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1 Maturity-onset diabetes of the young (MODY) This subgroup is a relatively rare monogenic disorder characterized by non insulin-dependent diabetes with autosomal dominant inheritance and an age at onset of 25 years or younger Patients are nonobese, and their hyperglycemia is due to impaired glucose-induced secretion of insulin Six types of MODY have been described Except for MODY 2, in which a glucokinase gene is defective, all other types involve mutations of a nuclear transcription factor that regulates islet gene expression MODY 2 is quite mild, associated with only slight fasting hyperglycemia and few if any microvascular diabetic complications It generally responds well to hygienic measures or low doses of oral hypoglycemic agents MODY 3 the most common form accounts for two-thirds of all MODY cases The clinical course is similar to that of idiopathic type 2 diabetes in terms of microangiopathy and failure to respond to oral agents with time 2 Diabetes due to mutant insulins This is a very rare subtype of nonobese type 2 diabetes, with no more than ten families having been described Since affected individuals were heterozygous and possessed one normal insulin gene, diabetes was mild, did not appear until middle age, and showed autosomal dominant genetic transmission There is generally no evidence of clinical insulin resistance, and these patients respond well to standard therapy
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3 Diabetes due to mutant insulin receptors Defects in one of their insulin receptor genes have been found in more than 40 people with diabetes, and most have extreme insulin resistance associated with acanthosis nigricans In very rare instances when both insulin receptor genes are abnormal, newborns present with a leprechaun-like phenotype and seldom live through infancy 4 Diabetes mellitus associated with a mutation of mitochondrial DNA Since sperm do not contain mitochondria, only the mother transmits mitochondrial genes to her offspring Diabetes due to a mutation of mitochondrial DNA that impairs the transfer of leucine or lysine into mitochondrial proteins has been described Most patients have a mild form of diabetes that responds to oral hypoglycemic agents; some have a nonimmune form of type 1 diabetes Two-thirds of patients with this subtype of diabetes have a hearing loss, and a smaller proportion (15%) had a syndrome of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) 5 Wolfram s syndrome Wolfram s syndrome is an autosomal recessive neurodegenerative disorder first evident in childhood It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD It is due to mutations in a gene named WFS1, which encodes a 1003 KDa transmembrane protein localized in the endoplasmic reticulum The function of the protein is not known The diabetes mellitus, which is nonimmune and not linked to specific HLA antigens, usually presents in the first decade together with the optic atrophy Cranial diabetes insipidus and sensorineural deafness develop during the second decade in 60 75% of patients Ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, peripheral neuropathy, and psychiatric illness develop later in many patients
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insulinoma restores normal insulin levels The main value of grouping these disorders as a syndrome, however, is to remind clinicians that the therapeutic goals are not only to correct hyperglycemia but also to manage the elevated blood pressure and dyslipidemia that result in increased cerebrovascular and cardiac morbidity and mortality in these patients Clinicians aware of this syndrome are more cautious in prescribing therapies that correct hypertension but may raise lipids (diuretics, -blockers) or that correct hyperlipidemia but increase insulin resistance, with aggravation of diabetes (niacin) Finally, the use of long-acting insulins and sulfonylureas that promote sustained hyperinsulinism may have to be moderated, with insulin-sparing drugs such as metformin or a thiazolidinedione being preferable, if the hypothesis behind the insulin resistance syndrome is ever substantiated
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