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Endocr Rev. May 2008; 29(3): 265–291.
Published online Apr 24, 2008. doi:  10.1210/er.2007-0029
PMCID: PMC2528857

Neonatal Diabetes Mellitus


An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life. These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis. Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of β-cell apoptosis and insulin processing, as well as the regulation of insulin release. For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes. For the clinician, these studies underscore the need to identify the genetic cause underlying each case. It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.

  • I. Introduction
  • II. Diagnosis of Neonatal Diabetes Mellitus
  • III. Frequency of TNDM vs. PNDM
  • IV. Etiology of Transient Neonatal Diabetes Mellitus (OMIM 601410, 600937, 600509)
  • V. Chromosome 6q Anomalies (OMIM 601410) Are the Main Cause of TNDM
  • VI. Hepatic Nuclear Factor 1β (OMIM 189907)
  • VII. Permanent Neonatal Diabetes Mellitus
  • VIII. Abnormal Pancreatic Development
    • A. Pancreas transcription factor 1, α subunit (PTF1a) (OMIM 607194, 609069)
    • B. Pancreatic and duodenal homeobox 1/insulin-promoter-factor 1 (PDX1/IPF-1) (OMIM 600733)
    • C. GLIS subfamily of Kruppel-like zinc finger proteins - 3 (GLIS3) (OMIM 610199)
  • IX. PNDM Attributable to Increased β-Cell Apoptosis or Necrosis: Pancreatic Eukaryotic Initiation Factor 2α Kinase (EIF2AK3); Wolcott-Rallison Syndrome (OMIM 226980)
  • X. Insulin
  • XI. Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX), FOXP3 (OMIM 304790/304930)
  • XII. PNDM Attributable to β-Cell Dysfunction and Impaired Glucose-Stimulated Insulin Secretion
  • XIII. Glucokinase (GCK) (OMIM 606176)
  • XIV. TNDM and PNDM Attributable to Reduced Insulin Secretion Secondary to Overactivity of ATP-Sensitive Potassium Channels, KCNJ11 and ABCC8 (OMIM 600509, 600937, 610374)
    • A. Clinical aspects
    • B. Channel aspects
  • XV. Location of KCNJ11 and ABCC8 Mutations
  • XVI. Sulfonylureas Are an Effective Therapy for NDM Caused by Overactive KATP Channels
  • XVII. Summary

With few exceptions, diabetes in childhood knows no cure, no matter how mild it may appear in the beginning, nor how gradual its development in the first months or even years.”

Carl von Noorden, great European authority, 1913

All cases which have come to my attention of youthful patients with diabetes living for many long periods of time have been hereditary.

E. P. Joslin, 1934

I. Introduction

DIABETES MELLITUS PRESENTING as uncontrolled hyperglycemia during the first 6 months of life is a rare disorder that affects all races and ethnic groups. The majority of the cases present with intrauterine growth retardation (IUGR), failure to thrive, decreased sc fat, and low or undetectable C-peptide levels (1). This form of hyperglycemia has been termed “early-onset” or neonatal diabetes mellitus (NDM) and is commonly of genetic origin. Because the neonatal period is defined as the first 4 wk of life, whereas diagnosis of these cases extends through 6 months of age, a reviewer pointed out that “congenital diabetes mellitus” is a more valid descriptor for a disorder that is present at birth although not always clinically apparent immediately. However, the term “neonatal diabetes” has become established in the literature; we use the terms interchangeably. Kitselle (2) in 1852 is credited with the first clinical description of the disorder that was present in his son (3,4). Temple and Shield (5) comment on the history of the disease, noting an early report by Ramsey (6) of a low birth weight boy who required insulin to control his transitory diabetes. Hutchinson et al. (7) were the first to distinguish the permanent (PNDM) vs. the frequently relapsing transient (TNDM) forms of congenital or neonatal diabetes, a term attributed to Gentz and Cornblath (8). A follow-up study of published cases by von Muhlendahl and Herkenhoff (9) in the New England Journal of Medicine established that a high percentage of children with TNDM relapsed and developed type 2 diabetes years after the initial hyperglycemic period. The etiology of NDM is genetically heterogeneous, producing abnormal development or absence of the pancreas or islets, decreased β-cell mass secondary to increased β-cell apoptosis or destruction, and β-cell dysfunction that limits insulin secretion. Recent studies defining the multiple underlying mechanisms that give rise to TNDM and PNDM continue to illuminate the developmental aspects and basic physiology of glucose homeostasis as well as increasing understanding of individual genes that may play a role in the etiology of more common polygenic forms of diabetes mellitus. Although the physiology underlying some of the genetic causes of NDM is relatively well understood, the mechanism(s) behind the remission, characteristic of TNDM, and subsequent relapse remain unexplored.

II. Diagnosis of Neonatal Diabetes Mellitus

Diagnosis of “early-onset” diabetes can occur within the first days or months of life with presentation of hyperglycemia. In rare cases there are neural complications. The time of presentation is variable, and a potential diagnostic problem is the differentiation of a monogenic cause vs. autoimmune type 1 diabetes in these early-onset children. In a study of 111 diabetic children who required insulin within the first year of life, Iafusco et al. (10) reported a greater frequency of protective HLA antigens and less frequent autoimmune markers in children with diabetes onset before 180 d vs. those with onset greater than 180 d. Many of these newborns were small for gestational age, a finding strongly correlated with diabetes onset before 180 d. Several studies indicate that the preponderance of diabetic cases identified before 6 months of age are of monogenic origin (11,12,13) with no evidence for autoimmune markers of β-cell destruction (13,14,15). Although sero-conversion has been reported in some patients with long-standing congenital diabetes (16), the available data strongly support the argument that cases of diabetes diagnosed before 6 months of age are probably of monogenic origin and thus are candidates for genetic screening.

III. Frequency of TNDM vs. PNDM

NDM is rare, variously quoted as one case per 300,000 to 500,000 live births (see Refs. 17 and 18 for reviews); Stanik et al. (19) have estimated the frequency of PNDM in Slovakia at one in 215,417 live births. Table 11 summarizes data from published studies where NDM cases were stratified into TNDM vs. PNDM. The number of cases continues to accumulate, but the available, combined data indicate that somewhat over half (~57%) of NDM cases are transient, require insulin treatment initially, and spontaneously resolve in less than 18 months, only to relapse in later years.

Table 1
Summary of data from published studies stratified into TNDM vs. PNDM

In a follow-up of cases in the literature, von Muhlendahl and Herkenhoff (9) noted that a reduced birth weight for gestational age was characteristic of NDM (Fig. 11).). This finding has been confirmed in multiple studies that included several racial and ethnic groups by Metz et al. (20), Babenko et al. (21), and Vaxillaire et al. (22) for cases from the French Network for the Study of Neonatal Diabetes; by Flanagan et al. (12) for a cohort of 97 cases with TNDM; by Flanagan et al. (11) for 37 cases of PNDM resulting from mutations in KCNJ11 (potassium inwardly-rectifying channel, gene identifier for KIR6.2); by Suzuki et al. (23) in 31 Japanese individuals; by Rica et al. (24) for 22 Spanish cases; and by Massa et al. (25) for 12 cases of Spanish origin. There is considerable overlap in the birth weights of TNDM and PNDM individuals as shown in Fig. 11,, thus limiting the diagnostic potential of this parameter.

Figure 1
Birth weights of 45 patients with NDM. The percentiles are those for normal girls from the study by Weller and Jorch (275). The third percentile for boys is higher by 20 g at 24 wk gestation, 125 g at 34 wk, and 150 g at term. Closed symbols denote girls; ...

The IUGR can be attributed, in part, to insulin acting as a fetal growth factor, coupled with the failure of maternal insulin to cross the placental barrier (26) unless it is bound to an antibody (27,28). The growth effects of fetal insulin are broadly supported by the incidence of macrosomia in neonates born to mothers that are hyperglycemic secondary to poorly controlled diabetes or gestational diabetes (Ref. 29; reviewed in Refs. 30 and 31), by the large birth weight associated with cases of familial hyperinsulinism (HI) (32,33), and by studies on knockout mice in which insulin action is impaired by altering expression of proteins in the insulin signaling pathway (34).

Does the rapid “catch-up” growth characteristic of TNDM contribute to relapse? Rapid “catch-up growth” has been reported in patients with NDM after the initiation of insulin treatment and a high-caloric diet (35). This is consistent with the idea that insulin acts as a growth factor in the fetus, but mainly as a regulator of energy metabolism after birth. Similar catch-up growth has been reported in individuals born small for gestational age as a consequence of IUGR, and multiple studies have linked the velocity of early growth with a predisposition for subsequent development of type 2 diabetes (for review, see Refs. 36 and 37) and the metabolic syndrome (38). The molecular mechanism(s) underlying this predisposition are controversial and not firmly established, but increased insulin resistance (39), perhaps as a consequence of reduced adiponectin levels (Ref. 40; but see Ref. 41), has been suggested as a contributing factor to the subsequent development of obesity and diabetes. Although the IUGR in these studies is secondary to maternal malnutrition, placental insufficiency, and/or other environmental factors, the low birth weight and catch-up growth in NDM of genetic origin might increase insulin resistance and contribute to the later relapse in these children. In this regard, Valerio et al. (42) report no evidence for insulin resistance in four patients with TNDM resulting from 6q24 anomalies, whereas others (43) described impaired insulin sensitivity in four cases of PNDM resulting from mutations in KCNJ11 (R201H and K170N) and showed improved sensitivity after a switch to sulfonylurea therapy (44). Studies using mouse models that lack the KCNJ11/ABCC9 type skeletal muscle KATP channels exhibit an improved insulin-dependent glucose uptake (45,46). This suggests that the increased channel activity that arises from KCNJ11 NDM mutations might underlie the impaired insulin sensitivity observed by Skupien et al. (43) and contribute to their diabetes. In this regard, it will be of considerable interest to determine whether NDM cases resulting from mutations in ABCC8, a subunit of neuroendocrine, but not skeletal muscle KATP channels, exhibit comparable impaired insulin sensitivity and whether there are differences in the frequency of relapse of TNDM cases attributed to these various genetic causes.

IV. Etiology of Transient Neonatal Diabetes Mellitus (OMIM 601410, 600937, 600509)

The hyperglycemia characteristic of TNDM is the result of reduced or absent insulin output during the fetal period that extends for a variable time into postnatal life. The genetic origin for more than 90% of TNDM cases has been established. Recent work suggests that the deficit in insulin output can arise either from delayed maturation of pancreatic islets and β-cells as a consequence of the altered expression of imprinted genes on chromosome 6 or from β-cell dysfunction that impairs insulin secretion. In the first case, islets and β-cells are poorly developed with reduced or absent insulin; in the latter instance, insulin is present but glucose sensing is defective, thus abrogating insulin release. In either case, reduced fetal insulin, acting as a growth factor, is expected to slow fetal growth.

Figure 22 summarizes pooled data from three studies of children diagnosed with TNDM where the genetic basis was identified. The majority of cases (68%) are due to abnormalities in the 6q24 region, whereas 10 and 13% of cases are attributable to mutations in KCNJ11 and ABCC8, respectively. In a study of 97 TNDM cases (12), it was noted that neonates with 6q24 anomalies had a lower average birth weight (1950 vs. 2570 g) and were diagnosed earlier (0 vs. 4 wk) compared with those with KATP channel mutations. In addition, the average period of neonatal hyperglycemia attributed to KATP channel mutations was longer (35 vs. 13 wk). During the hyperglycemic period, the insulin secretory response to glucose and other secretagogues was impaired, and insulin therapy was required to achieve normoglycemia. Ketoacidosis was present in some cases. After several weeks on insulin and high-caloric feeding, there was striking weight gain, and after more than 3 months, a range of 3–18 months, insulin could be discontinued. The remission period can last several years. For example, Schiff et al. (35) describe normal glucose tolerance (iv glucose tolerance test) in a TNDM case in remission over a 2-yr span. Shield et al. (47) analyzed a group of TNDM patients reporting relatively or entirely normal measures of β-cell function and insulin sensitivity in five individuals over several years; a sixth case exhibited a deficient insulin secretory response to iv glucose. Subsequently, perhaps as a consequence of developing insulin resistance and increased demands on β-cells during puberty, about 40% of cases relapse and present with common features of type 2 diabetes mellitus. The percentage of cases developing diabetes increases with age (12), and the 40% figure will undoubtedly be a minimal estimate as follow-up studies progress. Further work will determine whether relapse is secondary to the low birth weight and restricted intrauterine growth and can be connected to studies associating low birth weight in the general population with the development of type 2 diabetes, and to determine whether clinical markers can be identified to distinguish TNDM from PNDM.

Figure 2
Breakdown of the genetic causes of TNDM derived from studies on French, English, and Japanese cohorts. The data are from Metz et al. (20), Babenko et al. (21), Flanagan et al. (12), and Suzuki et al. (23).

V. Chromosome 6q Anomalies (OMIM 601410) Are the Main Cause of TNDM

A report (48) that insulin was preferentially expressed from the paternal allele in the mouse embryo yolk sac led Haig (49) to propose that a loss-of-function mutation in the paternal insulin gene, coupled with silencing (imprinting) of the maternal allele, might provide a mechanism to account for TNDM—the thought being that the hyperglycemia would resolve after postnatal activation of the maternal allele. This idea did not prove to be correct; however, the importance of imprinting for TNDM was shown in the seminal observation by Temple and Shield (50) of paternal uniparental isodisomy (UPD) of an imprinted region at chromosome 6q in two cases of TNDM. This finding has been confirmed extensively (reviewed in Refs. 5,20, and 51). Overexpression of genes in the 6q24 locus either as a consequence of loss of imprinting at 6q24 by UPD (50,52,53,54,55), by duplication of this region (paternal duplication) (56), or by loss of DNA methylation, and thus activation of the maternal allele (20,57), is the most common cause of TNDM (Fig. 33).). There are multiple imprinted genes in this region (see the imprinted gene catalog at www.otago.ac.nz/IGC), including ZAC [zinc finger protein which regulates apoptosis and cell cycle arrest—also called LOT1, for lost on transformation (58)] and HYMAI (hydatiform mole-associated and imprinted—also called PLAGL1, for pleomorphic adenoma of the salivary gland gene like 1). HYMAI is an untranslated RNA of undetermined function. ZAC is a C2H2 zinc-finger transcription factor (59) with multiple functions, including acting as a coactivator with p53 (60) of Apaf1 (apoptotic protease activating factor 1) (61) transcription, regulating the histone acetyl transferase activity of p300 (62), and serving as a coactivator or corepressor of several nuclear hormone receptors (63). ZAC and HYMAI are transcribed from overlapping genes, and a differentially methylated cytosine and guanine separated by a phosphate (CpG) island important for regulation lies at their 5′ end. The DNA of the ZAC gene is unmethylated in sperm and methylated in oocytes. The maternal alleles of ZAC and HYMAI are both silent, thus the loss of this imprinting is expected to increase the expression of both gene products. Little is known about the specific role(s) of ZAC or HYMAI during pancreatic islet development, but studies in other cell systems provide insight and suggest that the hypothesis that increased expression of tumor suppressor genes contributes to the IUGR associated with the disorder. In this hypothesis, up-regulation of a tumor suppressor gene(s) would lead to a reduction of fetal β-cell mass and thus IUGR secondary to reduced insulin. The 6q24–25 locus is a cancer hot spot, and ZAC has been described independently as a tumor suppressor gene that is reduced or absent in several types of tumors including nonfunctional pituitary tumors (64), primary breast tumors, and in cell lines isolated from breast and ovarian tumors (65,66,67). Overexpression of ZAC in cell lines resulted in a decreased rate of cell replication, increased apoptosis, and G1 arrest (58,68). In short, overexpression of ZAC could be anticipated to reduce growth rate and subsequently β-cell mass.

Figure 3
Potential roles of ZAC in chromosome 6q24 anomalies. A, The state of ZAC expression in control and TNDM cases due to paternal UPD or loss of imprinting (LOI) at the maternal locus. B, Four potential mechanisms by which overexpression of ZAC could reduce ...

The targets responsible for the antiproliferative effects of ZAC are under active investigation, and peroxisome proliferator-activated receptor γ (PPARγ), an insulin sensitizer and tumor suppressor gene expressed in islets (69), is a potential candidate. Barz et al. (70) have shown that ZAC can bind to the PPARγ1 proximal promoter and activate transcription in human colon carcinoma cells. Somatostatin analogs have an antiproliferative effect on pituitary tumors, and the treatment of pituitary tumor cells with the somatostatin analog, octreotide, induces the transcription of ZAC, which in turn up-regulates the expression of PPARγ to slow proliferation. The targeted deletion of PPARγ in β-cells results in marked islet hyperplasia (71). PPAR βγ knockout mice exhibit no significant changes in glucose homeostasis when maintained on lab chow, but interestingly show an impaired increase in β-cell mass in response to a high-fat diet (71). Administration of thiazolidinediones to islets and β-cell lines is reported to potentiate glucose-stimulated insulin secretion (72), enhance fatty acid oxidation (73), and reduce cell proliferation (71). Although a role for PPARγ in islet/β-cell development has not been examined, an increase in ZAC expression during embryogenesis could increase PPARγ expression and slow β-cell proliferation.

ZAC has also been implicated in the regulation of an imprinted region on human chromosome 11 (11p15.5) near the Beckwith-Wiedemann fetal overgrowth syndrome (BWS) locus and two classic imprinted growth regulatory genes, igfr2 and igfr2r. Specifically, ZAC is reported to bind to and regulate a differentially methylated region, KvDMR, in the KvLQT1/KCNQ1 gene. Loss of methylation and activation of the maternal allele of KvDMR are frequent alterations associated with BWS (74). KvDMR is a complex multipartite, multifunctional regulatory region with distinct promoter, repressor, and enhancer modules (75). Paternal inheritance of a deletion of KvDMR results in the loss of expression of a noncoding RNA, Kcnq1ot1 (also called LIT1), and the derepression in cis of imprinted, normally silent, paternal genes on both sides of the deletion (76,77). Two mechanisms have been suggested to account for the gene silencing in this region: 1) blocking of transcription enhancer activity by a process called “CTCF-mediated insulation” which involves a ubiquitously expressed zinc-finger protein, CTCF; or 2) a process that involves the noncoding RNA, Kcnq1ot1. A recent dissection of the KvDMR locus suggests that both mechanisms may be operating (for example, see Refs. 77 and 78). One gene that is normally expressed exclusively from the maternal chromosome is Cdkn1c, a cyclin-dependent kinase inhibitor also called P57KIP2. Cdkn1c/P57KIP2 is a tumor suppressor gene whose down-regulation contributes to the fetal overgrowth characteristic of BWS. Mutations in the maternal copy of Cdk1c/P57KIP2, while infrequent, are a cause of BWS (79). In rodents, overexpression of Cdkn1c/P57KIP2 significantly reduced fetal growth, whereas deletion of the Cdkn1c/P57KIP2 gene resulted in overgrowth (80). The data are consistent with the idea that an increase in the level of ZAC, secondary to UPD or loss-of-imprinting at the 6q24 locus, can up-regulate tumor suppressor genes including PPARγ and Cdkn1c and thus contribute to the growth restriction characteristic of TNDM (summarized in Fig. 33).

The molecular link(s) between 6q24 anomalies and islet development have not been elucidated directly. It seems reasonable to speculate that the effects of increased ZAC and its downstream targets would lead to reduced fetal β-cell mass and concomitant reduction in fetal insulin. Potentially, the combined effect of tumor suppressor gene activity and reduced fetal insulin could synergize to produce a greater growth restriction than reduced insulin secretion alone. This synergism would be consistent with the lower average birth weights associated with 6q24 anomalies vs. overactive KATP channels. The potential overlap between genes or chromosomal regions involved in BWS and TNDM is interesting and could help to explain the overlapping features, macroglossia and umbilical hernia, observed in both disorders.

To develop an animal model of TNDM, Ma et al. (81) generated mice carrying multiple copies of the human 6q24 region in an effort to enhance expression from the 6q24 locus. These animals recapitulate the TNDM phenotype seen in human neonates. TNDM mouse neonates were hyperglycemic, whereas older adults shown impaired glucose tolerance. Neonatal hyperglycemia occurred only with paternal transmission of the transgene, consistent with the paternal dependence of TNDM in humans. Significantly, pancreata of TNDM mouse embryos showed fewer positive structures staining for insulin, glucagon, somatostatin, and pancreatic polypeptide and had reduced expression of several endocrine differentiation factors consistent with impaired islet development. At postnatal stages, β-cell mass was normal or increased, although neonatal pancreatic insulin content and adult peak serum insulin levels in response to glucose infusion were reduced. The mouse phenotype is consistent with the hypothesis that overexpression of a gene or genes in the 6q TNDM locus restricts or slows islet development.

VI. Hepatic Nuclear Factor 1β (OMIM 189907)

Mutations in hepatocyte nuclear factor-1β (HNF1β), also called transcription factor-2 (TCF2), are responsible for two syndromic diabetes phenotypes, maturity-onset diabetes of the young (MODY) 5 and TNDM. In these patients, hyperglycemia cosegregates with renal abnormalities and genital malformations including vaginal and Müllerian aplasia (82,83,84). HNF1β/TCF2 is a member of the POU-homeobox family of basic helix-loop-helix proteins that bind to DNA as dimers. HNF1β is structurally similar to HNF1α (TCF1), with greatest identity in their DNA-binding domains. Although termed hepatic factors, their tissue distribution is not restricted to the liver, being also present in the kidney, gut, genital tract, thymus, lung, and pancreas. N-terminal dimerization domains allow these transcription factors to homo- or heterodimerize and transactivate a variety of genes including those for insulin (85), polycystic kidney hepatic disease 1 (PKHD1) (86), and suppressor of cytokine signaling-3 (SOCS-3) in kidney epithelial cells (87). These presumably represent a small subset of the genes potentially regulated by HNF1β as the up- and down-regulation of a large number of genes, more than 200, in mouse hepatoma cells treated with HNF1β-targeted RNA interference has been reported (88).

Heterozygous mutations in HNF1β are responsible for MODY5 as shown initially by Horikawa et al. (89). More than 30 nonsense, missense, and frame-shift mutations are currently known, and the structural basis for their effects involve both impaired DNA-binding and loss of association with transcriptional coactivators (90,91). The loss of HNF1β expression in different tissues is consistent with the syndromic phenotype. HNF1β is expressed in visceral endoderm at the onset of gastrulation and is essential for the differentiation of visceral endoderm. Consistent with a role in early visceral development, there are several reports of MODY 5 patients with pancreatic atrophy (90,92). The complete loss of HNF1β in TCF2 null mice results in lethality in utero at embryonic day 7.5 (E7.5), resulting in a fetus with disorganized visceral endoderm (93). Haumaitre et al. (94) partially rescued TCF2 null animals and showed that the complete lack of HNF1β, normally expressed in pancreatic buds, results in the absence of a pancreas. In vitro studies have identified an HNF1 binding site in the promoter of the PKHD1 gene and showed that HNF1α and HNF1β bind and stimulate PKHD1 transcription (86,95). The PKHD1 gene encodes a large, single transmembrane-spanning protein called fibrocystin, which is located on the primary cilia of renal cells and is present in fetal and adult kidney cells and to a lesser extent in liver and pancreas (96,97). Loss of fibrocystin produces abnormal cilia and leads to the formation of renal cysts. HNF1β has also been shown to bind to the SOCS-3 promoter and repress SOCS-3 transcription (87). Overexpression of a dominant-negative HNF1β increases SOCS-3 mRNA levels significantly and suppresses tubule formation (87). Morphogenetic growth factors including hepatocyte growth factor are important for kidney tubule formation via stimulation of epidermal growth factor/ hepatocyte growth factor receptors that activate JAK/STAT and MAPK pathways. Increased SOCS-3 can suppress this activation and impair formation of kidney tubules. Therefore, mutations in TCF2 that impair the ability of HNF1β to stimulate transcription can affect renal development by both up- and down-regulation of gene expression.

HNF1β is a key member of the network of transcription factors controlling the differentiation of the endodermal pancreatic precursor cells that assemble the exocrine and endocrine pancreas. HNF1β has been shown to regulate expression of pancreas transcription factor 1α (PTF1a)/P48, part of the PTF1 transcription factor critical for the formation of the exocrine pancreas (see Section VIII), to bind to and activate transcription of HNF6 (98), a ONECUT transcription factor required for expression of Ngn3, a factor critical for β-cell differentiation. The partial loss of HNF1β in mice with a targeted deletion of TCF2 in β-cells resulted in increased expression of HNF1α and pancreatic and duodenal homeobox 1 (PDX1), decreased expression of HNF4α and HNF4γ, and impaired glucose-stimulated insulin release (99).

Yorifuji et al. (84) were the first to report a mutation in HNF1β that produced transient NDM. The S148W mutation was identified in heterozygosity in two siblings presenting variable phenotypes. The first had NDM and a few small renal cysts, but normal renal function. The second had a short episode of hyperglycemia, neonatal polycystic kidneys, and early renal failure. The parents were asymptomatic. Genetic analysis indicated that the mother was a low-level mosaic of normal and mutant TCF2, suggesting that the phenotypic heterogeneity of the children may have resulted from germline mosaicism. A second heterozygous mutation, S148L, was identified during screening of 27 NDM patients for whom no known mutation was found (100). The patient was diagnosed at 17 d of age with transient diabetes that relapsed 8 yr later. Low birth weight, pancreatic atrophy, and exocrine insufficiency were also present, consistent with the role of HNF1β in pancreatic development.

VII. Permanent Neonatal Diabetes Mellitus

As with the transient form of NDM, the hallmark of PNDM is hyperglycemia early in life, but without the period of remission that defines TNDM. To date, 10 genes involved in pancreatic development, β-cell apoptosis, or dysfunction have been identified as being able to give rise to PNDM. In most cases, TNDM and PNDM cannot be distinguished clinically, and genetic analysis needs to be performed because the identification of a known molecular defect will determine the clinical prognosis, treatment, and genetic counseling. Although hyperglycemia is the main manifestation, the majority of PNDM cases also present IUGR and failure to thrive (reviewed in Ref. 101). Diabetes has also been reported in syndromic disease reflecting the roles the affected genes have beyond the β-cell, for example as described for HNF1β. Table 22 summarizes the genes identified to date. The etiologies are grouped loosely in terms of abnormal pancreatic development, reduction in β-cell mass due to increased apoptosis or necrosis, and β-cell dysfunction. It is worth noting that mutations in two genes, PDX1/IPF-1 and glucokinase (GCK), that cause MODY in the heterozygous condition produce PNDM in the homozygous state, whereas TNDM has been seen in children with two MODY5 (HNF1β) mutations as described in Section VI.

Table 2
Etiology of congenital diabetes mellitus

VIII. Abnormal Pancreatic Development

A. Pancreas transcription factor 1, α subunit (PTF1a) (OMIM 607194, 609069)

Hoveyda et al. (102) identified a recessively inherited syndrome in three children from an inbred Pakistani family that was characterized by NDM, severe IUGR, microcephaly, facial dysmorphism, respiratory distress, and hypoplastic cerebellar tissue. The family had a strong history of type 2 diabetes mellitus, with more than five relatives presenting the disease in their early thirties in the absence of obesity and one case of gestational diabetes. Sellick et al. (103) reported on a second family of Caucasian northern European ancestry with the same features, including low, but detectable C-peptide levels and the absence of pancreatic tissue upon postmortem examination. Genome-wide linkage analysis identified a new locus for NDM on 10p13-p12.1, and positional cloning uncovered two mutations, 705insG→R296X and C886T→P236fsX270, in the PTF1a (or PTF1a/P48) gene in these families.

PTF1a/P48 is a member of the basic helix-loop-helix family of transcription factors and is essential for the development and maintenance of the adult pancreas (104,105) and for development of the cerebellum. PTF1a/P48 is a subunit of the unusual, heterotrimeric transcription factor, PTF1, that consists of one PTF1a/P48 subunit, one of several ubiquitous class A basic helix-loop-helix proteins [e.g., E12, E47, HEB reported to activate expression of several cyclin-dependent kinase inhibitors (106)], and a third subunit identified as either the mammalian Suppressor of Hairless (RBP-J) or its paralogue, RBP-L (107). The composition of PTF1 changes with development, with RBP-L directing high-level transcription in the adult exocrine pancreas. Two conserved tryptophan-containing motifs are important for the binding of the RBP isoforms to PTF1a/P48. The two disease mutations truncate one or both motifs and thus impair the binding of PTF1a/P48 to RBP-J and to a lesser extent to RBP-L (107). Deletion of PTF1a/P48 in mice results in neonatal death with pancreatic and cerebellar agenesis (103,105,108), consistent with the human phenotype. PTF1a/P48 is expressed early in embryogenesis (~E9.5 in mice) throughout the developing pancreas. The ventral pancreatic bud is absent in PTF1a/P48 null mice, outgrowth of the dorsal bud is impaired, and exocrine cells fail to differentiate. Interestingly, the patients have low, but detectable levels of C-peptide (103), and in PTF1a/P48 null mice the pancreatic endocrine cells are present, albeit in reduced numbers and mislocalized to the spleen. PTF1 regulates the expression of multiple genes, but recent work demonstrates that it binds to a conserved element, termed area III, in the promoter of PDX1, a key player in the network of transcription factors that regulate the development and maintenance of the adult endocrine and exocrine pancreas (109,110). The results are consistent with the idea that PTF1 transactivates the expression of the PDX1 gene via binding to area III and that this expression generates PDX1+ cells required for the differentiation of the exocrine pancreas (Fig. 44).). The persistence of endocrine cells in both patients and PTF1a/P48 null mice suggests that there is a parallel or synergistic pathway controlling PDX1 expression and that regulation by PTF1 is not essential for islet cell differentiation and maintenance. Further studies would be needed to determine whether the reduced endocrine mass is a consequence of reduced PDX1 level vs. loss of pancreatic tissue architecture.

Figure 4
Schematic representation of the central role of PDX1/IPF-1 within the network of transcription factors critical for pancreas differentiation and development. The accompanying table relates MODY classification with the affected protein. Glut2, Glucose ...

The focus of this review is diabetes; therefore our discussion of PTF1a has centered on the pancreas. Impaired cerebellar development is also a feature of cases with PTF1a/P48 mutations, and the reader is urged to see Ref. 111 for a review of the role of PTF1a in that arena.

B. Pancreatic and duodenal homeobox 1/insulin-promoter-factor 1 (PDX1/IPF-1) (OMIM 600733)

Initially cloned by Thomas Edlund’s group (112), PDX1, also known as IPF-1 or insulin-promoter factor 1, is a homeodomain transcription factor that plays a critical role as noted above in the formation of the pancreas by determining the fate and regulating the propagation of both pancreatic exocrine and endocrine precursor cells (113). Mice with a targeted mutation in the PDX1/IPF-1 gene expressed in the homozygous state lack a pancreas and die within a few days of birth (114). Subsequent work in a number of laboratories has shown that PDX1/IPF-1 is a central regulator in the interacting network of transcription factors that govern islet cell differentiation and development (115,116,117,118). Mutations in several of the genes encoding these transcription factors are known to cause MODY (Fig. 44;; for review, see Ref. 119).

The importance of PDX1/IPF-1 in human pancreas development was confirmed when a child with a single-nucleotide deletion in exon 1 (Pro63fsdelC) of the human PDX1/IPF-1 gene was described (120). This mutation produces a frame shift that truncates PDX1 prematurely and results in pancreatic agenesis. The child was homozygous for the mutation and required insulin treatment and pancreatic enzymes to replace pancreatic function. Within the child’s extended family, eight relatives in six generations were heterozygous for the mutation and developed early-onset type 2 diabetes (MODY4) (121,122). The diabetes in these cases was generally treatable with diet, oral hypoglycemic agents, and in a few instances with insulin. The findings support the idea that haploinsufficiency of PDX1 impairs β-cell function and the increasing demand for insulin with age results in hyperglycemia, whereas the lack of PDX1 blocks endocrine and exocrine tissue differentiation. This would suggest that other MODY genes, if present in the homozygous state, would produce NDM, an idea supported by the finding discussed below that homozygous loss of GCK is a cause of NDM.

A second case was reported by Schwitzgebel et al. (123) in a patient with compound heterozygosity of two mutations in exon 2, E164D and E178K. This patient presented with low birth weight and length and was diagnosed at 12 d of age with a glycemia of 854 mg/dl (47 mmol/liter). DNA binding was unaffected, but the two mutations significantly decreased the half-life of PDX1 (36 and 27%). The reduced PDX1 content altered transcriptional activity, implying that the level of expression is important for pancreatic development. The parents, each a carrier of one mutation, had slightly elevated fasting glucose levels with normal oral glucose tolerance test. The severity of the phenotype correlated with the mutation, the reduced activity attributed to a single heterozygous mutation being insufficient to give a severe diabetes phenotype.

C. GLIS subfamily of Kruppel-like zinc finger proteins-3 (GLIS3) (OMIM 610199)

Taha et al. (124) reported a family with a novel autosomal recessive syndrome in two infants affected with multiple organ involvement. Both siblings presented with IUGR, nonautoimmune congenital diabetes, severe congenital hypothyroidism, cholestasis and subsequent hepatic fibrosis, congenital glaucoma, polycystic kidneys, and minor facial abnormalities. The children were the product of a consanguineous family of Saudi Arabian descent with no history of diabetes, thyroid, liver, and eye or kidney disease. The two infants, a girl and a boy, were the family’s first and fourth children (two normal siblings) and were born after full-term and 37-wk pregnancies without complications. The index cases presented with IUGR and hyperglycemia in the first days after birth, supporting the idea that they had intrauterine insulin deficiency secondary to defects in pancreatic development. The rest of the manifestations appeared in subsequent weeks. Computed tomography scan of the abdomen demonstrated hepatosplenomegaly with a small pancreas in the first case and no visualization of the organ in the second case. The hyperglycemia and hypothyroidism were brought under control, but the infants died at ages 14 and 4 months, respectively, after pneumonia and Escherisia coli sepsis.

Senee et al. (125) undertook a genome-wide scan in the available members of the original family plus two other consanguineous families with a similar but more heterogeneous syndrome where congenital diabetes and congenital hypothyroidism were present. Mutations in GLI Similar-3, a novel transcription factor of the GLIS subfamily of Kruppel-like zinc finger proteins, were identified as responsible for the syndrome. This novel transcription factor was identified and characterized by Kim et al. (126) as a member of the GLI family of proteins that play an important role in neuronal and skeletal development in mammals. GLIS3 can function as both a repressor and activator of transcription via binding to GLI-response element consensus sequences. Both N and C termini are necessary for optimum transcriptional activity, including the zinc finger motif and the nuclear localization signal. Mouse studies suggest that GLIS3 plays an important role in multiple cellular processes during development, including a possible role in apoptosis in the interdigital regions (126). GLIS3 is expressed in the pancreas mainly in β-cells at an early developmental stage. The multiorgan involvement implies a wider role for GLIS3 in thyroid, eye, liver, and kidney development.

In the first family reported by Taha et al. (124), patients were homozygous for an insertion (2067insC) that caused a frame shift and resulted in a truncated protein (625fs703stop). In the other two families, the probands had two distinct deletions affecting the 11 or 12 most 5′ exons of the gene. The individuals studied in the second family were homozygous for a 426-kb deletion encompassing part of the 5′ untranslated region of GLIS3 and SLC1A1, the high-affinity glutamate transporter. In the third family, the homozygous probands carried a 149-kb deletion that overlapped a small portion of the GLIS3 5′ untranslated region. These changes reduced the expression of GLIS3 by more than 90%. Senee et al. (125) also looked at expression in human and rodent tissues in the developing and adult pancreas and showed that GLIS3 is expressed as a major transcript as early as E15.5, increases after birth, and is preferentially expressed in β-cells, consistent with an important role in β-cell development.

IX. PNDM Attributable to Increased β-Cell Apoptosis or Necrosis: Pancreatic Eukaryotic Initiation Factor 2α Kinase (EIF2AK3); Wolcott-Rallison Syndrome (OMIM 226980)

In the early 1970s, Wolcott and Rallison (127) reported a novel recessive disorder in three siblings presenting with permanent congenital or infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and growth retardation. A decade later, a brother and a sister were reported with the same phenotype (128), supporting the hypothesis that the association of endocrine (NDM) and chondro-osseous (epiphyseal and spondylo-epiphyseal dysplasias) abnormalities could be the manifestation of a pleiotropic gene. After these two reports, other cases with additional clinical signs including learning difficulties, hepatic and renal dysfunction, cardiac abnormalities, and exocrine pancreatic dysfunction have been reported (129,130,131). The heterogeneity of this disorder was underscored by the observation at autopsy of a Wolcott-Rallison syndrome (WRS) case with severe pancreatic hypoplasia and congenital diabetes, abnormal bone histology, cardiomegaly, mental retardation and cerebellar cortical dysplasia, and hepatic and renal dysfunction (130,131). This patient had a mosaic deletion of part of chromosome 15 (15q11–12) in 65% of examined karyotypes. Islet architecture was disorganized, with few insulin-positive cells and a preponderance of glucagon-positive cells.

Using linkage analysis, Delepine et al. (132) identified eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3; also called PERK) as the WRS gene in two consanguineous families of Tunisian and Pakistani descent. EIF2AK3/PERK is highly expressed in pancreatic islets (133), plays an important role in the regulation of protein translation and the unfolded protein response (UPR) (134,135), and maps to chromosome 2p12, a previously identified WRS locus. EIF2AK3/PERK is a single pass transmembrane protein with a lumenal domain that binds unfolded proteins in the endoplasmic reticulum (ER) and a cytoplasmic kinase domain. In professional secretory cells like β-cells, EIF2AK3/PERK plays a pivotal role in the UPR, a homeostatic signaling pathway that adjusts the protein-folding capacity of the ER in response to demand. EIF2AK3/PERK is one of three types of sensors that recognize unfolded proteins in the ER and activate the transcription of multiple genes to increase the ER-folding capacity or, if the stress is sufficient, to initiate apoptosis (reviewed in Refs. 136,137,138,139). The binding of unfolded protein to EIF2AK3/PERK results in phosphorylation of eIF2α, a factor critical for initiation of translation. Phosphorylation of eIF2α reduces the rate of synthesis of the majority of proteins (140,141) and thus decreases protein load and stress on the ER. The loss of PERK activity secondary to mutation abolishes this feedback, and the increased stress on the ER can initiate apoptosis. Cells with the greatest secretory load are those likely to be at greatest risk, and impaired EIF2AK3/PERK function will affect many tissues.

Two inactivating mutations have been identified that segregate with the disorder. 1103insT, identified in three of four probands, introduces a termination codon that truncates the EIF2AK3/PERK catalytic domain. A second missense mutation, G1832A, changes a highly conserved residue in the catalytic domain. Recent reports (142,143,144,145,146) have identified 17 novel mutations in the EIF2AK3 gene with variable expressivity, including three cases with developmental regression secondary to hepatic failure in consanguineous families of different racial and ethnic background (Table 33).). Durocher et al. (144) reported on two, possibly related, patients of French Canadian origin with the same mutation, E331X, that exhibit different phenotypes possibly as a result of modifier genes and/or environmental and epigenetic interactions. Although none of the mutations that result in a truncated protein have been characterized, the absence of the catalytic and most of the regulatory domain suggests they will be inactive.

Table 3
Missense mutations identified in patients with WRS (all consanguineous marriages)

Two independently derived Eif2ak3 knockout mouse lines have been generated (134,147) that display a phenotype similar to that seen in WRS patients, i.e., normal birth weight, slow growth, hyperglycemia, low insulin levels, and bone abnormalities including osteoporosis, deficient mineralization, and developmental abnormalities. During the first 2 wk of life, these mice are euglycemic with normal pancreatic histology. By 4–6 wk, the animals become hyperglycemic secondary to β-cell death. There is a parallel increase in α-cells and a severe reduction in digestive enzymes; massive apoptosis was observed histologically in the pancreas. Electron microscopy of endocrine and exocrine tissue revealed abnormalities in the ER lumen consistent with the accumulation of misfolded proteins (134,147). Zhang et al. (148) generated a series of tissue- and cell-specific PERK transgenes and showed that PERK is required during embryogenesis to maintain postnatal β-cell function and glucose homeostasis but is not required to maintain normoglycemia in adult mice.

Scheuner et al. (149) generated another model in which the PERK phosphorylation site on eIF2α, Ser51, was replaced with an alanine. This model emphasized the importance of PERK in the regulation of glucose homeostasis via the liver; the animals died of hypoglycemia within 18 h due to impaired gluconeogenesis. Animals could be rescued by giving glucose every 8 h but displayed severe growth retardation. Islet studies showed that β-cell insulin content and mass were reduced by approximately 50%.

X. Insulin

Støy et al. (150) have reported that mutations in the insulin (INS) gene and its precursors are a novel cause of PNDM. Ten recessive de novo mutations were identified in 16 cases, but this initial report stimulated additional screening (151,152) that identified further variants (Table 44).). The mutations are localized to amino acid residues that could potentially affect cleavage and/or folding of pre-proinsulin and proinsulin. Some of these properties are summarized in Table 44.. An accumulation of improperly folded insulin precursors would induce prolonged ER stress, the UPR, and the initiation of β-cell apoptosis. Unlike the EIF2AK3/PERK mutations that affect multiple tissues, increased apoptosis and cell death due to increased UPR should be restricted to pancreatic β-cells.

Table 4
NDM mutations in the insulin gene

The initial missense mutations were identified in a cohort of patients with NDM. Although there is heterogeneity in the age of presentation, most cases were diagnosed in the first 6 months of life, with three cases diagnosed between 6 and 12 months. The father of one patient was diagnosed at 30 yr of age with a mild form of the disease. Most of the infants presented with severe hyperglycemia (681 mg/dl, median plasma value) or ketoacidosis and low or undetectable values of C-peptide. Interestingly, although the birth weights were reduced, the median [2846 g (20th centile)] was above that found in cases of NDM resulting from other causes. The authors note that in three cases the mothers developed gestational diabetes, which may have increased infant birth weight.

It is worth pointing out that the C96Y mutation was previously identified in the Akita mouse (153) and shown to impair folding and processing because a disulfide bond between the two insulin chains is not formed and the protein is partially retained in the ER. Akita mice are born normoglycemic with normal-sized islets but become hyperglycemic with age secondary to the loss of β-cells. Overexpression of mutant C96Y insulin in MIN6 cells resulted in apoptosis (154). A second mouse, the Munich Ins(C95S) model (155), was identified in a mouse mutagenesis screen using N-ethyl-N-nitrosourea. This mutation, which will disrupt the A6-A11 disulfide bond, produces hyperglycemia by 1 month of age secondary to reduced insulin release. Electron microscopy of male mouse β-cells revealed a lack of insulin secretory granules, enlarged ER, and swollen mitochondria consistent with UPR. The available data are consistent with loss of β-cells during the fetal period secondary to activation of the UPR by an excess of abnormally folded mutant insulin; however, this is a recent discovery, and additional molecular mechanisms may be uncovered.

XI. Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX), FOXP3 (OMIM 304790/304930)

Initially described by Powell et al. (156) and later by Bennett et al. (157), IPEX (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked) includes a rare, heterogeneous group of disorders that are almost always fatal. The disease can affect multiple tissue types, is reported under various names, and includes congenital diabetes, colitis and diarrhea, hypothyroidism, and frequent infections among others. Chatila et al. (158) and Wildin et al. (159) showed that the FOXP3 gene encoding scurfin (160) was altered in IPEX patients and in the scurfy mouse, which has an IPEX-like phenotype (reviewed in Ref. 161). Scurfin is a member of the forkhead/winged helix domain family of DNA-binding proteins, both transcriptional activators and repressors, that function in the control of lineage commitment and developmental differentiation (reviewed in Ref. 162). The mutations identified in IPEX patients (158,159,163,164) affect protein dimerization or alter the forkhead/winged helix domain, thus impairing scurfin-DNA interactions. Scurfin binds to and represses IL-2 promoter activity and has been suggested to be required for the development of CD4+/CD25+ regulatory T cells, a naturally occurring population of regulatory T cells, that can inhibit harmful immunopathological responses against foreign or self antigens (see Ref. 165 for review). Bettelli et al. (166) showed that scurfin associates with and inhibits nuclear factor κB and nuclear factor of activated T cells, proteins important for cytokine expression. Overexpression of scurfin suppressed IL-4 and interferon-γ, whereas T cells derived from scurfy mice and patients with IPEX had increased nuclear factor of activated T cells and nuclear factor κB expression that could be normalized by adding scurfin. Bacchetta et al. (167) showed that the number of CD4+/CD25+ T cells from IPEX patients lacking scurfin was comparable to controls, but they had a profoundly impaired ability to suppress autologous effector T cells. All IPEX patients had normal proliferative responses after T cell receptor stimulation but were unable to produce IL-2 or interferon-γ. Bacchetta et al. (167) concluded that CD4+/CD25+ T cells can be present in normal numbers in IPEX patients, but their capacity to suppress is impaired depending on the type of mutation, the strength of T cell receptor stimuli, and the genotype of the effector T cells. Patients positive for type 1 diabetes-associated autoantibodies (insulin autoantibody, islet cell antibodies, and glutamic acid decarboxylase) have been described by Wildin et al. (159), and immunosuppressant therapy has been used with limited results. Although congenital hyperglycemia is a characteristic clinical feature of IPEX, further work is needed to differentiate the relative role(s) that overproduction of cytokines vs. β-cell and/or islet destruction play in the NDM associated with this syndrome.

XII. PNDM Attributable to β-Cell Dysfunction and Impaired Glucose-Stimulated Insulin Secretion

Multiple proteins involved in the control and facilitation of glucose-stimulated insulin secretion by pancreatic β-cells are potential candidates for producing β-cell dysfunction and impaired glucose homeostasis. Mutations in five genes expressed in β-cells have been associated with hyper- or hypoinsulinemia and provide insight into the control of insulin release. Reduced KATP channel activity due to mutations in sulfonylurea receptor (SUR1 = ABCC8) or KIR6.2 (KCNJ11), decreased enzymatic activity of short-chain-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (SCHAD), or glutamate dehydrogenase, and the increased activity of GCK are associated with neonatal hypoglycemia secondary to HI. Alterations in three of the same genes that cause loss-of-activity of GCK or increased KATP channel activity secondary to mutations in KCNJ11 and ABCC8 are the cause of the hyperglycemia present in NDM. Figure 55 highlights the functions of the NDM genes in β-cell glucose sensing and subsequent insulin release.

Figure 5
Schematic representation of a pancreatic β-cell illustrating the roles of GCK and KATP channels. The entry of glucose (G) is facilitated by a transporter (Glut) and converted to glucose-6-phosphate (G-6-P) by GCK. Glycolysis converts G-6-P to ...

In a normal individual before a meal, the activity of KATP channels reduces the membrane potential (Vm) of pancreatic β-cells below the threshold for activation of voltage-gated Ca2+ channels, thus turning off the stimulatory action of Ca2+ on insulin secretion. During a meal, blood glucose increases and enters β-cells via glucose transporters. The conversion of glucose to glucose-6-phosphate by GCK is the key step governing substrate input into the glycolytic pathway in β-cells. Subsequent metabolism via glycolysis and oxidative phosphorylation raises the ATP/ADP ratio. This increase closes KATP channels, depolarizing the β-cell membrane to allow Ca2+-dependent insulin secretion via activation of voltage-sensitive Ca2+ channels (Fig. 55).). Adenine nucleotides therefore serve as the currency that links metabolism with membrane potential, cellular Ca2+ levels, and insulin secretion. GCK and KATP channels play critical roles on the input and output ends of this link, and mutations in either one have dramatic effects on insulin release. Mutations in GCK directly affect ATP/ADP by modulating the input of glucose into the glycolytic pathway, whereas mutations in ABCC8 and KCNJ11 alter the response of KATP channels to ATP and ADP. Changes in the intermediate steps in this linkage might be anticipated to give rise to alterations in glucose homeostasis, and an impaired ability to generate ATP from ADP has been implicated, for example, as one contributing factor in mitochondrial diabetes (see for example Refs. 168 and 169).

XIII. Glucokinase (GCK) (OMIM 606176)

GCK has a limited tissue distribution, with expression in pancreatic β-cells, liver, some endocrine cells in the gastrointestinal tract, and in specialized glucose-excited neurons in the hypothalamus and anterior pituitary. GCK has been termed the glucose sensor of the pancreatic β-cell where it is the primary determinant of the threshold for glucose-stimulated insulin secretion (reviewed in Ref. 170). Although β-cells have some hexokinase with a higher affinity for glucose, the major capacity for input of glucose into the glycolytic pathway is determined by the kcat and affinity of GCK for glucose and by the cellular concentrations of GCK and ATP. In normal human β-cells these parameters set the glucose threshold for insulin release near 5 mmol/liter. Matschinsky and colleagues (171) have developed the concept of a GCK-glucose sensor and have used mathematical modeling to evaluate the β-cell glucose phosphorylation rate (BGPR) (reviewed in Refs. 170,172,173, and 174). They estimate that the flux of glucose through GCK at the threshold for insulin release is approximately 25% of the total phosphorylation potential. Approximately 200 mutations have been identified in GCK. The majority are heterozygous, inactivating mutations that reduce the input of glucose into the glycolytic pathway and are a cause of MODY (reviewed in Ref. 175). Six homozygous inactivating GCK mutations are associated with PNDM (176,177,178), whereas five activating mutations that increase glucose metabolism have been associated with HI (175,179,180). Froguel et al. (181) and Prisco et al. (182) noted that GCK mutations might account for some cases of PNDM, and Njolstad et al. (177) reported the first homozygous mutations, M210K and T228M, in two consanguineous families of Norwegian and Italian ancestry that presented with complete GCK deficiency, IUGR, and severe hyperglycemia (300 and 715 mg/dl on the second and third days of life) that required insulin treatment. This was the first identification of GCK mutations producing MODY when heterozygous and PNDM when homozygous. Kinetic analysis of the recombinant proteins revealed dramatically reduced enzymatic activities (0.05 and 0.16% of wild type for T228M and M210K, respectively). To date six patients have been described with this severe form of PNDM resulting from homozygous or compound heterozygous GCK mutations (176,177,178). These are of European (M201K, T228M), Turkish, (A378V), Israeli/Arab (G264S and IVS8 + 2 T to G), and Asian (R397L) descent. Table 55 summarizes some of the characteristics of GCK-PNDM patients. It is interesting to note that although the sample size is small, the average birth weight in the GCK neonates is on the lower side of the data presented in Fig. 11.

Table 5
Clinical and laboratory characteristics due to GCK mutations

As expected from its key role in governing the input of glucose into the glycolytic pathway, GCK mutations have a dramatic effect on the β-cell glucose phosphorylation rate. This is illustrated in Fig. 66 using the minimal model described by Davis et al. (171) and the parameters for the A378V mutation taken from Njølstad et al. (176). In the heterozygous condition the A378V GCK mutation increases the glucose threshold for insulin release from 5 to more than 8 mmol/liter to produce the MODY phenotype. In the homozygous condition, the effect is profound and the threshold is never attained. The complete loss of β-cell GCK activity in the homozygote blocks the increase in the ATP/ADP ratio needed to close KATP channels, open voltage-gated Ca2+ channels, and thus initiate insulin release.

Figure 6
Effect of the A378V GCK mutation on the β-cell glucose phosphorylation rate. The threshold for insulin release with wild-type GCK is approximately 5 mm glucose. The loss of GCK activity due to the A378V mutation in the heterozygous condition ( ...

Several models have been generated to study MODY and NDM either by making animals heterozygous or homozygous for deletion of GCK, respectively, or by specifically targeting β-cells (184,185,186). Heterozygous (GCK+/−) mice with lower GCK activity display reduced glucose-induced insulin secretion during a hyperglycemic clamp, a phenotype comparable to MODY. Generating homozygous mice proved harder. The GCK−/− mice made by Bali et al. (184) were embryonic lethal (E9.5). Those from Grupe et al. (185) displayed high glucose levels and ketoacidosis at birth. In addition, they had lipid (high cholesterol and triacylglycerol) and liver (steatosis, glycogen depletion) abnormalities and died in the first week of life. Reconstituting GCK activity normalized the lipid abnormalities. Targeting β-cells produced mice with decreased pancreatic GCK activity (185,186). Heterozygous animals had a mild phenotype that produced hyperglycemia at 2–3 months of age. Animals lacking β-cell GCK presented a phenotype similar to the global knockout, including growth retardation and lethality within the first week of life.

XIV. TNDM and PNDM Attributable to Reduced Insulin Secretion Secondary to Overactivity of ATP-Sensitive Potassium Channels, KCNJ11 and ABCC8 (OMIM 600509, 600937, 610374)

Although GCK controls the input of glucose into the glycolytic pathway, KATP channels are at the end of the chain poised to translate changes in nucleotide balance into the variations in membrane potential that regulate influx of Ca2+ via voltage-sensitive calcium channels. The first indication that overactive channels might produce early diabetes came from the generation of transgenic mice expressing a KIR6.2 subunit lacking a segment of its amino terminus (187). Earlier studies had shown the KIR amino terminus played a key role in channel gating and that its deletion resulted in channels that were nearly continuously open [open probability (PO), ~0.95] and had reduced sensitivity to inhibitory ATP and hypoglycemic sulfonylureas (188,189,190). The transgenic animals exhibited a dramatic hyperglycemia that proved lethal within the first weeks of life.

A. Clinical aspects

Gloyn et al. (191) were the first to report the identification of six heterozygous, missense activating mutations, V59G/M, Q52R, R201C/H, and I296L, in KCNJ11 that were associated with PNDM in 29 cases, mainly from the International Society for Pediatric and Adolescent Diabetes (ISPAD) Rare Diabetes Collection. This study provided insight into the dramatic phenotypic heterogeneity resulting from the expression of KATP channel mutations in different tissues. Marked hyperglycemia [270 to 972 mg/dl (15 to 54 mmol/liter)] was diagnosed at a mean age of 7 wk, C-peptide concentrations were less than 200 pmol/liter, and none of the cases had elevated concentrations of autoantibodies associated with type 1 diabetes. Three patients had ketoacidosis. Insulin controlled the hyperglycemia in these patients (median dose, 0.8 U/kg). The father of one proband had received tolbutamide since childhood and was in good glycemic control. Similar to cases of NDM attributed to other causes, all of the patients had low birth weight, with 58% at or below the third percentile. Rapid catch-up growth was seen in patients with diabetes alone, and their weights and heights were normally distributed by a mean of 9.3 yr. Consistent with differences in the severity of the mutation and the expression of KCNJ11 in the central nervous system (CNS) and skeletal muscle, there is a marked heterogeneity of the disease presenting a phenotypic spectrum. One patient with the V59M mutation displayed neurological abnormalities including developmental delay and muscle weakness. Three patients, with Q52R, V59G, and I296L mutations, displayed more severe neurological signs including marked developmental delay, muscle weakness, epilepsy associated with periods of hypoglycemia, and dysmorphic features in addition to their diabetes. The more severe clinical picture including epilepsy has been termed the DEND (delayed development, epilepsy, NDM) syndrome (192), whereas patients without seizures are classified as intermediate (iDEND) (192,193,194). Some of the characteristics of the DEND phenotype are summarized in Table 66.. The remaining patients had diabetes, but otherwise developed normally. Gloyn et al. (191) described the properties of KATP channels with the R201H mutation and confirmed an earlier report (195) that substitution at this position reduced the apparent affinity for inhibitory ATP compared with the wild-type channel (IC50ATP ~ 245 vs. 6.6 μm). The expected increase in activity of the mutant channels in pancreatic β-cells was proposed to limit their closure, prevent depolarization, and thus reduce Ca2+ influx and insulin release.

Table 6
Characteristics of patients described with DEND syndrome

The initial association of KCNJ11 mutations with diabetes was for PNDM cases, but substitutions in KCNJ11 are also associated with TNDM. The same group (196) reported that mutations G53S, G53R, and I182V, with a weaker effect on the apparent affinity of KIR6.2 for ATP (IC50ATP ~ 30 vs. 7 μm for wild-type), were associated with relapsing NDM. Three of 11 patients diagnosed with diabetes in the first 4 months of life carried these mutations and went into remission by 7 to 14 months.

There was some initial doubt that mutations in ABCC8 would be found that produced more active channels. However, screening of NDM cases with no 6q24 anomalies, GCK deficit, or alterations in KCNJ11 independently uncovered one mutation (F132L) in ABCC8 in transmembrane domain (TMD) 0 (197) and seven mutations (L213R, C435R, L582V, H1023Y, R1182Q, R1379C, and I1424V) more generally distributed throughout the molecule (21) that were associated with the disorder. The hallmark of channels carrying these mutations was their reduced sensitivity to MgATP. A detailed analysis of the H1023Y and I1424V channels demonstrated the importance of Mg2+ and showed that their apparent affinity for inhibitory ATP was unchanged (21). These results strongly supported our earlier arguments (reviewed in Refs. 198,199,200,201) that SUR1 exerts a Mg-nucleotide dependent stimulatory action on KIR6.2 that antagonizes the inhibitory effect of ATP. This is a novel mechanism, independent of the affinity KIR6.2 for ATP; thus, understanding how these mutations increase the stimulatory action of SUR on the pore will shed deep insight into the regulation of these channels. These cases further emphasized the phenotypic heterogeneity produced by alterations in KATP channels. The F132L mutation, in TMD0, produced the DEND syndrome (197). The patient had low birth weight, progressively increasing glycosuria, and formal diagnosis of diabetes at 13 wk of age based on an oral glucose tolerance test. The patient had motor and social developmental delays, nonspecific generalized epileptiform activity on electroencephalography, and, as an adult, is unable to speak, has difficulty standing due to muscle spasms, and requires anticonvulsant medication. Analysis of F132L channels indicated a strongly reduced sensitivity to MgATP, 448 vs. 16 μm for wild-type channels. The seven ABCC8 mutations described in Babenko et al. (21) produced milder phenotypes. The L213R and I1424V mutations were associated with PNDM, and the other five with TNDM. These patients were diagnosed within the first 6 months of life (range, 3 to 125 d) and presented with low birth weights (range, <3 to 67 percentile) and hyperglycemia (range, 6.9 to 66 mm) with no indication of islet cell autoantibodies associated with type 1 diabetes. Two patients (H1023Y and I1424V) presented with ketoacidosis, and four patients (L213R, C435R, I1424V, and R1379C) had minor neurological symptoms including dyspraxia, mild distonia, and developmental delay. The finding of the complete phenotypic spectrum, TNDM through DEND, in patients with ABCC8 mutations implies that the major deficit(s) involve primarily the neuroendocrine channels, whereas the contribution of the KCNJ11/ABCC9 KATP channels in skeletal and cardiac muscle is subtler. In this regard, insulin resistance has been reported in some patients with the R201H and K107N KCNJ11 mutations (43).

B. Channel aspects

The β-cell neuroendocrine-type KATP channels are comprised of four KIR6.2 (KCNJ11) molecules that make up the K+ conducting pore and four SUR1 (ABCC8) subunits that surround the pore and regulate its activity (Refs. 202,203,204,205; and reviewed in Ref. 206). The KATP channels found in muscle are built on the same plan from SUR2A/KIR6.2 (207) or in the case of smooth muscle channels from SUR2B/KIR6.1 subunits (208,209). ABCC8 was cloned using its high affinity for the oral hypoglycemic agent, glibenclamide (210). The loss of SUR1/ABCC8 (and KIR6.2/KCNJ11) function was associated with neonatal hypoglycemia secondary to HI, confirming a key role for KATP channels in the regulation of insulin release (211). More than 200 HI mutations in ABCC8 and KCNJ11 are now known (see Refs. 212,213,214,215,216,217 for review). SUR1/ABCC8 was subsequently coexpressed with KIR6.2/KCNJ11 to reconstitute functional neuroendocrine-type KATP channels (218). Structure-function studies by many groups have mapped important domains within the subunits and defined the properties of this channel family (reviewed in Refs. 198,201, and 219).

Abrogation of ER retention signals designed to ensure that only fully assembled (220,221), full length (222) channels reach the cell surface allows surface expression of KIR6.2 without SUR. KIR alone forms a poorly active (PO ~ 0.1), weakly ATP-inhibited (IC50 ~ 100–200 μm) channel (223,224). Reconstitution with SUR increases the apparent affinity for inhibitory ATP (IC50 ~ 5–10 μm), restores bursting, and increases the PO (~0.5–0.6). The domain critical for restoration of bursting and PO is TMD0 (225,226), whereas adjacent segments of L0 exert a bidirectional control, either fully activating (PO > 0.9) or inhibiting channel activity, thus demonstrating the importance of this segment (Ref. 225); and reviewed in Ref. 198). Assembly of KIR6.2 with TMD0-L0 does not restore the full sensitivity to inhibitory ATP, indicating that there are important, additional interactions between KIR6.2 and the ABC core (227).

Deletion of fewer than 35 amino acids from the KIR amino terminus fully activates KATP channels (PO > 0.9) and reduces their sensitivity to sulfonylureas (188,189,190). We have suggested that interactions between the KIR amino terminus and L0 are a key part of the structural link between the ABC core and the gate (198,201,225). We have proposed a semimechanical structural model where the NBDs in the SUR core undergo a cyclic dimerization when ATP binds and is hydrolyzed, which results in movements of the TMDs (198,201), exactly like any other ABC transporter (see Ref. 228 for review). These TMD movements are hypothesized to link to the gate via interactions between L0 and the KIR amino terminus. This structural model is an attempt to link the underlying enzymology with channel gating and builds on the idea that a particular enzymatic intermediate(s), i.e., a specific conformation of the SUR core, stabilizes the open configuration of the KIR channel. Terzic and colleagues (229,230) have provided evidence that a posthydrolytic state of SUR, presumably with MgADP bound, is the activating enzymatic intermediate. This concept implies that mutations in ABCC8 that “trap” or increase the amount of time SUR1 spends in the activating conformation will result in net stimulation of KATP channels that produce NDM.

Understanding the dual role that nucleotides play in the control of channel activity is critical for interpreting NDM (and HI) mutations. The binding of ATP to KIR6.2 inhibits channel activity. This inhibition is independent of Mg2+, and the dose-response curves are well described by a single-site binding isotherm consistent with one bound ATP inhibiting the channel (231). Mutations that reduce the apparent affinity of KIR6.2 for ATP will result in more active channels at a given level of nucleotide. The binding and hydrolysis of MgATP, acting via the dimerization of the NBDs of SUR, antagonizes the inhibitory action of ATP on the KIR, presumably via movements of the TMDs and the L0-KIR amino-terminal link as discussed above. This Mg-nucleotide dependent stimulation can also be described by a binding isotherm, and the dual action of ATP can be described by taking the product of the two binding curves. This is illustrated in Fig. 7A7A comparing MgATP stimulation of wild-type vs. one SUR1 NDM mutant (H1023Y) KATP channel associated with TNDM (21). Babenko (232) has described this mechanism in detail using the Q1178R ND ABCC8 mutation. MgATP potentiates the activity of both channels, but stimulation is greater in the mutant, resulting in approximately a 5- to 6-fold greater net stimulation, the ratio of the relative activities of the mutant channel/WT channel–1 (Fig. 7B7B).). The curve is the fit of a modified Hill equation (as shown) to the data.

Figure 7
MgATP Stimulation of WT and H1023Y KATP channels. A, Inhibition of KATP channels by ATP in the presence and absence of Mg2+. The lines are fits of the relative activity (channel activity with ATP/activity without ATP) to a modified Hill equation ...

A similar analysis can be performed on any of the KCNJ11 or ABCC8 mutations that produce NDM and/or DEND. Figure 88 compares the net Mg-dependent stimulation, calculated from published data (21,232,233,234), for the H1023Y (ABCC8, TNDM), R201H (KCNJ11, PNDM), and Q52R (KCNJ11, DEND) mutations. These three mutations reflect alternative activating mechanisms, i.e., an increased stimulatory action of ABCC8 (H1023Y) vs. a decreased apparent affinity of KCNJ11 for inhibitory ATP (R201H and Q52R), and also reflect the heterogeneity, mild vs. severe forms, of NDM. Without Mg2+, the H1023Y ABCC8 mutation does not affect the inhibitory action of ATP on KIR6.2 (Fig. 7A7A),), whereas both R201H, the most common KCNJ11 mutation, and Q52R substitutions reduce the apparent affinity of KIR6.2 for ATP (Fig. 8A8A and Refs. 234,235,236). Figure 8B8B shows the correlation between greater channel activity and the increased severity of the NDM phenotype.

Figure 8
Comparison of net Mg-dependent stimulation for three KATP channel mutants. A, An illustration of the inhibition of homozygous WT and mutant KATP channels by ATP with and without Mg2+ present. Both mutations have a reduced apparent affinity for ...

To explore this “genotype-phenotype” correlation further, we estimated the net Mg-dependent stimulation for all of the NDM mutations for which data were available. The results are summarized in Fig. 99 by plotting the mutant-dependent net stimulation in 1 mm MgATP, a plausible nucleotide concentration for β-cells. The data are somewhat sparse, particularly for ABCC8 mutations, and there is no quantifiable measure of the severity of the disease. Therefore, we grouped the data based on the reported diagnosis and included the iDEND values in the DEND group. There is considerable overlap between the TNDM and PNDM groups, and the difference between their mean values is not significant by ANOVA (P > 0.05); the mean value for the DEND group is significantly different from the TNDM and PNDM values (P < 0.001). Mutations that increase channel activity less than 15-fold are associated with both TNDM and PNDM, whereas those that stimulate, on average, more than 15-fold are associated with the DEND syndrome. It is worth noting that some KCNJ11 mutations, e.g., R201H and D209E, are associated with cases of both TNDM and PNDM. There are several weaknesses in attempting to make a correlation only between enhanced channel activity measured in vitro and clinical phenotype. First, the electrophysiological techniques used to assess activity measure only channels that successfully reach the cell surface. However, the contribution that a mutant channel makes to the β-cell membrane potential will depend on both activity and the number of channels at the cell surface. Second, successful surface expression requires efficient protein folding and subunit assembly that is often impaired in mutant proteins, including KIR6.2 (237). We suggest that impaired folding and trafficking of SUR1 and KIR6.2 would tend to reduce the impact of overactive channels on β-cell membrane potential. However, given the known effects of UPR on islets, it is likely that these mutations will also reduce β-cell mass.

Figure 9
Summary of mutation-dependent stimulation for KCNJ11 and ABCC8 NDM mutations. The net stimulation values for control and mutant channels were estimated as outlined in Fig. 77 using published data (21,194,197,236,266,268,278,279,280,281,282,284 ...

It is worth pointing out that the results in Fig. 99 are not a genotype-phenotype correlation in the structural sense; the data are for mutations sprinkled throughout KCNJ11 and ABCC8 (Fig. 1010).). Rather the correlation is between the increased K+ conductance of the mutant channels at a given nucleotide level, and therefore their increased contribution of a hyperpolarizing current that will reduce the cell membrane potential, Vm. This correlation suggests a reasonable underlying cellular interpretation for why highly active KATP channels are associated with DEND. Although ABCC8 and KCNJ11 subunits are expressed in multiple tissues including islet cells, neurons, and striated muscle, their contributions to determining Vm vary greatly. In pancreatic β-cells in low glucose, ABCC8/KCNJ11 KATP channels are the major, perhaps sole, K+ channels able to lower Vm. A number of pieces of evidence support this idea, including observations with KATP channel antagonists like sulfonylureas and the inability of both KIR6.2 and SUR1 knockout mice to reduce β-cell Vm in low glucose (238,239,240). Therefore, even a small increase in the nucleotide-dependent conductance of a mutant KATP channel can have the significant effect of lowering the β-cell membrane potential below the threshold for activation of voltage-gated Ca2+ channels, thus blocking Ca2+ influx necessary for insulin exocytosis. On the other hand, the resting membrane potential of neurons and striated muscle is determined by other, non-ATP-sensitive, K+“leak” currents (see for example Refs. 241 and 242). With the exception of some glucose-depolarized (glucose-excited) neurons in the arcuate nucleus and ventromedial hypothalamus, KATP channels have been argued to be closed and serve a protective role, opening primarily under conditions of CNS hypoxic stress (see Ref. 243 for review). This idea is supported by clinical observations on HI patients that do exhibit a blunted glucagon counter-regulatory response attributable to loss of KATP channels in hypothalamic glucose-depolarized neurons (244) but display no other obvious neural symptomatology. There are equivalent observations on KATP channel knockout mice (245,246). Thus, for many CNS neurons KATP channels appear to make little contribution to the neuronal membrane potential, and modest increases in their conductance appear to have a limited effect on reaching the threshold for generating action potentials. The data are consistent with the idea that mutant KATP channels with larger net stimulation values, and thus generating more significant hyperpolarizing currents, are necessary to reduce the neuronal firing rates and produce the delayed development and epilepsy characteristic of the DEND syndrome. This concept implies that the clinical phenotype will be determined mainly by the degree of channel activation rather than the gene involved.

Figure 10
Approximate location of NDM mutations in KIR6.2 and SUR1. The KIR6.2 backbone is a homology model based on the structure of a chimeric protein (287). Two of the four subunits are shown with the locations of the mutations shown on both chains. The green ...

XV. Location of KCNJ11 and ABCC8 Mutations

Figure 1010 summarizes the location of the KCNJ11 and ABCC8 NDM mutations on KIR6.2 and SUR1, respectively. The KCNJ11 mutations are clustered below the plasma membrane on the N terminus, around the inhibitory ATP binding site, and in the cytoplasmic domain. Understanding of the structural bases for the mutant channel properties will require a high-resolution model of the entire channel and is beyond the scope of this review. It is worth pointing out several features. Mutations in or near the nucleotide binding pocket, e.g., R201H (198,247), reduce the apparent affinity for ATP and are the most common alterations associated with NDM. Both the N- and C-terminal domains contribute residues to the nucleotide binding pocket (195,198,225,247), and substitutions in this region affect the apparent affinity for inhibitory ATP. Amino acids in this region are also part of the transduction machinery that couples the pore with the ABCC8 core via interactions with L0 (198,201,225,226). Additionally, mutations at several other positions, e.g., L164, C166, K170, E292, and I296, are in the ionic pathway where substitutions could sterically hinder closing of the gate and increase intrinsic channel activity.

ABCC8 mutations have been found throughout the molecule, but are most frequent in L0 (Fig. 1010),), consistent with earlier work indicating the importance of L0 in control of channel gating. The mechanism(s) by which these mutations produce more active channels remain to be discovered. If we assume that stimulation of channel openings requires a specific enzymatic intermediate, then one hypothesis is that an ABCC8 NDM mutation increases the time that the mutant SUR1 spends in this activated state, i.e., the mutations “trap” SUR1 in the stimulatory conformation. However, the enzymatic activity of SUR1 is not well understood. A second viable hypothesis is that SUR1 is a “slow” enzyme; catalysis is the rate-limiting step in formation of the stimulatory intermediate. In this view, mutations that increase enzymatic activity will stimulate channel activity. de Wet et al. (248) have reported that isolated NBD2 domains with mutations in R1380 show increased activity consistent with this idea.

How does a KATP channel mutation, active in the heterozygous state, lead to TNDM? This is an interesting and puzzling question. The simple expectation is that a channel mutation affecting β-cell membrane potential would produce a consistent phenotype. Although the evidence, as discussed above, is accumulating that TNDM caused by abnormalities in 6q24 results from a delay in the development of pancreatic islets and/or β-cells that are able to “catch up” in postnatal life, there is no simple mechanism to explain how the activity of a mutant channel would be modulated for an extended period of time. Several potential mechanisms could attenuate channel activity. The rate of glucose metabolism might rise sufficiently to inhibit the least active mutant channels (Fig. 99).). Although possible in principle, the magnitude of the required compensatory increase in ATP seems large. For example, the concentration of ATP required to half-maximally inhibit KCNJ11 C42R channels that are a cause of TNDM (249) is about 15-fold greater than controls (172 ± 52 vs. 11.2 ± 0.97 μm). These numbers are for homogenous channels; heterozygosity would reduce the difference, but it seems reasonable to estimate that the effective concentration of inhibitory ATP would need to at least double to compensate for this mutation. Another potential mechanism could be a compensatory reduction in the level of phosphoinositides and/or long-chain saturated acyl CoAs that bind to KIR6.2 and attenuate the inhibitory effect of ATP (for phosphoinositides see Refs. 250,251,252), and for review see Ref. 253; for long chain acyl-CoAs, see Refs. 254,255,256, and for review see Ref. 257).

We suggest a less direct mechanism. Several NDM mutant KIR6.2 subunits, C42R (249) and Q52R, V59G, V59M, R201C, R201H, and I296L (237) and a number of HI mutant KCNJ11 and ABCC8 mutant subunits display impaired surface expression due to improper folding. An inevitable consequence of impaired folding and surface expression will be an increased UPR due to subunit accumulation in the ER. This will be less dramatic than that seen with mutant insulin or mutation of EIF2AK3/PERK as the level of expression of channel subunits is considerably lower, but significant over time. We suggest that in addition to reducing insulin release by limiting β-cell depolarization, KCNJ11 and ABCC8 mutations can contribute to NDM by increasing β-cell apoptosis secondary to an increased UPR. Both factors would reduce insulin levels and impair fetal growth. We speculate that the less active TNDM mutations (Fig. 99)) do not completely suppress insulin release and that the postnatal increase in β-cell mass is sufficient to supply insulin and produce remission. With age, the increased rate of β-cell apoptosis would reduce β-cell mass in TNDM patients and increase the likelihood of relapse as requirements for insulin increase. This is essentially the same mechanism proposed to account for insulin insufficiency in type 2 diabetes where decreasing β-cell mass is attributed to glucolipotoxicity due to free radical damage.

XVI. Sulfonylureas Are an Effective Therapy for NDM Caused by Overactive KATP Channels

In a clinical setting, insulin is the immediate choice for establishing metabolic control in NDM patients because it will be effective in all cases where an insulin deficit is involved. If diagnosis of diabetes is made before 6 months of age and genetic screening is undertaken, the identification of mutations in KCNJ11 or ABCC8 provides an alternative therapeutic strategy. Given that NDM results from overactive KATP channels (data in Figs. 7–9),), that closing these channels is a key step in insulin release, and that sulfonylureas are well-studied KATP channel inhibitors, oral hypoglycemic agents present an attractive alternative to insulin injections. Chloropropamide was tried early on in the treatment of cases of NDM of unknown origin with only sporadic success (258,259,260). More recently, numerous single and small case studies (19,21,44,193,194,261,262,263,264,265,266,267,268,269,270,271) have evaluated the feasibility of using the oral hypoglycemic agents available for treatment of type 2 diabetes, e.g., tolbutamide, glibenclamide (glyburide), and glicazide, in the treatment of NDM. In an increasing number of cases, these agents have been shown to provide effective metabolic control and replace insulin in the majority of TNDM and PNDM cases caused by ABCC8 and KCNJ11 mutations. Studies with small numbers of patients (44,268,271) and with larger KCNJ11 (272) and ABCC8 (273) cohorts indicate that sulfonylurea therapy provides better long-term metabolic control as assessed by lower blood sugar levels and reduced glycated hemoglobin values. Transient gastrointestinal problems and some risk of hypoglycemic events have been reported, but these appear to be manageable on a case-by-case basis by selecting the appropriate agent, by controlling dosage, and/or by increasing the frequency of administration [e.g., three vs. two times per day (226)]. The effective doses vary, and not all mutations respond to sulfonylureas (summarized in Table 77).). Several of the severe DEND mutations are insensitive to glibenclamide even at quite high doses (266,272), reiterating the need to identify the underlying genetic defect to provide optimal care. There are several encouraging reports indicating that the neuromuscular symptoms of the less severe iDEND syndrome and the DEND syndrome respond to glibenclamide therapy [3-yr-old I167L (268), adult G53D (193), 6-yr-old H46L (194), and 23-month-old V59M (269)]. The reported improvements are primarily in motor function, and more extended studies are needed to determine whether the positive response will extend to learning skills and the importance of initiating treatment at an early stage. These studies are interesting and indicate that sulfonylureas cross the blood–brain barrier and are present at sufficient concentration to be effective, particularly because other members of the ABC transporter family, i.e., Pgp, have been implicated in glibenclamide efflux from the CNS (274). The development of a KATP channel antagonist that retained efficacy for the channel but was a poor transport substrate would likely improve the treatment outcome for severe forms of DEND where the channels are highly active but retain sensitivity to sulfonylureas (272).

Table 7
Response to oral hypoglycemic agents

XVII. Summary

Early-onset diabetes can arise from the expression of mutant genes that disrupt basic cellular processes. The understanding of how these genes produce diabetes and how best to provide treatment provides increasingly beautiful examples of bench-to-bedside research. Up-regulation of tumor suppressor genes and reduced fetal insulin attributable to changes in chromosomal imprinting can result in IUGR. Mutations in genes expressed early in fetal life can disrupt entire cell lineages and impair the development of multiple cells and tissues. The importance of protein folding and quality control is becoming increasingly apparent. Mutant proteins that fold improperly activate cellular quality control mechanisms, particularly the UPR, that accelerate cell death. Mutations in the UPR machinery itself affect a range of tissues including pancreatic islets. The expression of mutant insulin is restricted to β-cells, and the subsequent reduction in β-cell mass is a cause of diabetes. Defects in glucose sensing, the result of substitutions in GCK and KATP channels, lead to β-cell dysfunction and reduced insulin output. Several of the genes involved are associated with MODY, old friends to many diabetologists. The heterogeneity of early-onset diabetes, often associated with other clinical symptoms, presents physicians with a challenge. Testing and identification of mutant genes has become an increasingly important tool in the clinician’s arsenal, helping to provide an accurate diagnosis, adequate treatment, and appropriate genetic counseling.

Supplementary Material

[RPHR Note]


This work has been funded by National Institutes of Health Grant DK044311, Juvenile Diabetes Research Foundation Grant 1-2005-750, and the Thrasher Foundation.

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 24, 2008

Abbreviations: ABCC8, ATP-binding cassette, subfamily C, gene identifier for SUR1; BGPR, β-cell glucose phosphorylation rate; BWS, Beckwith-Wiedemann syndrome; CNS, central nervous system; CoA, coenzyme A; DEND, delayed development, epilepsy, NDM; DMR, differentially methylated region; E, embryonic day; EIF2AK3 (or PERK), eukaryotic translation initiation factor 2α kinase 3; ER, endoplasmic reticulum; GCK, glucokinase; HI, hyperinsulinism; HNF1β, hepatocyte nuclear factor-1β; HYMAI, hydatiform mole-associated and imprinted; iDEND, intermediate DEND; IPEX, immunodysregulation, polyendocrinopathy, and enteropathy, X-linked; IPF-1, insulin-promoter factor 1; IUGR, intrauterine growth retardation; KCNJ11, potassium inwardly-rectifying channel, gene identifier for KIR6.2; MODY, maturity-onset diabetes of the young; NDM, neonatal diabetes mellitus; PDX1, pancreatic and duodenal homeobox 1; PKHD1, polycystic kidney hepatic disease 1; PNDM, permanent NDM; PO, open probability; PPARγ, peroxisome proliferator-activated receptor γ; PTF1a (or PTF1a/P48), pancreas transcription factor 1α; SOCS3, suppressor of cytokine signaling-3; SUR, sulfonylurea receptor; TCF2, transcription factor-2; TMD, transmembrane domain; TNDM, transient NDM; UPD, uniparental isodisomy; UPR, unfolded protein response; Vm, cell membrane potential; WRS, Wolcott-Rallison syndrome; ZAC, zinc finger protein which regulates apoptosis and cell cycle arrest.


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