The New England Journal of Medicine

 

Review Article
Mechanisms of Disease

Volume 345:971-980

September 27, 2001

Number 13

Molecular Mechanisms and Clinical Pathophysiology of Maturity-Onset Diabetes of the Young

Stefan S. Fajans, M.D., Graeme I. Bell, Ph.D., and Kenneth S. Polonsky, M.D.

 

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by nonketotic diabetes mellitus, an autosomal dominant mode of inheritance, an onset usually before the age of 25 years and frequently in childhood or adolescence, and a primary defect in the function of the beta cells of the pancreas. MODY can result from mutations in any one of at least six different genes (Table 1). One of these genes encodes the glycolytic enzyme glucokinase (associated with MODY 2),3 and the other five encode transcription factors: hepatocyte nuclear factor (HNF) 4{alpha} (associated with MODY 1),4 HNF-1{alpha} (MODY 3),5 insulin promoter factor 1 (IPF-1 [MODY 4]),6 HNF-1{beta} (MODY 5),7 and neurogenic differentiation factor 1 (NeuroD1), also known as beta-cell E-box transactivator 2 (BETA2 [MODY 6]).8 All these genes are expressed in beta cells, and mutation of any of them leads to beta-cell dysfunction and diabetes mellitus (Figure 1). These genes are also expressed in other tissues, and abnormalities in liver and kidney function may also be evident in some forms of MODY. Factors that affect insulin sensitivity, such as infection, puberty, pregnancy, and (in rare cases) obesity, may trigger the onset of diabetes and increase the severity of hyperglycemia in patients with MODY, but otherwise, nongenetic factors have no important role in the development of this disorder. Studies of MODY have led to a better understanding of the genetic causes of beta-cell dysfunction.


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Table 1. MODY-Related Genes and the Clinical Phenotypes Associated with Mutations in the Genes.

 


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Figure 1. Model of a Pancreatic Beta Cell and the Proteins Implicated in Maturity-Onset Diabetes of the Young (MODY).

Glucose is transported into the beta cell by a specific glucose-transporter protein (GLUT-2) on the cell surface. The MODY-associated glycolytic enzyme glucokinase (associated with MODY 2) catalyzes the transfer of phosphate from ATP to glucose to form glucose-6-phosphate. By means of this reaction, glucokinase functions as the glucose sensor of the beta cell. The generation of ATP by glycolysis and the Krebs cycle leads to inhibition and closure of the ATP-sensitive potassium channels (the target of sulfonylurea drugs), depolarization of the plasma membrane, opening of the voltage-dependent calcium channels, and influx of extracellular calcium and mobilization of calcium from intracellular stores, leading to the fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin into the circulation. A mutation in one of the alleles of the gene encoding glucokinase leads to a reduction in beta-cell glucokinase activity, resulting in decreased glucose phosphorylation in the beta cell and glucose-stimulated insulin release at any blood glucose concentration. The MODY-associated transcription factors — hepatocyte nuclear factor (HNF) 4{alpha} (associated with MODY 1), HNF-1{alpha} (MODY 3), insulin promoter factor 1 (IPF-1 [MODY 4]), HNF-1{beta} (MODY 5), and neurogenic differentiation factor 1 (NeuroD1), or beta-cell E-box transactivator 2 (BETA2 [MODY 6]) — function in the nucleus of the beta cell and regulate the transcription of the insulin gene (either directly, as in the case of HNF-1{alpha}, HNF-1{beta}, IPF-1, and NeuroD1 or BETA2, or indirectly, through effects on the expression of other transcription factors, as in the case of HNF-4{alpha}); they also regulate the transcription of genes encoding enzymes involved in the transport and metabolism of glucose as well as other proteins required for normal beta-cell function.

 
Clinical Presentation

The most common clinical presentation of MODY is mild, asymptomatic hyperglycemia in nonobese children, adolescents, and young adults who have a prominent family history of diabetes, often in successive generations (a pattern consistent with an autosomal dominant mode of inheritance). Some patients have mild fasting hyperglycemia for many years, whereas others have varying degrees of glucose intolerance for several years before the onset of persistent fasting hyperglycemia.9,10,11,12 Since mild hyperglycemia may not cause the classic symptoms of diabetes, the diagnosis may not be made until adulthood. However, according to prospective testing, it appears that in most patients the onset is in childhood or adolescence. In some patients, there may be rapid progression to overt asymptomatic or symptomatic hyperglycemia, necessitating therapy with an oral hypoglycemic drug or insulin.9,10,11,12,13 The presence of persistently normal plasma glucose concentrations in persons with mutations in any of the known MODY-related genes is unusual, and in the majority of them diabetes eventually develops (with the exception of many patients with glucokinase mutations, as discussed below). According to current estimates, MODY may account for 1 to 5 percent of all cases of diabetes in the United States and other industrialized countries.3,14

Several clinical characteristics distinguish patients with MODY from those with type 2 diabetes, including a prominent family history of diabetes in three or more generations, a young age at presentation, and the absence of obesity (Table 2). In recent years, type 2 diabetes has been recognized with increasing frequency in adolescents who are obese, as are most older patients with type 2 diabetes.


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Table 2. Distinguishing Clinical Characteristics of MODY and Type 2 Diabetes.

 
Function of the Gene Products Implicated in MODY

Glucokinase

Glucokinase is expressed at its highest concentrations in pancreatic beta cells and in the liver. It catalyzes the transfer of phosphate from ATP to glucose, generating glucose-6-phosphate (Figure 1). This reaction is the first, rate-limiting step in glucose metabolism. Glucokinase functions as the glucose sensor in beta cells by controlling the rate of entry of glucose into the glycolytic pathway (glucose phosphorylation) and by controlling the rate of its subsequent metabolism.16 The glucokinase that is expressed in the liver plays a key part in the ability of that organ to store glucose as glycogen, particularly in the postprandial state. Heterozygous mutations in the gene encoding glucokinase lead to a partial deficiency of this enzyme and are associated with MODY 2; homozygous mutations result in a complete deficiency of this enzyme and lead to permanent neonatal diabetes mellitus.17

HNF-1{alpha}, HNF-1{beta}, and HNF-4{alpha}

The liver-enriched transcription factors HNF-1{alpha}, HNF-1{beta}, and HNF-4{alpha} were first discovered in studies designed to identify the proteins responsible for the tissue-specific regulation of gene expression in the liver.18 They are also found in other tissues and organs, including the pancreatic islets, the kidneys, and genital tissues. HNF-1{alpha} and HNF-1{beta} are members of a family of transcription factors.18 HNF-4{alpha} is an orphan nuclear receptor.19 HNF-1{alpha}, HNF-1{beta}, and HNF-4{alpha} constitute part of a network of transcription factors that function together to control gene expression during embryonic development and during adulthood in tissues in which they are coexpressed. In pancreatic beta cells, these transcription factors regulate the expression of the insulin gene as well as the expression of genes encoding proteins involved in glucose transport and metabolism20 and mitochondrial metabolism21 — all of which are linked to insulin secretion. In the liver, these proteins regulate lipoprotein biosynthesis.22 The expression of HNF-1{alpha} is regulated at least in part by HNF-4{alpha}.21

IPF-1

IPF-1 is a transcription factor that was originally isolated as a regulator of the transcription of the insulin and somatostatin genes.23 It also plays a central part in the development of the pancreas and in the regulation of the expression of a variety of genes in the pancreatic islets, including (in addition to the insulin gene) the genes encoding glucokinase, islet amyloid polypeptide, and glucose transporter 2.23 IPF-1 also appears to mediate glucose-induced stimulation of insulin-gene transcription.24

NeuroD1 (BETA2)

The transcription factor NeuroD1, or BETA2, was isolated on the basis of its ability to activate the transcription of the insulin gene. It is required for the normal development of the pancreatic islets.25

Clinical Features of Subtypes of MODY

MODY 2

Glucokinase-related MODY (MODY 2) is a common form of this disorder, especially in children with mild hyperglycemia and in women with gestational diabetes and a family history of diabetes. It has been described in persons of all racial and ethnic groups.26 More than 130 MODY-associated mutations have been found in the glucokinase gene. Heterozygous mutations in glucokinase are associated with a mild form of nonprogressive hyperglycemia that is usually asymptomatic at diagnosis and is treated with diet alone.27 The mild fasting hyperglycemia (blood glucose concentration, 110 to 145 mg per deciliter [6.1 to 8.0 mmol per liter]) and impaired glucose tolerance in most affected carriers may be recognized by biochemical testing at a young age, possibly as early as birth.3,28 About 50 percent of the women who are carriers may have gestational diabetes.3,29 Less than 50 percent of the carriers have overt diabetes; of those who do, many are obese or elderly. Two percent of carriers require insulin therapy.30 Diabetes-associated complications are rare in this form of MODY.

The hyperglycemia in persons with glucokinase-related MODY appears to result from a reduction in the sensitivity of beta cells to glucose31 as well as a defect in postprandial glycogen synthesis in the liver.32 Heterozygous mutations in the gene encoding glucokinase are associated with MODY and gestational diabetes. They are also associated with a reduction in birth weight of 500 g or more, possibly because of their effect on fetal insulin secretion.33 As noted above, homozygous mutations cause a complete deficiency of glucokinase and are associated with permanent neonatal diabetes mellitus, which is characterized by low birth weight and severe diabetes, necessitating insulin treatment within the first few days of life.17

In patients with glucokinase-related MODY, the decrease in glucokinase activity in the pancreatic beta cells leads to a decrease in glucose phosphorylation in the beta cells, a reduction in the sensitivity of beta cells to glucose, and a shift to the right in the dose–response relation between the plasma glucose concentration and insulin secretion (Figure 2 and Figure 3). These effects occur across a broad range of glucose concentrations. There is an increase in the threshold concentration of glucose necessary to stimulate insulin secretion, from a normal basal concentration of about 90 mg per deciliter (5.0 mmol per liter) to approximately 108 to 126 mg per deciliter (6.0 to 7.0 mmol per liter). As a result of this upward shift in the plasma glucose threshold for stimulation of insulin secretion, patients with glucokinase mutations have mildly increased basal and postprandial plasma glucose concentrations (Figure 4).31 Surprisingly, in view of the key part played by glucokinase in the sensitivity of beta cells to glucose and in insulin secretion, the hyperglycemia in these patients is usually mild and does not increase substantially over the course of many years.3,27 It appears that in patients with glucokinase mutations, physiologic adaptation within the pancreatic beta cells limits the severity of hyperglycemia.



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Figure 2. Effect of Mutations in the Gene Encoding Glucokinase on the Threshold for Glucose-Stimulated Insulin Release.

The results of mathematical modeling to predict the effects of two mutations in the gene encoding glucokinase (substitution of alanine for valine at position 203 [V203A] and substitution of lysine for glutamic acid at position 70 [E70K]) on the capacity of the beta cell for glucose phosphorylation at various plasma glucose concentrations are shown. The responses in subjects with two wild-type alleles (WT/WT) and in subjects with one wild-type allele and one mutant allele (E70K/WT or V203A/WT) are shown. The enzymatic properties of the recombinant wild-type and mutant forms of glucokinase were determined, and the V203A form was found to have low activity and the E70K form to have intermediate activity relative to the wild-type protein. Mathematical modeling suggests that the threshold for glucose-stimulated insulin release is achieved when the glucose-phosphorylation capacity is about 25 percent of maximum. This occurs at a plasma glucose concentration of about 5.0 mmol per liter in subjects with two wild-type glucokinase alleles and at higher concentrations (6.0 and 7.0 mmol per liter) in subjects with one wild-type and one mutant allele, respectively. The glucose concentrations required for peak postprandial glucose-stimulated insulin release in subjects with two wild-type alleles and the higher required concentrations in subjects with a mutant allele are also indicated. To convert the values for glucose to milligrams per deciliter, divide by 0.05551. Adapted from Bell et al.26

 


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Figure 3. Relation between Average Plasma Glucose Concentrations and Insulin-Secretion Rates during Graded Glucose Infusions in Prediabetic Subjects with Mutations in the Genes for HNF-4{alpha}, Glucokinase, and HNF-1{alpha} and in Normal Subjects.

There is a linear relation between the insulin-secretion rate and plasma glucose concentration in the normal subjects. The subjects with mutations in the gene for HNF-4{alpha} or HNF-1{alpha} have a normal response at low glucose concentrations, but the response cannot be sustained as the glucose concentration continues to rise. The subjects with mutations in the glucokinase gene have a reduced response at all glucose concentrations; the greatest reduction occurs at plasma glucose concentrations below 7 mmol per liter. To convert the values for glucose to milligrams per deciliter, divide by 0.05551. The bars represent the standard errors.

 


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Figure 4. Mean Hourly Plasma Glucose Concentrations during a Weight-Maintenance Diet in Subjects with Type 2 Diabetes or Glucokinase-Related Maturity-Onset Diabetes of the Young (MODY) and in Normal Subjects.

Time 0 corresponds to 6 a.m., when sampling began. To convert the values for glucose to milligrams per deciliter, divide by 0.05551. The bars represent the standard errors. Adapted from Polonsky.34

 
This hypothesis was explored in a study of subjects with different types of glucokinase mutations and normal subjects.35 In two subjects who had glucokinase mutations associated with only a small decrease in enzymatic activity, the decrease in insulin secretion was directly proportional to the decrease in the glucokinase-mediated flux of glucose. However, in four subjects with glucokinase mutations that resulted in severe decreases in enzymatic activity, the amount of insulin secreted was less than that in normal subjects, but the difference was smaller than predicted, suggesting the presence of compensatory mechanisms within the pancreatic beta cells that resulted in a relative increase in the insulin-secretion response.

The nature of this compensatory or adaptive mechanism has been examined in mice with glucokinase-related MODY (mice with only one glucokinase-gene allele).36 Islets from these mice and from control mice were incubated at various glucose concentrations, and the findings suggested that mild hyperglycemia leads to increased expression of the single wild-type glucokinase-gene allele, thus limiting the severity of the defect in glucose-stimulated insulin secretion. Since the hepatic glucokinase promoter is regulated predominantly by insulin and not by glucose, the compensatory mechanism is probably operative only in beta cells.

MODY 1 and MODY 3

Not unexpectedly, the pathophysiologic mechanisms of MODY due to mutations in the HNF-4{alpha} gene (MODY 1) and MODY due to mutations in the HNF-1{alpha} gene (MODY 3) are very similar, since HNF-4{alpha} regulates the expression of HNF-1{alpha}. Like persons with glucokinase mutations, those with mutations in the HNF-4{alpha} gene or the HNF-1{alpha} gene may present with a mild form of diabetes. Despite similarly mild elevations in fasting plasma glucose concentrations, however, they have significantly higher plasma glucose concentrations two hours after glucose administration than do persons with glucokinase mutations.27 The hyperglycemia in patients with HNF-1{alpha}–related or HNF-4{alpha}–related MODY tends to increase over time, resulting in the need for treatment with oral hypoglycemic drugs or insulin in a substantial proportion of these patients (30 to 40 percent require insulin).9,10,11,12,13 These forms of MODY are associated with a progressive decrease in insulin secretion. For example, prospective studies in a large family with HNF-4{alpha}–related MODY revealed that glucose-induced insulin secretion decreased at a rate of 1 to 4 percent per year.12 This progression suggests that the beta cells are not able to compensate for the deficiency of HNF-4{alpha}.

In most populations, mutations in the HNF-1{alpha} gene (resulting in MODY 3) are the most common cause of MODY. To date, more than 120 mutations in this gene have been identified in persons of all racial and ethnic backgrounds — for example, European, Chinese, Japanese, African, and American Indian37 (and unpublished data). Mutations in the HNF-1{alpha} gene appear to be the most common cause of MODY among adults seen in diabetes clinics. In contrast, mutations in the HNF-4{alpha} gene (resulting in MODY 1) are relatively uncommon; to date, only 13 families worldwide have been identified as having this form of MODY.

Patients with HNF-1{alpha}–related or HNF-4{alpha}–related MODY may have the full spectrum of complications of diabetes. Microvascular complications, particularly those involving the retinas and kidneys, are as common in these patients as in patients with type 1 or type 2 diabetes (matched according to the duration of diabetes and the degree of glycemic control) and are thus probably determined by the degree of glycemic control (Table 1). 10,30,38,39

Studies performed in prediabetic carriers of HNF-4{alpha} and HNF-1{alpha} mutations showed that these two groups had similar defects in the pattern of glucose-induced insulin secretion, without impairment of insulin sensitivity. Thus, impaired beta-cell function, rather than a defect in insulin activity, appears to be the primary cause of diabetes in persons with these two forms of MODY.40,41,42,43 After an overnight fast, insulin secretion is normal. However, as plasma glucose concentrations increase to approximately 125 to 145 mg per deciliter (7.0 to 8.0 mmol per liter), insulin secretion does not continue to increase, as it would in nondiabetic persons, but rather begins to level off (Figure 3).41,42 It is possible to distinguish persons with an HNF-1{alpha} mutation from those with an HNF-4{alpha} mutation according to the ability of glucose to prime the insulin-secretion response to a subsequent glucose stimulus. In the prediabetic state, the normal priming effect of mild hyperglycemia on insulin secretion is retained in persons with HNF-1{alpha} mutations (as it is in those with glucokinase mutations or no mutations), but it is lost in those with HNF-4{alpha} mutations.

Both prediabetic and diabetic persons with mutations in the HNF-4{alpha} gene secrete decreased amounts of insulin in response to glucose and in response to arginine and also have an impairment of glucagon secretion in response to arginine.44 Impairment of glucagon secretion in response to arginine has also been reported in a patient with diabetes due to a mutation in the HNF-1{alpha} gene (MODY 3).45 Furthermore, a defect in the hypoglycemia-induced secretion of pancreatic polypeptide has been found in prediabetic and diabetic persons who have mutations in the gene for HNF-4{alpha}.46 These findings suggest that a deficiency of HNF-4{alpha} activity resulting from mutations in this gene may affect the function of the beta, alpha, and pancreatic polypeptide cells of the pancreatic islets.

To examine the molecular basis of the defect in insulin secretion resulting from decreased activity of HNF-1{alpha}, we have studied mice that lack this gene. These animals have marked hyperglycemia and defects in glucose-induced insulin secretion as a result of defective beta-cell glycolytic signaling.47,48 The consequences of HNF-4{alpha} deficiency have also been studied in embryonic stem cells,20 and the results show that HNF-4{alpha} regulates the expression of proteins involved in glucose transport and glycolysis, which are required for a normal, glucose-dependent insulin secretory response. In the INS-1 cell line, defective HNF-4{alpha}–dependent insulin secretion is linked to impaired mitochondrial metabolism.21

In addition to their effects on beta-cell function, deficiencies of HNF-1{alpha} and HNF-4{alpha} affect kidney and liver function, respectively. Patients with HNF-1{alpha} mutations have decreased renal reabsorption of glucose (i.e., a low renal threshold for glucose) and glycosuria.49,50 A deficiency of HNF-4{alpha} affects triglyceride and apolipoprotein biosynthesis and is associated with a 50 percent reduction in serum triglyceride concentrations and a 25 percent reduction in serum concentrations of apolipoproteins AII and CIII and Lp(a) lipoprotein.51,52

MODY 4

Mutations in the gene that encodes IPF-1 are a rare cause of MODY; in fact, the current understanding of this form of MODY (MODY 4) is based on studies of a single family. The proband was an infant with permanent neonatal diabetes and pancreatic exocrine insufficiency resulting from congenital agenesis of the pancreas.53 Molecular genetic studies revealed that this infant was homozygous for a frame-shift mutation in the gene for IPF-1 and that both parents were heterozygous for this mutation.6 Studies of the extended family revealed a high prevalence of a mild form of diabetes that had an autosomal dominant pattern of inheritance and was associated with the heterozygous mutation in IPF-1. The expression of diabetes in this pedigree may occur at later ages than in families with other types of MODY. Six diabetic family members who were heterozygous for the mutation (and whose mean fasting plasma glucose concentration was 169 mg per deciliter [9.4 mmol per liter]) had severe impairment of insulin secretion during a hyperglycemic clamp study; no such impairment was seen in five family members who did not have the mutation.54

MODY 5

Mutations in the gene encoding HNF-1{beta} are the cause of an uncommon but distinct form of MODY (MODY 5) that is characterized by both diabetes mellitus and renal cysts (hypoplastic glomerulocystic kidney disease).7,55,56,57,58 In addition, two of four female carriers in one family had internal genital abnormalities (vaginal aplasia and a rudimentary uterus),56 and in another family a female carrier had a bicornuate uterus.57 Thus, heterozygous mutations in the gene for HNF-1{beta} may be associated with a spectrum of clinical features, which may be determined by the nature of the specific mutation and its effect on HNF-1{beta} function.

MODY Associated with Mutations in Other Genes

The identification of mutations in the genes encoding glucokinase and transcription factors HNF-4{alpha}, HNF-1{alpha}, HNF-1{beta}, and IPF-1 suggests that MODY is a disorder involving abnormal gene expression, abnormal glucose metabolism, or both in the beta cells. This possibility has led investigators to screen for mutations in other genes in these pathways, especially those encoding transcription factors expressed in beta cells, in families with MODY or autosomal dominant forms of type 2 diabetes.

Mutations in the gene encoding transcription factor NeuroD1 (BETA2) were found in two families with autosomal dominant type 2 diabetes.8 One of these families met the criteria for MODY, including (in addition to an autosomal dominant pattern of inheritance) an onset of diabetes before 25 years of age in three carriers and a requirement for insulin treatment — a finding consistent with the presence of beta-cell dysfunction — in five carriers. Thus, mutations in NeuroD1 may be the cause of another subtype of MODY, designated MODY 6.

A nonsense mutation was found in the gene encoding beta-cell transcription factor Islet-1 in a Japanese family.59 This mutation led to decreased activity of this transcription factor and thus may have been pathogenic. However, additional genetic and clinical studies are required to determine whether mutations in Islet-1 are the cause of another subtype of MODY.

Families whose members have a clinical history compatible with a diagnosis of MODY and who do not have mutations in any of the six known MODY-related genes account for an estimated 15 to 20 percent of European persons who have clinical MODY and as many as 80 percent of Japanese persons with clinical MODY.37 We believe that, in time, additional MODY-related genes will be identified and that they will explain the molecular basis of diabetes in these patients.

Mutations in MODY-Related Genes in Type 2 Diabetes

It does not appear that mutations in known MODY-related genes contribute to the development of hyperglycemia in the majority of patients with type 2 diabetes, although mutations have been found in a few patients.60,61,62,63 One group in which a mutation in a MODY-associated gene, the gene encoding HNF-1{alpha}, may be a key genetic factor linked to type 2 diabetes is the Canadian Oji-Cree Indians, who live in northwestern Ontario and Manitoba.64 Thus, sequence variation in MODY-related genes may contribute to the polygenic background and to the development of type 2 diabetes (Table 2). The absence of an association with type 2 diabetes in one population should not deter investigators from studying these genes in other populations.

Despite the lack of evidence that mutations in MODY-related genes are responsible for the development of type 2 diabetes in the majority of patients with this disorder, the mechanisms by which these mutations lead to hyperglycemia may be relevant to the pathophysiology of the beta-cell defects in type 2 diabetes. Defects in the metabolism of glucose in pancreatic beta cells may be the mechanism by which insulin secretion is impaired in type 2 diabetes. Thus, lessons learned from studies of MODY may improve our understanding of the insulin insufficiency associated with type 2 diabetes.

Genetic Screening for MODY

With the identification of genes responsible for MODY, it is possible to identify members of pedigrees who have inherited the specific mutation affecting their family, even before carbohydrate intolerance develops. Indeed, in the past few years, some parents have requested that their children undergo genetic screening for the mutation in their family.65 If a child does not carry the mutation, further clinical testing is unnecessary. If a child does carry the mutation, periodic testing for slight abnormalities of carbohydrate metabolism is recommended. These principles can be applied to any family with MODY for which the mutation is known.

Genetic screening for and identification of a specific MODY-related mutation in children may have important prognostic and therapeutic implications. If carbohydrate intolerance or diabetes is due to a mutation in the gene encoding glucokinase, limited therapy and follow-up are adequate, because of the benign and nonprogressive course of diabetes in such cases. On the other hand, persons who are genetically susceptible to diabetes due to mutations in the genes for HNF-1{alpha} and HNF-4{alpha} should be monitored frequently so that appropriate therapy can be instituted early in the course of their hyperglycemia, because of the risk of progression to severe hyperglycemia and insulin-requiring diabetes. Early treatment to achieve normoglycemia should prevent vascular and neuropathic complications. Thus, MODY is one type of diabetes that warrants genetic counseling, because of the known mode of inheritance and high penetrance.

Genetic diagnosis may also be advised for patients who have been classified as having type 1 diabetes and who have a strong family history of diabetes. An appreciable fraction of these patients have been found to carry the HNF-1{alpha} mutation.66,67,68 The diagnosis of HNF-1{alpha}–related MODY rather than type 1 diabetes has implications for prognosis in these patients. Unfortunately, these approaches are currently applicable only in a research setting; commercial tests for the identification of MODY-related genes are not yet available.

Conclusions

A better understanding of the causes and pathophysiology of MODY is emerging from genetic, molecular biologic, and physiological studies of this disorder. We believe this knowledge will lead to new therapeutic approaches and agents that will prevent, correct, or at least delay the decline in pancreatic beta-cell function that characterizes not only MODY but also type 2 diabetes.

Supported by grants from the National Institutes of Health (DK-20572 and DK-20595, to the Diabetes Research and Training Centers at the University of Michigan and the University of Chicago, respectively; RR-00042 and RR-00055, to the General Clinical Research Centers at the University of Michigan and the University of Chicago, respectively; DK-31842; and DK-44840), by a gift from the Blum–Kovler Foundation, and by funds from the Howard Hughes Medical Institute.

We are indebted to Dr. Franz Matschinsky for valuable discussions about glucokinase mutations.


Source Information

From the Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Health System, Ann Arbor (S.S.F.); the Howard Hughes Medical Institute and Departments of Biochemistry and Molecular Biology, Medicine, and Human Genetics, University of Chicago, Chicago (G.I.B.); and the Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis (K.S.P.).

Address reprint requests to Dr. Fajans at 3920 Taubman Ctr., Box 0354, University Hospitals, Ann Arbor, MI 48109-0354, or at [log in to unmask].

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Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.