Long-term follow-up of oral glucose tolerance test-derived glucose tolerance and insulin secretion and insulin sensitivity indexes in subjects with glucokinase mutations (MODY2) Diabetes Care 2008;31(7):1321–3

  6. ^ Pearson ER, Velho G, Clark P, et al. Beta-cell genes and quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 2001;50(Suppl 1):S101–7

  7. ^ Steele A, Shields B, Shepherd M, et al. Microvascular complication risk in patients with 50 years of moderte are target ranges for glycaemic control appropriate? . Diabetic Med 2011; : 28–000

  8. ^ Steele AM, Shields BM, Wensley KJ, et al. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.

  9. ^ Schober E, Rami B, Grabert M, et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and experience from a large multicentre database. Diabet Med 2009;26(5):466–73

  10. ^ Gill-Carey OJ, Shields B, Colclough K, et al. Finding a glucokinase mutation alters treatment. Diabetic Medicine 2007;24(Suppl 1):A6–A20

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