The Molecular Endocrinology Of Diabetes Mellitus

Diabetes mellitus is a metabolic syndrome characterized by hyperglycemia resulting from variable defects in insulin secretion and action. Traditionally, diabetes mellitus has been divided into four categories: Type 1 diabetes, characterized by absolute insulin deficiency and requirement of insulin therapy to sustain life; Type 2 diabetes, characterized by variable defects in insulin secretion and action, without an absolute need for insulin therapy (although insulin might be necessary for adequate control of hyperglycemia); "other specific types" of diabetes; and gesta-tional diabetes. Type 1 diabetes is further subdivided into Type 1A, or autoimmune, diabetes and Type 1B, or idiopathic diabetes. The "other" category is very large, encompassing diabetes resulting from other illness or medications (such as cystic fibrosis-related diabetes) as well as many genetic syndromes that include diabetes (101). It is becoming increasingly apparent, however, that these categories are artificial and that the clinical syndrome of "diabetes mellitus" represents a heterogeneous group of disorders with widely varying etiologies.

7.1. MATURITY ONSET DIABETES OF THE YOUNG Maturity-onset diabetes of the young (MODY) is a syndrome of non-insulin-dependent diabetes characterized by autosomal dominant inheritance with at least two affected family members in at least two generations, at least one diagnosed before the age of 25. MODY patients are typically not obese (unlike T2DM patients) and have normal insulin sensitivity as well as negative islet cell autoantibodies (102-104). To date, six genes have been identified as causes of MODY (Table 2). Of these, one (glucokinase) is an enzyme, and the rest are transcription factors that are important in pancreatic and islet cell development as well as in maintenance of insulin secretion. These disorders are important because they offer insight into the regulatory pathways and because they suggest possible pathogenic mechanisms for other forms of diabetes. In addition, molecular diagnostic testing for two of the most common forms of MODY is now available.

MODY2 is caused by defects in the enzyme glucokinase (GCK) (OMIM 138079) and is the second most common form of MODY in European populations (105). GCK catalyzes the phosphorylation of glucose to glucose-6-phosphate, the rate-limiting step in the glycolytic pathway. This allows GCK to serve as the glucose sensor for the insulin-secreting p cells of the pancreatic islets (106). More than 130 mutations causing MODY2 have been described since the original description in 1992 (107,108). These mutations result in decreased activity of the enzyme, which, in turn, leads to decreased glucose sensing. The net result is an increase in the glucose "set point" for insulin secretion. Patients with MODY2/GCK deficiency have mild hyperglycemia both fasting and postprandially. This hyperglycemia often does not require therapy and diabetes-associated complications are rare (103). The remaining forms of MODY are due to mutations in several transcription factors (see Table 2 and below). These forms of MODY are generally more severe than MODY2/GCK, and patients may require treatment with oral agents and/or insulin. Patients with these forms of diabetes are at risk for diabetes-related complications.

MODY1 is caused by mutations in hepatic nuclear factor 4a (HNF4a) (OMIM 600281), a transcription factor originally identified from rat liver (109,110). HNF4a and its relatives are now understood to be expressed in many tissues and are involved in a transcriptional regulation network that controls both pancreatic development and insulin secretion (110). In particular, HNF4a has been found to have a pancreas-specific promoter (designated P2) located 46 kb upstream to the P1 promoter, which is expressed in hepatocytes (111). This upstream promoter contains binding sites for HNF1a, HNF1P, and IPF1, all of which are also associated with MODY syndromes (111). MODY1 is most commonly caused by mutations in the HNF4a coding region, which lead to decreased DNA binding and/or decreased transactivation (110); however, one family has been reported in which the mutation lies in the IPF-1-binding site of the P2 promoter (111), and another family has been reported with a balanced translocation {karyotype 46,XX t(3;20)(p21.2;q12)} with a breakpoint between the P2 promoter and the rest of the HNF4a gene (112).

MODY3 is the most common variant of MODY in European populations (105) and is caused by mutations in the hepatic nuclear factor 1a (HNF1a) (OMIM 142410) (113). Mutations have been described throughout the HNF1a gene and its promoter, and there appears to be a mutation "hot spot" in exon 4 (114).

MODY4, caused by mutations in the insulin promoter factor 1 (IPF1) (OMIM 600733) gene, is a rare form of MODY (115). IPF1 is a transcription factor that is essential for normal pancreas and islet cell development as well as islet cell function in the adult (116). Heterozygous dysfunction of the gene results in a MODY syndrome similar to the other forms of transcription factor-related MODY, whereas homozygotes have pancreatic agenesis and permanent insulin-requiring diabetes from the neonatal period (115,117).

MODY5 is the result of mutations in the hepatocyte nuclear factor-1p gene (HNF1P) (OMIM 189907) (118). Mutations in HNF1P are associated with progressive, nondiabetic renal failure and renal cysts in addition to diabetes (118,119), and one mutation has also been associated with vaginal and uterine aplasia in female carriers (120).

The most recent gene to be associated with a MODY syndrome (MODY6) is neurogenic differentiation 1 (NEUROD1, also called BETA2) (OMIM 601724) (121). NEUROD1 is a transcription factor that regulates insulin gene transcription; mice that are homozygous null for NEUROD1 have abnormal pancreatic islets, suggesting a role in pancreatic development as well (122).

7.2. OTHER MONOGENIC DIABETES SYNDROMES

Wolcott-Rallison syndrome (OMIM 226980) is an autosomal recessive disorder characterized by neonatal-onset diabetes in association with multiple epiphyseal dysplasia, decreased growth, osteoporosis, and renal insufficiency. The causative gene has been identified as eukaryotic translation initiation factor 2-a kinase 3 (EIF2AK3) (OMIM 604032) (123). This kinase is thought to play a role in regulating protein flux through the endoplasmic reticulum (ER), in particular in coupling the rate of insulin synthesis with the capacity for peptide processing in the ER (124).

Wolfram syndrome (WFS) (OMIM 222300) is also an autosomal recessive disorder, characterized by the mnemonic DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Diabetes typically occurs in childhood. The causative gene, WFS1 (OMIM 606201), has been identified (125,126); its protein product, wolframin, is a transmembrane protein of uncertain function, although it has been hypothesized to play a role in P-cell and neuronal cell survival pathways based on pathological data. Mutations have been found in more than 90% of patients with WFS and are located throughout the gene with a concentration in exon 8 (127).

The syndrome of maternally transmitted diabetes and deafness (OMIM 520000) is caused by a mutation (3243A > G) in the mitochondrial tRNA-LEU1 gene (MTTL1) (OMIM 590050) (128). Diabetes in these patients is similar to Type 2 diabetes, and defects of glucose-regulated insulin secretion have been found (129).

7.3. THE GENETICS OF TYPE 1A (AUTOIMMUNE) DIABETES MELLITUS Type 1A diabetes mellitus (T1ADM) is a relatively common disease, affecting approximately 1 in 300 children (130). It is caused by autoimmune destruction of the pancreatic islets. Twin studies reveal a clear genetic predisposition, with concordance rates of 21-70% in monozygotic twins and 0-13% in dizygotic twins. The major source of this genetic predisposition lies in the human leukocyte antigen (HLA) locus, with known haplotypes that confer either high risk for or protection from the disease (for review, see ref. 130). However, there appear to be modifying genes and environmental factors. One such modifying locus is the IDDM2 locus on chromosome 11p15, which corresponds to a variable number of tandem repeats (VNTR) 5' to the insulin gene. These insulin VNTRs are divided into classes based on the number of repeats: Class I (26-63), Class II (approx 80 repeats), and Class III (140-200 repeats). The number of repeats correlates with insulin gene expression in the thymus, and lower numbers of repeats create a higher risk of diabetes, whereas higher numbers are protective. Higher insulin gene expression in the thymus might allow T-cells that react to self-antigen to be selected out, thus decreasing the potential for autoimmunity (130).

There are two monogenic syndromes associated with T1ADM. The first of these is known as autoimmune poly-endocrinopathy syndrome type 1 (APS1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The most characteristic features of this syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism, Addison's disease, and T1ADM; other features include other autoimmune endocrinopathies (such as hypothyroidism or hypogonadism), malabsorption syndromes, pernicious anemia, and alopecia. The gene for this disorder is the autoimmune regulator or AIRE (OMIM 607358), which appears to be a transcription factor. The exact mechanism by which it causes the syndrome is not known (131,132).

The second monogenic syndrome is X-linked autoimmu-nity-allergic dysregulation syndrome (XLADD, also called immunodysregulation, polyendocrinopathy, and enteropathy, X-linked or IPEX) (OMIM 304790), a syndrome of multisystem autoimmunity including diabetes and thyroid disease as well as frequent infections, diarrhea, and hemolytic anemia. The disorder is usually fatal. Mutations in the transcription factor forkhead box P3 gene (FOXP3) (OMIM 300292) are causative (133).

7.4. TYPE 2 DIABETES: A POLYGENIC FORM OF DIABETES Type 2 diabetes mellitus (T2DM) arises out of a combination of insulin resistance and insulin secretory defects. This interaction is, in turn, influenced by environmental factors such as diet, obesity, and physical activity. T2DM is known to have an even stronger genetic predisposition than T1DM, with a high concordance rate among identical twins (approx 80% as opposed to dizygotic twins, for whom the risk is approx 10%) and an increased incidence in first-degree relatives (approx 10%) (134,135). Genome scanning approaches have shown linkages to a large number of chromosomal locations (136), which vary among populations. For only one of these, 2q37 in Mexican-Americans, has a candidate gene been localized and shown to associate with diabetes. That gene is calpain-10 (CAPN10) (OMIM 605286), a type of protease (137); how genetic variations in it lead to diabetes is not well understood, and association of T2DM with CAPN10 has not been reproduced in other populations (138).

The alternative approach to identifying genes associated with T2DM is to screen populations of patients with T2DM for variations in plausible candidate genes. At least 17 genes have been studied (139); such association studies are often not reproducible and associations might vary from population to population. However, at least three genes (ABCC8, PPARG, and SLC2A1) are significantly associated with T2DM when results from multiple studies are pooled (140).

It appears likely that susceptibility to T2DM is the result of combinations of variations in many genes. Although each variation in itself would be insufficient to cause diabetes, combinations of variations would create risk haplotypes, which would then lead to diabetes under environmental influences such as diet.

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