Abbreviation: MODY, maturity-onset diabetes of the young.

Abbreviation: MODY, maturity-onset diabetes of the young.

Glucose is transported into the b-cell by a glucose-transporter protein, GLUT-2, which is present in excess and is not a limiting factor (Fig. 1). Once in the cell, glucose is phosphorylated to glucose-6-phosphate, a step catalyzed by gluco-kinase, the gene mutated in MODY2. This step is considered the rate-limiting step in glucose metabolism [2] and results in an increase in the ATP/ADP ratio that closes K+ channels, resulting in insulin release. A decrease of glucokinase activity to half normal means that a higher glucose level is required to cause these changes, hence the reduced sensitivity of the b-cells to glucose [4]. Furthermore, because glucokinase is also responsible for glucose phosphorylation in hepa-tocytes, its mutation results in a defect in postprandial glycogen synthesis in the liver [5].

The pathophysiology of other forms of MODY is less well understood at the molecular level. Hepatocyte nuclear factors (three of which are MODY genes [see [Table 1]) play a role in the development of the b-cell, regulating both proliferation and metabolism [2]. Insulin promoter factor-1, the gene mutated in MODY4, is a pancreatic transcription factor that regulates early development of both endocrine and exocrine pancreas but persists in the mature b-cell, where it is necessary for the transcription of insulin [6]. Homozygosity for insulin promoter factor-1 mutation in an offspring of consanguineous heterozygous parents with MODY4 resulted in pancreatic agenesis that required pancreatic enzyme replacement in addition to insulin [7]. Finally NEUROD1, the gene mutated in MODY6, encodes a transcription factor that, in addition to playing a role in neuron development, also regulates insulin gene expression by binding to a critical E-box motif on the insulin promoter [8].

Fig. 1. Glucose enters the b-cell by the glucose transporter protein, Glut-2. Once within the cell, glucose is phosphorylated to glucose-6-phosphate, a rate-limiting step that is catalyzed by the enzyme glucokinase. This results in an increase in the ATP/ADP ratio with resultant closure of the ATP-dependent potassium channel and depolarization of the b-cell. Depolarization results in opening of the voltage-dependent calcium channel and influx of calcium leading to fusion of insulin-secretory granules with the cell membrane and release of insulin. (Courtesy of Z. Punthakee, Montreal, Quebec.)

Fig. 1. Glucose enters the b-cell by the glucose transporter protein, Glut-2. Once within the cell, glucose is phosphorylated to glucose-6-phosphate, a rate-limiting step that is catalyzed by the enzyme glucokinase. This results in an increase in the ATP/ADP ratio with resultant closure of the ATP-dependent potassium channel and depolarization of the b-cell. Depolarization results in opening of the voltage-dependent calcium channel and influx of calcium leading to fusion of insulin-secretory granules with the cell membrane and release of insulin. (Courtesy of Z. Punthakee, Montreal, Quebec.)

Clinical manifestations and diagnosis

The basic pathophysiology in all forms of MODY is mild, partial, but in most cases progressive, (3-cell failure in the face of normal insulin sensitivity. Patients can be mildly hyperglycemic for many years before diagnosis. Although the age of onset and rate of progression can vary among the different types of MODY, the clinical management of the hyperglycemia depends on the metabolic status of the patient, not on the specific molecular diagnosis. Specific diagnosis is helpful in anticipating nonmetabolic features of the particular syndrome, most notably progressive renal disease in MODY5 patients, unrelated to diabetic nephropathy. It consists of renal cysts, oligomeganephronia, and hypoplastic glo-merulocystic kidneys that cause renal impairment and end-stage renal failure in 50% of cases by age 45 [9-11].

Specific diagnosis is also helpful in distinguishing between MODY and type 2 or, less commonly but even more significantly, type 1 diabetes. It is neither necessary nor logistically feasible to screen all patients with diabetes for all MODY genes. Common sense dictates, however, to test genetically any nonobese individual with impaired carbohydrate tolerance or overt diabetes, regardless of age of diagnosis, who has either a close relative known to have MODY of any type or who has a parent or offspring with diabetes. To this one should, perhaps, add testing for MODY5 in the presence of dominant coinheritance of diabetes with nondiabetic renal disease. The presence of obesity or insulin resistance, both common phenotypes, does not protect against MODY, so in the presence of a family history strongly suggesting dominant inheritance, insulin-resistant individuals also should be tested.

Molecular diagnosis

Molecular diagnosis based on DNA obtained from a few milliliters of blood is offered by many laboratories, but logistical and financial considerations must be kept in mind. Unless the mutation is already known from the study of an affected family member, an exhaustive search for mutations in six different genes is a time-consuming and expensive proposition, difficult to apply to all patients who meet the criteria. Prior probability may be used to rationalize the use of resources, keeping in mind that some of these forms of MODY are extremely rare. MODY4, for example, has been described in a single family [7]. For diabetes diagnosed in the pediatric age group, most cases are diagnosed with a mutation search in glucokinase and HNF1-a (MODY2 and MODY3, respectively).


Treatment should be guided by the patient's metabolic status, not the specific molecular diagnosis. It is helpful, nevertheless, to distinguish between MODY

and type 2 diabetes, because insulin sensitizers are of no use in MODY and sulfonylureas should be the first line of treatment. The increased sensitivity of MODY3 patients to sulfonylureas, with consequent need for low doses, should be kept in mind [12]. Some patients go on to need insulin. Even in those patients, significant residual endogenous insulin persists, which makes excellent glycemic control possible in compliant patients, with doses lower than those used in type 1 diabetes [12]. The physician should be aware, however, of the risk that the mild nature of the symptomatology might not motivate compliance. Diabetic complications can certainly be seen in MODY [13-15].

Neonatal diabetes

Both permanent and transient neonatal diabetes are extremely rare entities with an estimated incidence of 1 per 500,000 births [16]. Between 50% and 60% of cases of neonatal diabetes are transient [16].

Transient neonatal diabetes

Transient neonatal diabetes is defined as diabetes beginning in the first 6 weeks of life in term infants with recovery by 18 months of age. Clinically, patients have intrauterine growth retardation, low birth weight, and decreased adipose tissue. Macroglossia is sometimes seen. Patients may present with dehydration, failure to thrive, hyperglycemia, and mild ketosis [17]. Most patients present with diabetes within the first week of life and insulin-dependence disappears by 3 months of age [18]. Endogenous insulin production is low during this time period with the requirements for exogenous insulin. Approximately 40% of patients go on to develop recurrence of diabetes, most commonly during adolescence [18]. It is usually mild and does not require insulin.

In most cases, transient neonatal diabetes seems to be caused by a double dose of a gene on chromosome 6q24 that is normally expressed only from the paternal copy [17,18]. Any one of three distinct molecular pathologies may be responsible for this overexpression. Most sporadic cases are caused by paternal uniparental disomy of chromosome 6 (UPD pat 6), in which both copies of chromosome 6 are inherited from the father, with no contribution from the mother. Familial cases have a paternal duplication of 6q24 [18]. This duplication results in transient neonatal diabetes only when paternally inherited. Rarely, transient neonatal diabetes can be caused by absent or defective methylation of the maternal copy of chromosome 6q24 [19], methylation being the molecular mechanism for silencing the maternal copy of the gene. The maternal copy behaves as if paternal. Two paternally expressed imprinted genes are located in the critical interval: ZAC, encoding a zinc-finger transcription factor that inhibits proliferation and promotes apoptosis; and HYMAI, encoding an untranslated RNA of unknown function (if any). It is widely believed, but not proved, that ZAC is the gene involved.

Permanent neonatal diabetes

In contrast to transient neonatal diabetes, the etiology of permanent neonatal diabetes (PND) is more heterogeneous. PND may be caused by mutations in genes encoding the transcription factors insulin-promoter factor-1, eukaryotic translation initiation factor-2a kinase 3 (EIF2AK3), and forkhead box-P3. In addition, homozygous inactivating mutations in the genes encoding the glucose-sensing enzyme of the (3-cell, glucokinase, and activating mutations of the Kir 6.2 subunit of the ATP-sensitive K+ channel of the (3-cell, which prevents its closure and hence insulin secretion, may also cause PND.

The most common cause of PND is a heterozygous activating mutation in the gene, KCNJ11, encoding the Kir 6.2 subunit of the ATP-sensitive K+ channel of the (-cell [20]. It has been described to cause both familial and sporadic (usually because of new mutations) PND [21]. The ATP-sensitive K+ channel regulates the release of insulin from the pancreatic 3-cell. Activating mutations in the Kir 6.2 subunit increase the number of open channels on the cell membrane, resulting in hyperpolarization of the 3-cell and subsequent prevention of insulin release. Most cases reported resulted from sporadic mutations. In addition to diabetes, some patients with mutations in KCNJ11, the gene encoding the Kir 6.2 subunit, have been reported to have global developmental delay, muscle weakness, epilepsy, and dysmorphic features [21]. These features include a prominent metopic suture, bilateral ptosis, downturned mouth, and limb contractures [21]. Conversely, homozygous inactivating mutations in the gene KCNJ11 encoding the subunit Kir6.2 cause familial persistent hyperinsulinemic hypoglycemia of infancy [22]. Generally, treatment for PND has been insulin therapy. Recently, however, it has been shown that some patients with PND caused by mutations in Kir 6.2 respond to high-dose oral sulfonylureas [20]. Sulfonylureas stimulate insulin secretion by binding to the sulfonylurea receptor on the 3-cell and closing the ATP-sensitive K+ channel, stimulating insulin release. In one study, patients with PND caused by activating mutation of the Kir 6.2 subunit were progressively weaned off of insulin while increasing doses of glibenclamide were instituted [20]. The glibenclamide was initiated at a dose of 0.1 mg/kg/d and increased to 0.4 mg/kg/d after 4 to 6 months of initiation of treatment, at which point insulin was discontinued [20]. Patients studied had either stable or improved A1c on glibenclamide as compared with insulin therapy [20]. Although these findings are still preliminary and long-term follow-up studies are needed, PND caused by KCNJ11 mutations is an excellent example of molecular diagnosis making a dramatic difference in treatment options.

Cases of PND have also been found to be caused by homozygosity to the MODY genes glucokinase and insulin promoter factor-1 [7,23], the latter associated with pancreatic agenesis [7]. Both are rare causes of PND.

Other associations with PND include a rare autosomal-recessive syndrome known as Wolcott-Rallison syndrome (OMIM # 22698). The syndrome results from mutations in the gene encoding the eukaryotic translation initiation factor-2a kinase 3 (EIF2AK3) [24]. It is characterized by PND and spondyloepiphyseal dysplasia [24]. Another association with PND is the immunodysregulation, polyendocrinopathy, enteropathy, and X-linked disorder (OMIM #304790). This is a rare, x-linked recessive disease caused by mutations in the gene Forkhead Box P3 (FOXP3) [25], a gene essential for the development of regulatory T-cells that prevent autoimmune reaction. In addition to the diabetes, autoimmune manifestations of this syndrome include intractable diarrhea, hemolytic anemia, autoimmune hypothyroidism, eczema, and variable immunodeficiency [25,26]. The onset of diabetes is generally soon after birth [27]. The prognosis is poor and most of the cases reported have been lethal [28].

Wolfram syndrome

Wolfram syndrome is an autosomal-recessive, progressive, neurodegenerative disease. Also referred to as the acronym DIDMOAD, it is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The insulin-dependent diabetes mellitus is a nonautoimmune process. In a United Kingdom nationwide series of 45 patients with Wolfram syndrome, diabetes mellitus presented at a mean age of 6 years with optic atrophy following at 11 years [29]. The optic atrophy is progressive with eventual blindness. Central diabetes insipidus occurred in 73% of patients in the second decade of life and sensorineural deafness in 28% [29]. Genitourinary abnormalities, including incontinence and neuropathic bladder, presented in the third decade of life [29]. The neurologic manifestations are diverse including cerebellar ataxia, peripheral neuropathies, horizontal nystagmus, mental retardation, and a variety of psychiatric illnesses (Box 1) [29,30]. Abnormalities of brain MRI have been reported in patients [29]. Typical abnormalities include generalized cerebral atrophy, absence of posterior pituitary signal, and reduced signal from the optic nerves [29]. The psychiatric illnesses reported in patients with Wolfram syndrome include depression, suicide, and psychosis with a prevalence of approximately 25% in patients [30]. There also has been a reported increased risk of psychiatric illnesses, hear-

Box 1. Neurologic manifestations of Wolfram syndrome

Truncal ataxia Startle myoclonus Areflexia of lower limbs Horizontal nystagmus Loss of taste and smell Hemiparesis Cerebellar dysarthria Central apnea Autonomic neuropathy ing loss, and diabetes mellitus in first-degree relatives of patients with Wolfram syndrome [31,32]. Primary gonadal atrophy is common in males and females may have menstrual irregularity [29]. The median age of death is 30 years, often caused by respiratory failure from brainstem atrophy [33]. Wolfram syndrome is caused by a loss-of-function mutation of the gene (WFS1) encoding the protein wolframin on chromosome 4p [34]. The human WFS1 gene is expressed at high levels in the heart, pancreas, placenta, brain, and lung [35] and encodes a transmembrane protein that primarily localizes in the endoplasmic reticulum for which its function has still not been elucidated. A second locus, WFS2, mapped to chromosome 4q, was discovered after linkage analysis of four families with Wolfram syndrome [36]. These patients did not have evidence of diabetes insipidus, however, but did have upper gastrointestinal bleeding and ulcerations.

For diagnosis of Wolfram syndrome at a minimum patients must have insulin-dependent diabetes mellitus and progressive, bilateral optic atrophy occurring before 15 years of age [29]. Using these criteria, screening for WFS1 mutations identifies a mutation in 90% and compound heterozygosity for at least two mutations in 78% of patients [37]. The diagnosis of Wolfram syndrome is mainly clinical with genetic analysis used to confirm the diagnosis.

Mitochondrial diabetes

Mitochondria are intracellular organelles that are responsible for generating energy through the process of oxidative phosphorylation. These are the only intracellular organelles apart from the nucleus that has its own DNA. The DNA is exclusively maternally inherited, double-stranded, and encodes proteins involved in the oxidative phosphorylation process. Mutations in mitochondrial DNA have characteristically been associated with neurologic disease, but diabetes can also be a feature. The most common clinical presentation is the syndrome of maternally inherited diabetes and deafness, caused by a point mutation in the A3243G nucleotide pair of mitochondrial DNA [38], encoding the Leucine tRNA. The age of diagnosis of diabetes varies widely, generally occurring in the fourth decade of life, although the onset may be as early as adolescence [39]. At onset, hyperglycemia is usually mild but many patients go on to require insulin treatment because the insulin deficiency is progressive [39]. Carriers of the A3243G mutation characteristically have sensorineural hearing impairment, the onset of which typically precedes the onset of diabetes by several years. Patients also develop pigmentary retinal dystrophy. Some patients may develop neuro-muscular disorder characterized by a cardiomyopathy or muscular weakness [39]. The mutation seems to impair glucose-induced insulin secretion by the pancreas. Patients are treated with insulin, diet, or sulfonylureas. Metformin seems to be contraindicated because of its risk of inducing lactic acidosis and the vulnerability of these patients of developing it. The same mutation may result in the less common disease of mitochondrial encephalopathy with lactic acidosis and strokelike episodes, which is also associated with diabetes [40]. Drastically different phenotypes on the basis of the same mutation are mainly determined by the degree of heteroplasmy in the mitochondrial DNA. Unlike nuclear DNA, which is restricted to only two copies, mtDNA exists in several hundred copies per cell, any proportion of which can have the mutation while the rest of the copies can be normal; this is referred to as "heteroplasmy."

Two other syndromes, caused by deletions in mitochondrial DNA, tend to be severe and associated with diabetes. One of these, the Kearns-Sayre syndrome, is characterized by cardiomyopathy, pigmentary degeneration of the retina, chronic progressive external ophthalmoplegia, ataxia, and sensorineural hearing loss. In Pearson's syndrome, patients present with exocrine pancreatic dysfunction, sideroblastic anemia, and lactic acidosis [41]. The onset of diabetes is usually in early infancy and requires treatment with insulin. Patients generally do not survive beyond the first decade of life.

Cystic fibrosis-related diabetes

Cystic fibrosis is a multisystem disorder caused by deficiency of the CFTR chloride channel with resultant inspissated secretions of the lungs, pancreas, intestine, and male reproductive tract. Because cystic fibrosis patients are living longer, such complications as glucose intolerance and cystic fibrosis-related diabetes (CFRD) are becoming common. Cystic fibrosis initially affects the exocrine pancreatic function but the pancreatic islet cells are also affected in many patients, with decreasing insulin secretion.

Up to 50% of cystic fibrosis patients develop CFRD [42]. The median age of onset is 20 years. Risk factors for the development of diabetes include pancreatic insufficiency, recurrent pulmonary infections, corticosteroid treatment, and supplemental feeding [43]. Patients with CFRD present with polyuria and polydipsia usually associated with poor growth velocity, failure to gain or maintain weight despite nutritional intervention, unexplained decline in pulmonary function, and failure of pubertal progression [42]. CFRD patients tend to have increased weight loss, more of a decline in lung function, and increased mortality compared with cystic fibrosis patients without diabetes [42]. Retrospective studies have shown that the increase in weight loss and decline in lung function may occur a few years before the onset of CFRD [42]. Because insulin deficiency is usually incomplete, diabetic ketoacidosis is much less common and slower to develop compared with type 1 diabetes. Patients with CFRD develop diabetic microvascular complications with a reported prevalence of 5% to 21% [42].

According to the North American 1998 cystic fibrosis consensus conference report there are four glucose tolerance categories in cystic fibrosis: (1) normal glucose tolerance, (2) impaired glucose tolerance, (3) CFRD without fasting hyperglycemia, and (4) CFRD with fasting hyperglycemia [42]. CFRD may be chronic or intermittent, with or without fasting hyperglycemia [42]. Patients with intermittent CFRD may require insulin therapy at times of stress, with corticosteroid therapy for lung disease or with high-calorie nutritional inter vention [42]. Between periods of stress the blood glucose is normal. The consensus report recommends the following criteria for diagnosis of CFRD [42] (1 mmol/L =18 mg/dL):

• On two or more occasions a fasting plasma glucose > 7 mmol/L

• One fasting plasma glucose > 7 mmol/L and a random plasma glucose > 11.1 mmol/L

• On two or more occasions a random plasma glucose > 11.1 mmol/L with symptoms

• 2-hour plasma glucose > 11 on a 75-g oral glucose tolerance test

For screening, cystic fibrosis patients should have random plasma glucose done annually. Fasting plasma glucose should be done in all patients with a random glucose greater than 7 mmol/L [42]. An oral glucose tolerance test is recommended if cystic fibrosis patients present with symptoms of CFRD.

Insulin therapy is the standard treatment for CFRD. Patients generally require multiple daily injections of short-acting insulin before each meal, with dosage dependent on insulin-to-carbohydrate ratios for the meal. Patients should monitor their blood glucose at least three to four times per day, with occasional 2-hour postprandial tests to assess the mealtime insulin adequately. Screening for diabetic complications should begin at the diagnosis of CFRD, because the diabetes may have been unrecognized for years [42]. These include regular measurement of blood pressure, foot examination, annual ophthalmologic examination, and urinary albumin measurements [42].

Insulin receptor defects

Mutations in the insulin receptor gene result in three syndromes that are characterized by insulin resistance. These include type A severe insulin resistance, Rabson-Mendenhall syndrome, and leprechaunism. The various mutations affect the function of the insulin receptor in a number of ways including (1) interfering with insulin receptor synthesis, (2) impairment of posttranslational processing and intracellular-transport of the receptor to the cell membrane, (3) defective insulin binding to the insulin receptor, (4) decreasing the insulin receptor activation, and (5) increasing degradation of the insulin receptor [44]. Patients with Rabson-Mendenhall syndrome and leprechaunism are homozygous or compound heterozygotes for insulin receptor mutations [45,46]. In both Rabson-Mendenhall syndrome and leprechaunism patients have abnormal glucose homeostasis with problems initially with fasting hypoglycemia, elevated postprandial hyperglycemia, and extremely elevated insulin levels [46].

Leprechaunism (OMIM # 246200) is the most extreme form of insulin resistance, typically characterized by near complete absence of functional insulin receptors [45]. During infancy patients present with intrauterine and postnatal growth retardation, acanthosis nigricans, characteristic facial facies, abdominal distention, bilateral cystic ovaries, and lipoatrophy [46]. Characteristically they have elfin facies, upturned nose, prominent eyes, low-set ears, micrognathia, and hirsutism [46]. Male infants have penile enlargement and female infants have clitoromegaly. Most patients do not survive beyond infancy.

Rabson-Mendenhall syndrome (OMIM#262190) is also caused by severe insulin resistance, although less complete than in leprechaunism. Unlike patients with leprechaunism, patients with Rabson-Mendenhall syndrome over time develop persistent hyperglycemia and severe diabetic ketoacidosis that is refractory to insulin therapy [47]. Classically, patients have coarse facial features, pineal gland hyperplasia, acanthosis nigricans, hirsutism, severe growth retardation, and abnormal early dentition. Patients survive longer than those with leprechaunism to an approximate age of 9 years [46].

Type A insulin resistance is the least severe form of insulin resistance. Age of onset is generally in the adolescent period [48]. Patients typically have acanthosis nigricans and hyperandrogenism in female patients [48]. The hyperandro-genism manifests as hirsutism, polycystic ovaries, virilization, and increased serum testosterone [48]. In some cases removal of the enlarged ovaries has been done to control the hyperandrogenism [48]. In general, patients are not obese. Patients require enormous amounts of exogenous insulin to improve the hyper-glycemia, despite which they still have poor glycemic control, with a very high morbidity and mortality [48].

Congenital lipoatrophic diabetes

Lipoatrophic diabetes is a heterogeneous group of disorders characterized by complete or partial absence of adipose tissue associated with diabetes mellitus. This adipose insufficiency results in consequent insulin resistance, diabetes mellitus, and hypertriglyceridemia. The term "lipoatrophy" refers to the characteristic loss of fat, whereas "lipodystrophy" is a generalized term and refers to the abnormal distribution of fat. Two inherited forms exist: congenital generalized lipoatrophy and familial partial lipodystrophy. Congenital generalized lipoatrophy has an autosomal-recessive inheritance, characterized by generalized absence of subcutaneous adipose tissue within the first year of life [49]. Before adolescence patients typically have evidence of acanthosis nigricans, insulin resistance, and diabetes mellitus [49]. Patients also develop severe hypertriglyceridemia resulting in frequent episodes of pancreatitis. Leptin levels are low [50].

Familial partial lipodystrophy, also known as Dunnigan syndrome, is inherited in an autosomal-dominant fashion. It is caused by mutations in the lamin A/C gene located at 1q21-23 [51,52]. How lamin A/C mutations cause lipoatrophy is unclear. Typically, patients are born with normal fat distribution but begin to lose subcutaneous adipose tissue in the extremities and trunk in early puberty [53]. As puberty is completed there is an increase in subcutaneous fat in the face and neck [53]. Patients may develop acanthosis nigricans, hirsutism, and poly-

cystic ovary syndrome. Patients develop diabetes mellitus and hypertriglycer-idemia. In female patients, however, the onset tends to be earlier and more severe as compared with males [49,54].


This article covers some unusual or rare causes of diabetes mellitus chosen not necessarily on the basis of frequency or rarity, but rather on the basis of how well the disease and its implications in diabetes management is understood. A specific diagnosis is of help in these rare syndromes but not absolutely necessary for optimal management. The basic principles of diabetes management are well-defined, regardless of etiology. What is important in each case is to understand the relative contribution of insulin resistance versus insulin deficiency, regardless of etiology, as the most important guide to management.


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