Maturity-onset diabetes of the young (MODY) owes its name to a time when diabetes was defined by age of onset. The nomenclature has stuck, however, and MODY defines usually non-insulin dependent diabetes occurring before the age of 25 years and with a striking autosomal dominant inheritance. Beta-cell dysfunction is usually present but in contrast to type 2 diabetes, obesity and insulin resistance are unusual. MODY accounts for about 1 – 2% of patients with diabetes in most white Europid populations. The diagnostic criteria which should suggest a diagnosis of MODY are listed in Box 8.1.
A recent survey of newly presenting non-type 1 diabetes in children < 16 years of age in the UK revealed 17 cases of MODY, giving an incidence of 0.13/100,000 patient-years. This is almost certainly an underestimate as MODY 2 is often undetected for many years because it is largely asymptomatic….
The most common causes (accounting for > 75% of cases) are mutations in nuclear transcription factors that control insulin production and secretion. They are listed in Table 8.1 together with associated clinical features. MODY 2 is a defect in the glucose-sensing glucokinase enzyme which means that insulin release occurs at higher than usual circulating blood glucose levels, usually leading to a raised fasting blood glucose. These patients are commonly detected either in pregnancy during screening for gestational diabetes, or as part of a health screening program. MODY 2 needs no treatment, is largely benign and not associated with diabetes complications.
Box 8.1 Diagnostic criteria for MODY
Other forms of MODY, however, are progressive and require treatment. Sulphonylureas are often initially effective but many patients ultimately need insulin. Because blood glucose levels are higher than MODY 2, these patients are prone to both micro- and macrovascular complications.
Many pancreatic diseases can cause diabetes, but in total they account for < 1% of all cases. Acute pancreatitis (commonly associated with alcoholism or gallstones) (Figure 8.1) usually results in transient hyperglycemia, but permanent diabetes occurs in up to 15% of patients.
Tropical calcific pancreatitis is confined to India and developing nations, and results in diabetes in 90% of cases. Even in these countries, it accounts for only 1% of diabetes.
It is often associated with malnutrition, its aetiology is not understood and most patients require insulin.
This is a common autosomal recessive condition which results in abnormal chloride and water transport across epithelial membranes. Over 1500 mutations in the cystic fibrosis transmembrane conductance regulator gene have been described and they result in differing severities of the condition. Pancreatic and pulmonary disease predominate and better treatment has resulted in much improved survival. Diabetes results from β cell failure secondary to exocrine pancreatic damage. A recent UK survey of 8029 patients on the cystic fibrosis register studied from 1996 to 2005 revealed an annual incidence of diabetes of 3.5%, but this was 1 – 2% in the first decade of life, and 6 – 7% in the fourth. Female sex, more severe lung dysfunction, liver disease, exocrine pancreatic insufficiency, steroid use and severity of gene expression were all positively related to diabetes development.
The earliest biochemical abnormality tends to be postprandial hyperglycemia. The majority of patients require insulin treatment.
This is an autosomal recessive inborn error of metabolism, usually caused by a mutation in the hemochromatosis gene, HFE, on chromosome 6. The HFE protein is expressed on duodenal enterocytes and modulates iron uptake. Hemochromatosis is associated with increased iron absorption and tissue deposition, notably in the liver, pancreatic islets, skin and pituitary glands. The classic clinical triad is one of hepatic cirrhosis, glucose intolerance with insulin-requiring diabetes in 25%, and skin hyperpigmentation, which has led to the term ‘bronzed diabetes’. Serum iron and ferritin concentrations are raised. Secondary hemochromatosis may occur in patients who undergo frequent blood transfusions, for example those with Β- thalassemia or other hemoglobinopathies.
Rarely, diabetes can be a presenting feature of pancreatic cancer. Usually, however, there are other features such as profound weight loss and back pain. The prognosis is very poor; insulin treatment is usual.
Permanent neonatal diabetes (PNDM) is caused by a mutation in the gene coding the Kir 6.2 and SUR1 sub units of the KATP channel on the β cell. This defect results in an inability to release insulin and consequent ketoacidosis, usually occurring before 6 months of age. Sulphonylureas close this channel by an ATP-independent route and are effective in over 50% of cases of PNDM.
Mitochrondrial DNA is inherited maternally. A heteroplasmic mutation at position 3243 results in type 2 diabetes and sensorineural deafness. Other features include myopathy, pigmented retinopathy, cardiomyopathy and neurological abnormalities. Its most severe form comprises the MELAS syndrome (Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). Prevalence studies suggest that Mt 3243 accounts for 1 – 2% of Japanese and 0.2 – 0.5% of European type 2 diabetes.
This rare autosomal recessive disorder was first described in 1938. The most common features are Diabetes Insipidus, type 1 Diabetes Mellitus, Optic Atrophy (Figure 8.3) and Deafness (DIDMOAD). There are many other features, notably psychiatric illness. A gene defect on chromosome 4 coding for a transmembrane protein (wolframmin) has been described, together with some mitochondrial DNA abnormalities (but not 3243). Diabetes usually occurs in the second decade and prevalence has been estimated as between 1 in 100,000 – 800,000 of the population.
These are rare inherited conditions characterized by a partial or total absence of adipose tissue and have an associated insulin resistance. In many cases, the genetic basis has been discovered, leading to new insights into the causes of insulin resistance. Patients with partial lipodystrophy (sometimes called the Kobberling – Dunnigan syndrome) have an abnormality in the LMNA (encoding lamin A/C which is a constituent of nuclear lamina) or PPAR γ gene. These changes result in defective adipocyte differentiation and/or cell death. Apart from type 2 diabetes, some of these patients also have problems with severe hypertriglyceridemia, hepatic steatosis and pancreatitis.
Generalized lipoatrophy usually presents in early childhood and several different genetic causes have been described for this. Severe insulin resistance, diabetes and hyperlipidemia are the norm.
This autosomal dominant disorder is the most common adult form of muscular dystrophy (prevalence 1 in 8000 population) and is characterized by abnormal insulin secretion, insulin resistance and type 2 diabetes. The abnormal mutation is in the protein kinase gene on chromosome 19 and this may affect insulin receptor RNA and protein expression or perhaps calcium-dependent insulin release from the β cells.
Genetic abnormalities in the insulin receptor can give rise to rare but well-described syndromes characterized by severe insulin resistance. Clinically these patients have acanthosis nigricans (hyperpigmented velvety skin in the flexures of the neck, axillae or groin) (Figure 8.4) and hyperandrogenism. Mutations of the gene encoding the α subunit of the insulin receptor can lead to leprechaunism or the less severe Rabson – Mendenhall syndrome (Figure 8.5).
A 22-year-old woman was referred to the medical obstetrics clinic for booking at 6 weeks gestation of her first pregnancy. She had had diabetes for 10 years, initially on sulphonylureas for 6 months but now on insulin. She had never been ketotic. Her control was fair (HbA1c 8.2%). She had a strong family history of diabetes; her mother had type 2 diabetes and was now on insulin and currently an inpatient, having required a below-knee amputation for neuroischemia and gangrene. Her brother was in the army and had recently been diagnosed with type 2 diabetes at the age of 19 years. Another brother aged 24 years had ad diet-controlled diabetes for 6 years.
DNA testing revealed a mutation in the HNF1 α gene, confirming a diagnosis of MODY 3. During pregnancy her glycemic control improved dramatically but unfortunately she developed rapidly progressive retinopathy requiring laser photocoagulation. Postpartum she was tried again on sulphonylureas but her glycemia worsened and she was recommenced on insulin. Three years later she has established nephropathy and has required vitreoretinal surgery.
Comment: This case shows many of the typical features of MODY as outlined in Box 8.1. Not all can be managed on oral agents and many are prone to severe complications. This woman and her family have received counselling from the UK Regional MODY Service.
Type A insulin resistance affects mainly adolescent girls and shares many features with the polycystic ovary syndrome (Figure 8.4). In 25% of cases there is a mutation of the tyrosine kinase domain of the β subunit of the insulin receptor.
Rare mutations of the human preproinsulin gene can lead to abnormal levels of insulin precursors. Such patients are heterozygous (homozygosity would be incompatible with life), and develop diabetes in later life in response to other factors such as obesity.
Type B insulin resistance is very rare and the result of circulating antibodies to the insulin receptor. There is a link with other autoimmune diseases and with these shares a female preponderance. Patients may have fluctuating hyper-and hypoglycemia and are very difficicult to treat.
Diabetes complicating other endocrine diseases
Several endocrine conditions are associated with diabetes mellitus. Cushing’s syndrome is the result of glucocorticoid excess from any cause, including steroid drug induced, pituitary adenomas, adrenal tumors and ectopic ACTH production. Glucocorticoid excess results in central obesity which causes insulin resistance. This in turn stimulates hepatic gluconeogenesis, peripheral adipose tissue lipolysis and NEFA release. All of these inhibit peripheral glucose uptake and the net result is hyperglycemia. Most patients have some degree of glucose intolerance, with overt diabetes in 10 – 20% of cases.
Acromegaly is a condition of growth hormone excess almost always arising from an anterior pituitary tumor. This causes glucose intolerance by inducing insulin resistance. Overt diabetes and impaired glucose tolerance each affect around one-third of patients with acromegaly. Glucose tolerance returns to normal with effective treatment and reduction of circulating growth hormone levels.
Pheochromocytomas are tumors that arise from the chromaffin cells of the sympathetic nervous system, usually in the adrenal medulla but they can occur anywhere along the sympathetic nervous chain. They secrete excess catecholamines, and typically the clinical presentation is that of high blood pressure, headache, tachycardia and sweating, sometimes occurring in paroxysms. Up to 75% have evidence of glucose intolerance but this rarely needs treatment with insulin. Resolution is usual with removal of the tumour.
Glucagonomas are rare tumors of the islet α cells (Figure 8.6). They are slowly growing but often malignant. The most striking clinical features are weight loss and a characteristic rash, termed ‘necrolytic migratory erythema’ affecting skin flexures and the perineum. There is also a tendency to thromboembolism and neuropsychiatric disorders. Diabetes is common and the result of enhanced gluconeogenesis and glycogenolysis induced by high circulating glucagon levels. It usually resolves with removal of the tumor.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33 (Suppl 1): S62 – S69.
Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004; 350: 1220 – 1234.
Maleciki MT. Genetics of type 2 diabetes mellitus. Diabet Res Clin Pract 2005; 68 (Suppl 1): S10 – S21.
McCarthy MI, Hattersley AT. Learning from molecular genetics. Diabetes 2008; 57: 2889 – 2898.
Next Week: Metabolic control and complications
For more information and to purchase this book, just follow this link: