Diabetes may result from mutations in a single gene, and monogenic forms of diabetes account for 1–2% of cases in young people. The gene is inherited from a parent in most instances, but may arise from spontaneous mutation. Most forms of monogenic diabetes are caused by a reduced ability to process or secrete insulin, but rare variants result in insulin resistance. Monogenic diabetes should be suspected in those who develop diabetes under the age of 6 months, in familial diabetes, when there is mild to moderate fasting hyperglycaemia (5.5–8 mmol/l), or where there are extrapancreatic features. Maturity onset diabetes of the young (MODY) is the commonest form of monogenic diabetes, followed by neonatal diabetes, but a large number of gene variants have now been described. It is important to be alert to the possibility of monogenic diabetes, since correct diagnosis may have profound implications for management, prognosis and genetic counselling.
Type 1 and type 2 diabetes are common, complex polygenic disorders whose aetiologies are hard to unravel. In contrast, rapid progress has been made over the past two decades in the identification of a range of single-gene disorders that may result in diabetes. Some of these form part of distinct genetic syndromes in which other abnormalities are prominent, and these are considered separately. The term monogenic diabetes is generally reserved for single gene disorders whose principal manifestation is diabetes, although extra-pancreatic features may also be present. Investigation of these uncommon causes of diabetes has provided considerable insight into the mechanisms underlying insulin secretion and action.
Although monogenic diabetes may be responsible for no more than 1–2% of all cases in most populations, the diagnosis may have profound implications for treatment and prognosis, and clinicians need to be alert to this diagnosis.
Classification of monogenic diabetes
Monogenic diabetes may arise because of defects in insulin secretion or insulin action. Insulin secretory defects account for all cases of MODY, and most cases of neonatal diabetes. Insulin resistance syndromes my be subdivided into those due to a defect in insulin signalling and those in which adipose tissue is unresponsive to insulin ('adipose failure').
Mutations in at least ten genes have been shown to lead to a MODY phenotype, but three account for more than 90% of cases in the UK. These are due to mutations in the genes encoding the enzyme glucokinase (GCK) and the nuclear transcription factors hepatocyte nuclear factors HNF1A and HNF4A. The clinical aspects of MODY vary according to its specific cause, but a number of generic features are present and should prompt clinical suspicion. These are, according to ISPAD guidelines :
- Early onset of diabetes, usually (but not necessarily) diagnosed before the age of 25
- Family history of diabetes in a parent (even if this has been labelled type 1 or type 2)
- Hyperglycaemia initially easy to control, no history of diabetic ketoacidosis
- No features suggestive of insulin resistance (e.g. obesity, acanthosis nigricans)
- Persistence of C-peptide secretion beyond the 'honeymoon' period (3 years)
- Absence of islet autoantibodies at diagnosis
Genes associated with MODY GCK mutations result in modest elevations of fasting glucose that are present from birth and usually asymptomatic; these are more likely to be recognised in countries that screen young people for hyperglycaemia. Conversely, HNF mutations are more commonly diagnosed in countries without screening programmes.
GCK is a key regulatory enzyme in the beta cell, and has been called the pancreatic glucose sensor. Heterozygous inactivating mutations cause mild fasting hyperglycaemia, the hallmark of GCK-MODY; rare homozygous inactivating mutations result in more severe hyperglycaemia presenting as permanent neonatal diabetes mellitus (PNDM). Other GCK mutations result in oversecretion of insulin and present with hyperinsulinemic hypoglycaemia.
The other common forms of MODY are due to mutations in the genes encoding nuclear transcription factors of the hepatocyte nuclear factor (HNF) family, the common variants being HNF1α and -4α, which account for 50% and 10%, respectively, of cases in the UK. These have similar presentations, and are differentiated by genetic testing.
GCK-MODY is typically asymptomatic, is present from birth, is non-progressive, and has a benign prognosis. In contrast, HNF1A/HNF4A-MODY leads to progressive beta-cell dysfunction, with normoglycaemia in childhood and diabetes presenting in the 2nd-4th decade. Treatment requirements increase with time and insulin is often required for its management. Poor control is associated with the characteristic long-term complications of diabetes.
Neonatal diabetes is defined as diabetes occurring in the first 6 months of life, and is very rare (1/100,000 live births). Two main subgroups are recognised in about equal proportions: permanent neonatal diabetes (PMND) and transient neonatal diabetes (TNDM). The latter remits in infancy/childhood but may recur later in life. Neonatal diabetes is a monogenic disorder with mutations in more than 15 genes reported. It differs from type 1 diabetes in that it lacks any features of autoimmunity. Early genetic diagnosis is important, since some forms involve the ATP-sensitive potassium channel (KATP channel) on the beta cell membrane and respond to treatment with high dose sulfonylureas.
Insulin resistance syndromes
Rare, often monogenic, forms of severe insulin resistance were first described in the 1970s. New molecular methods of diagnosis coupled with greater clinical awareness have resulted in spectacularly rapid proliferation of newly discovered genetic mutations and their (often overlapping) associated syndromes. This, in turn, has resulted in enormously greater insight into the underlying mechanisms of insulin action and tissue response.
As a result of these newer insights, an updated classification of severe insulin resistance (IR) has recently been proposed.. The new proposed classification, based upon mechanism, distinguishes two main types of disorder: those in which there is a primary defect in insulin signal transduction, and those in which there is a failure of insulin signal recognition by adipose tissue, or 'adipose failure'.
Primary insulin resistance can then be subdivided into a 'generalised' form, in which there is a defect at the level of the insulin receptor, and 'partial' insulin resistance in which the signaling defect is limited to some elements of the postreceptor signal transduction pathway or to some tissues but not others. Although few forms of the latter are currently recognised, modern sequencing technologies are likely to result in greater expansion of this subgroup.
Adipose failure may be subdivided into a group with manifest lipodystrophy, arising from a failure of adipose tissue formation, and leading to severe insulin resistance in the presence of a low or normal adipose tissue mass. The second group is characterised by unrestrained accumulation of adipose tissue, usually due to hyperphagia. This is sufficient to overwhelm the body's capacity to handle triglyceride and adipose tissue metabolism.
^ Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes in the young (MODY). BMJ 2011;d6044. doi 10.1136/bmjd6044
^ ISPAD Guidelines. www.ispad.org/FileCenter/ISPAD%20Guidelines%202009%20-%20Monogenic%20diabetes.pdf
^ Osbak KK et al. Update on mutations in glucokinase (GCK) which cause maturity onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Human Mutation 2009;30(11):1512–26
^ Semple RK et al. Genetic syndromes of severe insulin resistance. Endocrine Reviews 2011;32(4):498–512