Clinical and Genetic Characteristics of <i>ABCC8</i> Nonneonatal Diabetes Mellitus: A Systematic Review

Li, Meng; Han, Xueyao; Ji, Linong

doi:https://doi.org/10.1155/2021/9479268

Journal of Diabetes Research

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Review Article | Open Access

Volume 2021 | Article ID 9479268 | https://doi.org/10.1155/2021/9479268

Clinical and Genetic Characteristics of ABCC8 Nonneonatal Diabetes Mellitus: A Systematic Review

Meng Li,¹Xueyao Han,¹and Linong Ji¹

Academic Editor: Karim Gariani

Received30 May 2021

Revised11 Aug 2021

Accepted16 Aug 2021

Published30 Sept 2021

Abstract

Objectives. Diabetes mellitus (DM) is a major chronic metabolic disease in the world, and the prevalence has been increasing rapidly in recent years. The channel of K_ATP plays an important role in the regulation of insulin secretion. The variants in ABCC8 gene encoding the SUR1 subunit of K_ATP could cause a variety of phenotypes, including neonatal diabetes mellitus (ABCC8-NDM) and ABCC8-induced nonneonatal diabetes mellitus (ABCC8-NNDM). Since the features of ABCC8-NNDM have not been elucidated, this study is aimed at concluding the genetic features and clinical characteristics. Methods. We comprehensively reviewed the literature associated with ABCC8-NNDM in the following databases: MEDLINE, PubMed, and Web of Science to investigate the features of ABCC8-NNDM. Results. Based on a comprehensive literature search, we found that 87 probands with ABCC8-NNDM carried 71 ABCC8 genetic variant alleles, 24% of whom carried inactivating variants, 24% carried activating variants, and the remaining 52% carried activating or inactivating variants. Nine of these variants were confirmed to be activating or inactivating through functional studies, while four variants (p.R370S, p.E1506K, p.R1418H, and p.R1420H) were confirmed to be inactivating. The phenotypes of ABCC8-NNDM were variable and could also present with early hyperinsulinemia followed by reduced insulin secretion, progressing to diabetes later. They had a relatively high risk of microvascular complications and low prevalence of nervous disease, which is different from ABCC8-NDM. Conclusions. Genetic testing is essential for proper diagnosis and appropriate treatment for patients with ABCC8-NNDM. And further studies are required to determine the complex mechanism of the variants of ABCC8-NNDM.

1. Introduction

Diabetes mellitus (DM) is a major chronic metabolic disease in the world, and its prevalence has increased rapidly in recent years. Genetic and environmental conditions contribute to DM. The type of monogenic diabetes is the main etiology for diabetes. Maturity-onset diabetes of the young (MODY) is a kind of monogenic diabetes characterized by autosomal dominant inheritance. It is reported that the prevalence of MODY is 1 ~ 5% [1]. The activating variants of ABCC8 also could cause MODY. The ABCC8 gene encoding sulfonylurea receptor (SUR), which is the regulatory subunit of K_ATP channel, plays a key role in regulating insulin secretion [2, 3]. K_ATP channel is a hetero-octamer and consists of four inwardly rectifying proteins of the potassium channel Kir6.2 and four regulatory subunits of the sulfonylurea receptors [4, 5]. The enhanced glucose metabolism results in a change of ADP/ATP and leads to the closure of the K_ATP channel, which in turn induces membrane depolarization and triggers the opening of the voltage-dependent Ca²⁺ channel, which stimulates the release of insulin [6, 7]. Besides, variants in ABCC8 gene could cause hyperinsulinemic hypoglycemia (HH) due to inactivating variants which have an impaired response to magnesium adenosine diphosphate- (MgADP-) mediated opening of the channel [6, 8, 9]. Therefore, variants in ABCC8 gene could cause variable phenotypes: diabetes and HH, due to the different effects of the variants on channel function [9–13]. According to the onset age, DM induced by the ABCC8 variants are classified as two major groups of disorders—ABCC8-induced nonneonatal diabetes mellitus (ABCC8-NNDM) and ABCC8-induced neonatal diabetes mellitus ABCC8-NDM. Although the features of ABCC8-NDM have been well evaluated, the studies on the clinical and genetic features of ABCC8-NNDM were limited. And these studies were mainly conducted in Europe and America. Bowman et al. first identified ABCC8 missense variants as a cause of MODY by testing sulfonylurea-sensitive HNF1A and HNF4A variant-negative MODY cases with no family history of neonatal diabetes [10]. Then, Johansson et al. identified a patient with ABCC8-MODY by exome sequencing in an analysis of variant-negative MODY cases by Sanger sequencing [14]. Additionally, potential pathogenic alterations in the ABCC8 gene were also identified in genetic studies. It has been shown that the prevalence of ABCC8 variants was estimated to be 0.5 ~ 1.5% in different cohorts [15–17]. However, the clinical phenotype has not been well established. In addition, the development in the field of ABCC8 gene-related diabetes has included de novo variants identified by new rapid molecular genetic features, symptoms, and medical therapy (sulfonylureas, DPP4-inhibitor).

Therefore, we systematically reviewed the literature related to ABCC8-NDM and ABCC8-NNDM to comprehensively conclude the genetic and clinical features of ABCC8-NNDM. The review article has summarized the updated advance of ABCC8-NNDM and included de novo variants, clinical symptoms, and medical therapy.

2. Materials and Methods

2.1. Study Subjects

A total of 144 patients with ABCC8-NNDM were included to analyze the clinical and genetic features in previous literature. The literature search has been conducted until Sep. 2020. We systematically identified all potentially relevant articles from the following three electronic databases: MEDLINE, PubMed, and Web of Science. Search terms about diabetes—such as “maturity-onset diabetes of the young (MODY),” “Neonatal diabetes mellitus,” “Neonatal diabetes” and “ABCC8-MODY,” and Sulfonylurea receptor 1, for example, “Sulfonylurea receptor 1,” “ABCC8,” and “KATP channels”—were used in various combinations and permutations across the databases. Language restriction (English) was applied. The criteria for inclusion were patients with ABCC8-NNDM and those with ABCC8-NDM in previous studies. We systematically reviewed the related studies, including population-based studies, reviews, functional studies, and meta-analysis. The criteria for exclusion were repetitive literature and unavailable data. The genetic information of ABCC8 gene was as follows: accession number: NM_000352.4, NP_000343.2.

For data extraction, clinical information, including demographics, initial presentation, treatment of diabetes, physical examination results, laboratory test results, and information of genetic variants of the patients, was extracted.

2.2. Classification of the Pathogenicity of ABCC8 Variants

The pathogenicity of the variants was classified according to the established guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) [18]. We classified these variants into the following categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. We used two or more lines of computational evidence (PROVEAN (http://provean.jcvi.org), SIFT (http://sift.jcvi.org/), Polyphen2 (http://genetics.bwh.harvard.edu/pph2/index.shtml), and MutationTaster (http://mutationtaster.org)) to support a deleterious effect on the gene for pathogenic supporting 3 (PP3) according to the guidelines of the ACMG-AMP. According to the guidelines, each pathogenic criterion is weighted as very strong (PVS1), strong (PS1–4), moderate (PM1–6), or supporting (PP1–5).

2.3. Conservation of the Variants

We conducted multiple sequence alignment (MSA) to align sequences of ABCC8 protein from a few vertebrate species by ClustalW server (https://www.genome.jp/tools-bin/clustalw) to interpret the conservation of these sequences. The result of MSA from ClustalW was plotted using ESPript (Easy Sequencing in Postscript 3.0, http://espript.ibcp.fr) [19, 20]. The species and GenBank accession numbers of the ABCC8 sequences adopted were the following: Homo sapiens—NP_000343.2, Callithrix jacchus—XP_035121815.1, Chlorocebus sabaeus—XP_008003585.1, Danio rerio—NP_001166118.2, Sus scrofa—XP_008003585.1, and Vulpes vulpes—XP_025863953.1. We followed the methods of Li et al. [21].

2.4. Statistical Analysis

Normally distributed variables were expressed as , and they were compared using -tests. Categorical variables were presented as numbers and percentages. A Chi-square was adopted for categorical data. Analyses were performed using SPSS version 23.0.

3. Results

3.1. The Clinical and Genetic Characteristics of Patients with ABCC8-NDM Described in Previous Studies

We have systematically reviewed the literature reporting variants in ABCC8-NDM. 175 probands with ABCC8-NDM (including 139 patients with heterozygous variants, 21 patients with homozygous variants, one patient with a mosaic variant, and 14 patients with compound heterozygous variants) variants were found owing to 110 ABCC8 (Table 1). Among those probands, 66 patients were reported as having transient neonatal diabetes mellitus, 92 as having permanent neonatal diabetes, and 17 as having an unknown type of diabetes due to a lack of follow-up. These variants caused ABCC8-NDM with either a dominant or recessive genetic pattern and were scattered throughout the functional regions of the gene (Table 1 and Supplementary Figure 1).

All these patients presented with impaired insulin secretion, and 18 of the 110 variants were confirmed to be activating in functional studies and affect the channel inhibition by different molecular mechanisms. Then, those variants led to impaired insulin secretion and diabetes, as shown in Table 1.

The birth weight of 99 probands was available. Thirty-two probands (32%) had a birth g, and only one proband (1%) had a birth weight of >4,000 g. Forty-three of the 175 (24.6%) probands with ABCC8-NDM had neurological manifestations. In addition, 21 (12.0%) patients had developmental delay and epilepsy syndrome (DEND), 5 (2.9%) patients had intermediate DEND syndrome, 5 (2.9%) had seizures, and 12 (6.9%) had other neurological symptoms. This was similar to the previous study reporting approximately 20% of patients with K_ATP channel variants developed neurological symptoms [22]. The variants reportedly associated with the neurological phenotype were across all functional regions of the ABCC8 gene.

3.2. The Genetic Characteristics of Patients with ABCC8-NNDM Reported in Previous Studies

After systematical reviewing the literature related to the ABCC8-NNDM studies, 87 probands were identified with 71 ABCC8 genetic variant alleles, including 75 patients with heterozygous variants, four with homozygous variants, and eight with compound heterozygous variants (Table 2, Supplementary Table 1, Supplementary Figure 1). The domains where the variants are located have been displayed in Table 2. By available data and bioinformatics analysis, 47 and 15 variants of the 71 variant alleles were classified as likely pathogenic and pathogenic, respectively, while nine variants were of uncertain significance (VUS) (Supplementary Table 2).

Nine (including p.Y356C, p.R370S, p.L582V, p.R825W, p.R1182Q, p.P1198L, p.R1418H, p.R1420H, and p.E1506K) of 71 genetic variant alleles were confirmed to be activating or inactivating through functional studies (Table 2). Among them, five activating variants (p.Y356C, p.L582V, p.R825W, p.R1182Q, and p.P1198L) have been demonstrated that channel inhibition by ATP was reduced and less insulin was secreted [15, 23–26]. The remaining four inactivating variants (p.R370S, p.E1506K, p.R1418H, and p.R1420H) were found to decrease K_ATP channel activity and bring about diabetes [27–30]. The patients with inactivating variants had hyperinsulinemic hypoglycemia in early life and progressed to diabetes later.

In addition, twelve variants (including p.A269D, p.G296R, p.R306H, p.C435R, p.L582V, p.V607M, p.R825W, p.R1182W, p.R1182Q, p.P1198L, p.F1067I, and p.R1379H) of ABCC8 were reported both in patients with ABCC8-NDM and in those with ABCC8-NNDM (Table 2 and Figure 1). The above variants were located in the domains of the L0 linker region (L0), transmembrane domain 1 (TMD1), nucleotide-binding domain 1 (NBD1), transmembrane domain 2 (TMD2), and nucleotide-binding domain 2 (NBD2) (Figure 1). The same variant could cause different onset ages of diabetes.

3.2.1. Evolutionary Conservation of Sites of Variants Both in Patients with ABCC8-NDM and in Those Patients with ABCC8-NNDM

The conservation analysis was carried out using ClustalW and ESPript 3.0 tools. Multiple sequence alignments of ABCC8 in the vertebrate species were selected for this analysis to show the sequence conservation of amino acid residues between them (Figure 2). It has been demonstrated that the amino acid residues of these twelve variants of ABCC8 both in ABCC8-NDM and ABCC8-NNDM in the literature were conserved across the organisms queried.

3.2.2. ABCC8-NNDM due to Gain-of-Function and Loss-of-Function of Variants

Previous studies reported that both gain-of-function and loss-of-function variants in ABCC8 could cause diabetes. The first loss-of-function ABCC8 variant was a heterozygous inactivating ABCC8 p.E1506K variant, which presented with HH, followed by glucose intolerance and diabetes in later life [31]. This distinct phenotype was demonstrated in a mouse model carrying the p.E1506K variant of ABCC8 [28] and in patients carrying other rare variants of ABCC8, such as p.R370S, p.R1418H, and p.R1420H [29, 30, 32]. Two Japanese probands with hypoglycemia in infancy due to heterozygous inactivating variants progressing to hyperglycemia were also reported [33, 34]. Therefore, the subtype of ABCC8-NNDM due to inactivating variants could implicate the etiology of diabetes.

Among the 87 probands previously reported, 24% (21/87) carried inactivating ABCC8 variants reported in hyperinsulinemia, whereas 24% (21/87) carried activating ABCC8 variants were also associated with NDM. And the remaining 52% (45/87) carried variants with undetermined molecular mechanism. In the previously reported cases of ABCC8-NNDM, it was estimated to be ~25% patients with activating ABCC8 variants and ~25% with inactivating variants. The molecular mechanisms of the remaining ~50% variants were needed further investigation.

3.2.3. The Clinical Characteristics of Patients with ABCC8-NNDM Reported in Previous Studies

A total of 144 patients with ABCC8 variants including the probands and their hyperglycemic relatives (125 Caucasians, 15 East Asians, three Africans, and one Chinese) were analyzed. The clinical and genetic characteristics of them are shown in Table 2 and Supplementary Table 1. The diagnosed age was reported in 71 probands. Among them, three (4%) were diagnosed with diabetes when <6 years old, 28 (39%) when 6–18 years old, and 40 (56%) when 18–40 years old. According to their body mass index (BMI) at diabetes onset, 10 (27%) of the 37 patients (seven probands and three relatives) who were diagnosed when ≥18 years old were overweight or obese. According to the available data, 30 patients were described using sulfonylureas (SUs) for glucose control. 22/30 (73.3%) patients have shown to be effective with SUs, while the levels of HbA1c were less than 7.0%. We found that just three probands with ABCC8 variants, including compound variants of p.H103Y and p.R74Q and missense variants of p.A1457T and p.E1506K, had microalbuminuria [35–37]. Reilly et al. have described that retinopathy was also common microvascular complication and that 5 out 10 patients with ABCC8 variants had diabetic retinopathy [37]. A similar case was reported by Ovsyannikova et al. [36], where the patient was diagnosed with diabetes at age 27 years (p.A1457T variant in ABCC8), and during the initial investigation, he had nonproliferative retinopathy and a raised microalbumin creatinine ratio.

As is known to all, neurological features are essential for ABCC8-NDM, and forty-three (24.6%) probands had neurological manifestations among the 175 reported probands with ABCC8-NDM according to the published literature. In the ABCC8-NNDM group, just one proband with the variant of p.A1457T had epilepsy independent of hypoglycemia [36], and two probands with the variants of p.R1418H and p.R1420H had seizure due to hypoglycemia [29, 30]. Compared with the ABCC8-NDM group, the frequency of the neurological phenotype in the ABCC8-NNDM group was significantly lower (1/87 (1%) vs. 43/175 (24.6%), P <0.001), and we did not include neurological features due to hypoglycemia.

We have descripted above that there were 24% probands carrying activating variants, 24% carried inactivating variants, and 52% carrying undetermined variants among the 87 probands. Based on the available data, we further compared the clinical features between the probands with activating and inactivating variants. There was no significant difference in diagnosed age and BMI between the two groups (diagnosed age: , vs. , , ; diagnosed BMI: , vs. , , ). Among the inactivating group, two probands with the variants of p.R1418H and p.R1420H had seizures due to hypoglycemia [29, 30], while no probands were reported with neurological symptoms among the activating group. And one proband with inactivating p.E1506K variant had microalbuminuria [37]. In addition, the prevalence of hyperinsulinemia and hypoglycemia was significantly higher in the inactivating group than the activating group (13/21 (61.9%) vs. 0/21 (0.0%), ).

4. Discussion

To the best of our knowledge, it is the first time for our study to systematically review the literature and comprehensively investigate the genetic and clinical features of ABCC8-NNDM. From the previous studies, we identified 144 patients with ABCC8–NNDM and found that ~25% and ~25% of the previously reported ABCC8-NNDM cases had activating and inactivating ABCC8 variants, while the remaining ~50% had uncertain functional variants. These patients had relatively successful glucose control after the treatment of SUs and might have a relative high risk of diabetic microvascular complications.

As is known to all, gain-of-function variants in the ABCC8 gene are one of the main causes of NDM. With the development of genetic analysis, the ABCC8 variants in NNDM were also reported. Many potential pathogenic alterations were also identified in ABCC8. A study performed in a French adult type 2 diabetic outpatient cohort with 139 patients identified two (1.5%) likely causative variants in ABCC8 [15]. Another study in a large cohort of nonobese patients with diagnosed years and a family history of diabetes found 8 (8/1564, 0.5%) ABCC8 variants [16]. In addition, an East Asian study found one (0.9%) ABCC8 variant among 109 suspected monogenic diabetes patients [17]. The prevalence of ABCC8 variants was estimated to be 0.5 ~ 1.5% in different studies. It suggests that the subunit K_ATP channel of SUR1 encoding the ABCC8 gene is responsible for a small subset of NNDM.

The ABCC8 gene encodes SUR subunit of K_ATP channels, which links cell metabolism to electrical activity by regulating potassium movement across the membrane [38]. Closure of the channel as a result of ATP-binding led to β-cell membrane depolarization and opening of voltage-dependent and calcium-channels and calcium mediated release of insulin. Activating variants in the ABCC8 gene led to an increased probability of opening of the potassium channel, therefore preventing any activation of the voltage-dependent calcium channel and any glucose-induced insulin secretion [39], leading to NDM, early onset diabetes, and MODY [10, 40]. In previous studies, there are 18 variants that were confirmed to be activating by functional studies. However, the pathophysiology of inactivating variants in ABCC8 means that lack of functional K_ATP channels leads to depolarized β-cells and elevation of cytosolic calcium, which result in continuous insulin secretion and independent of plasma glucose concentration [6, 8]. In addition, 21 (24%) probands with dominant loss-of-function variants in ABCC8 previously reported could cause hyperinsulinism in the early period and progress to diabetes later. Four inactivating variants (p.R370S, p.E1506K, p.R1418H, and p.R1420H) have been demonstrated to decrease K_ATP channel activity and dysregulation of insulin secretion in functional studies, with the consequence that patients with these variants progressed to diabetes in later life. As a consequence, both activating and dominantly inactivating variants have been considered the key cause of ABCC8-NNDM.

The underlying mechanism by which loss-of-function variants of ABCC8 subsequently cause the remission of HH and future hyperglycemia is complex and required to be elucidated. Recently, basal insulin secretion was observed to be elevated in human islets with inactivating ABCC8 variants, but insulin secretion response to glucose was impaired [41]. And apoptotic beta cells increased in transgenic mice with inactivating K_ATP channels [42, 43]. Besides, insulin content and gene expression decreased and led to the disruption of insulin secretion and glucose intolerance in the mouse model with an inactivating variant of ABCC8 [28]. The above factors could partly address the mechanism by which K_ATP defects cause diabetes in patients with loss-of-function variants. To date, there have been far-from adequate functional studies to elucidate the exact impact of the different variants. Further studies are still needed to account for the complex underlying mechanisms resulting in the remarkable phenotypic heterogeneity related to inactivating ABCC8 variants.

Great importance is to be attached to the diabetic complications. It could be seen that just three probands with variants were reported to have diabetic kidney injury. It is uncertain whether patients with ABCC8-NNDM had a higher risk of diabetic kidney disease (DKD). Mice with the homozygous ABCC8 p.E1506K^+/+ variant (an inactivating variant), presenting with hyperinsulinemia early in life followed by diabetes and early DKD later in life, were observed [28, 44]. In the mouse model, glucose could induce histone modifications, which drove the expression of proinflammatory genes and thereby predisposed to diabetic kidney disease. Further studies are also required to confirm the risk and the precise diabetic kidney disease mechanism of ABCC8 variants. Besides, the frequency of diabetic retinopathy was ~50 percent among the patients with ABCC8 variants. Although dyslipidaemia, hypertension, and possible genetic factors contribute to the early manifestation of diabetes complications, the ABCC8 variants may be responsible for the rapid progression to proliferative retinopathy. SUR1 is also expressed in the retinal vessels, and glibenclamide could inhibit adenosine-induced retinal vasodilation [45, 46], which occurs by interacting with K_ATP channels in retinal vessel pericytes. In models of postinfarct central nervous system oedema, the SUR1 expression has been observed to upregulate in injured nervous tissue, and inhibiting SUR1-induced ion channel modulation with the drug glibenclamide could protect the central nervous system from ischaemia-reperfusion and traumatic brain injury [47].

As we known, neurological features are important features for ABCC8-NDM. From the published literature, we found that sixty (34%) probands had neurological manifestations among 175 reported probands with ABCC8-NDM. K_ATP channels are predominately expressed in endocrine tissues such as the pancreatic islet cells and the nervous system. The deleterious effect on the nervous system of K_ATP channel activating variants is likely related to the neurological features, including more severe DEND and iDEND [48, 49]. The reported variants associated with a neurological phenotype were distributed across all functional regions of the gene, while only one patient had a neurological manifestation independent of hypoglycemia (1%) among patients with ABCC8-NNDM [36]. Compared to the ABCC8-NDM group, the frequency of a neurological phenotype in the ABCC8-NNDM group was significantly lower. Activating variants reduce the ability of ATP to inhibit ion channel activity, thus increasing the magnitude of the K_ATP current, which hyperpolarizes brain and muscle cells and accounts for the neurological phenotype [39, 50, 51].

According to the previous published studies reporting SUs on the treatment of ABCC8 variants induced diabetes, we found that 73.3% of the patients owing to ABCC8 variants with SUs got successful glucose control. As the widely used drugs for the treatment of patients with type 2 diabetes, SUs could bind specifically to the SUR1 subunit, then closing the K_ATP channel via an ATP-independent mechanism and therefore increasing the insulin secretion of β cells [52]. Several studies observed that patients with NDM were transferred to SUs successfully after molecular genetic diagnosis of ABCC8 variants [53, 54]. Up to 90–95% of patients with NDM due to using ABCC8 and KCNJ11 variants are able to be taken off of insulin therapy after initiation of SUs therapy [55, 56]. A recent meta-analysis also showed the estimated success rate was 90.1% in the SU treatment for ABCC8-NDM [57]. Therefore, SUs are effective for diabetic patients due to activating ABCC8 variants. However, due to different types of variants and variable clinical phenotypes, the correct treatment may be different. In addition, the sensitivity to SUs was variable in patients with ABCC8 variants. As majority, but not all, patients were successful to transfer from insulin to SUs [58]. In addition, two Japanese patients with hypoglycemia in infancy progressed to diabetes later in life due to the ABCC8 heterozygous inactivating variants and got better glucose control treated with DPP4 inhibitors [33, 34]. It might be useful for patients with inactivating variants to be treated with incretin-related drugs. We need to consider the genetic features and the response of treatment to facilitate individualized therapy.

Although we systematically reviewed the previous studies on ABCC8-NNDM, the sample size was limited. More studies are needed to better summarize its characteristics. In addition, we found that a few patients in the case reports were effective for new hypoglycemic drugs, but there was a lack of randomized controlled trials and longitudinal follow-up studies to help us determine the long-term efficacy and the impact on complications and neuropathy. Although we used the ACMG guideline to interpret the pathogenicity of ABCC8 variants, the precise molecule mechanisms are still needed to clarify in vivo and vitro studies.

5. Conclusion

Our study comprehensively concluded the genetic and clinical features of ABCC8-NNDM. The variants of ABCC8-NNDM consist of activating and inactivating ones. The phenotypes of these patients varied with good effect for SUs and had a risk of diabetic complications. It is also essential to make a precise genetic diagnosis for appropriate treatment of them to reduce episodes of hypoglycemia and diabetic complications. Next generation sequencing (NGS) enables a rapid and cost-effective diagnosis, and it should be taken into consideration for the ABCC8 gene in early onset diabetes. In the future, studies are needed to account for the mechanisms resulting in the remarkable phenotypic heterogeneity related to ABCC8 variants.

Data Availability

The data used to support the findings of this study were included within the article.

Conflicts of Interest

We have no conflicts of interest to declare.

Authors’ Contributions

Meng Li conducted this study, analyzed the data, and completed the original manuscript. Linong Ji contributed to the study design, critically revised the manuscript, and obtained funding. Xueyao Han contributed to the study design and critically revised the manuscript. All authors read the final manuscript and approved the final submission. Linong Ji and Xueyao Han contributed equally to this work.

Acknowledgments

This research was supported by the National Key R&D Program of China (2016YFC1304901), the Peking University People’s Hospital Research and Development Fund (RDY2019-21), the National High-Technology Research and Development Program of China (863 Program 2012AA02A509), and the Beijing Science and Technology Committee Fund (Z141100007414002 and D131100005313008).

Supplementary Materials

Supplement Table 1: the clinical and molecular genetic characteristics of the patients with ABCC8-NNDM in the previous studies. Supplement Figure 1: a diagram illustrates the inheritance of ABCC8 variants in probands with neonatal diabetes mellitus and nonneonatal diabetes mellitus. Variants showed in red represent that the variants were identified both in neonatal diabetes mellitus and nonneonatal diabetes mellitus. Abbreviations: ABCC8-NDM: ABCC8 variant-induced neonatal diabetes mellitus; ABCC8-NNDM: ABCC8 variant-induced nonneonatal diabetes mellitus. STROBE statement—checklist of items that should be included in reports of cohort studies. (Supplementary Materials)

References

M. Shepherd, B. Shields, S. Hammersley et al., “Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes,” Diabetes Care, vol. 39, no. 11, pp. 1879–1888, 2016.
View at: Publisher Site | Google Scholar
M. Vaxillaire, A. Dechaume, K. Busiah et al., “New ABCC8 mutations in relapsing neonatal diabetes and clinical features,” Diabetes, vol. 56, no. 6, pp. 1737–1741, 2007.
View at: Publisher Site | Google Scholar
M. S. Islam, “Stimulus-secretion coupling in beta-cells: from basic to bedside,” Advances in Experimental Medicine and Biology, vol. 1131, pp. 943–963, 2020.
View at: Publisher Site | Google Scholar
L. Aguilar-Bryan, C. G. Nichols, S. W. Wechsler et al., “Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion,” Science (New York, N.Y.), vol. 268, no. 5209, pp. 423–426, 1995.
View at: Publisher Site | Google Scholar
L. Aguilar-Bryan and J. Bryan, “Molecular biology of adenosine triphosphate-sensitive potassium channels,” Endocrine Reviews, vol. 20, no. 2, pp. 101–135, 1999.
View at: Publisher Site | Google Scholar
F. M. Ashcroft, “ATP-sensitive potassium channelopathies: focus on insulin secretion,” The Journal of Clinical Investigation, vol. 115, no. 8, pp. 2047–2058, 2005.
View at: Publisher Site | Google Scholar
C. G. Nichols, “K_ATP channels as molecular sensors of cellular metabolism,” Nature, vol. 440, no. 7083, pp. 470–476, 2006.
View at: Publisher Site | Google Scholar
G. Taschenberger, A. Mougey, S. Shen, L. B. Lester, S. LaFranchi, and S. L. Shyng, “Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels,” The Journal of Biological Chemistry, vol. 277, no. 19, pp. 17139–17146, 2002.
View at: Publisher Site | Google Scholar
P. M. Thomas, G. J. Cote, N. Wohllk et al., “Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy,” Science (New York, N.Y.), vol. 268, no. 5209, pp. 426–429, 1995.
View at: Publisher Site | Google Scholar
P. Bowman, S. E. Flanagan, E. L. Edghill et al., “Heterozygous ABCC8 mutations are a cause of MODY,” Diabetologia, vol. 55, no. 1, pp. 123–127, 2012.
View at: Publisher Site | Google Scholar
P. Haghverdizadeh, M. Sadat Haerian, P. Haghverdizadeh, and B. Sadat Haerian, “ABCC8 genetic variants and risk of diabetes mellitus,” Gene, vol. 545, no. 2, pp. 198–204, 2014.
View at: Publisher Site | Google Scholar
A. L. Gloyn, E. R. Pearson, J. F. Antcliff et al., “Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes,” The New England Journal of Medicine, vol. 350, no. 18, pp. 1838–1849, 2004.
View at: Publisher Site | Google Scholar
J. T. V. V. Bennett, M. Zhang, J. Narayanan, P. Gerrits, and S. H. Hahn, “Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism,” Molecular Genetics and Metabolism, vol. 114, no. 3, pp. 451–458, 2015.
View at: Google Scholar
S. Johansson, H. Irgens, K. K. Chudasama et al., “Exome sequencing and genetic testing for MODY,” PLoS One, vol. 7, no. 5, article e38050, 2012.
View at: Publisher Site | Google Scholar
J. P. Riveline, E. Rousseau, Y. Reznik et al., “Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations,” Diabetes Care, vol. 35, no. 2, pp. 248–251, 2012.
View at: Publisher Site | Google Scholar
on behalf of the Monogenic Diabetes Study Group of the Société Francophone du Diabète, X. Donath, C. Saint-Martin et al., “Next-generation sequencing identifies monogenic diabetes in 16% of patients with late adolescence/adult-onset diabetes selected on a clinical basis: a cross-sectional analysis,” BMC Medicine, vol. 17, no. 1, p. 132, 2019.
View at: Publisher Site | Google Scholar
S. S. Park, S. S. Jang, C. H. Ahn et al., “Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an east Asian population,” The Journal of clinical endocrinology and metabolism, vol. 104, no. 9, pp. 4188–4198, 2019.
View at: Publisher Site | Google Scholar
on behalf of the ACMG Laboratory Quality Assurance Committee, S. Richards, N. Aziz et al., “Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology,” Genetics in Medicine, vol. 17, no. 5, pp. 405–423, 2015.
View at: Publisher Site | Google Scholar
X. Robert and P. Gouet, “Deciphering key features in protein structures with the new ENDscript server,” Nucleic Acids Research, vol. 42, W1, pp. W320–M324, 2014.
View at: Publisher Site | Google Scholar
J. Mathew, S. M. Jagadeesh, M. Bhat, S. Udhaya Kumar, S. Thiyagarajan, and S. Srinivasan, “Mutations in ARSB in MPS VI patients in India,” Molecular genetics and metabolism reports, vol. 4, pp. 53–61, 2015.
View at: Publisher Site | Google Scholar
M. Li, S. Gong, X. Han et al., “Genetic variants of ABCC8 and phenotypic features in Chinese early onset diabetes,” Journal of Diabetes, vol. 13, no. 7, pp. 542–553, 2021.
View at: Publisher Site | Google Scholar
K. Shimomura and Y. Maejima, “K_ATP channel mutations and neonatal diabetes,” Internal medicine, vol. 56, no. 18, pp. 2387–2393, 2017.
View at: Publisher Site | Google Scholar
A. I. Tarasov, T. J. Nicolson, J. P. Riveline et al., “A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults,” Diabetes, vol. 57, no. 6, pp. 1595–1604, 2008.
View at: Publisher Site | Google Scholar
H. de Wet, P. Proks, M. Lafond et al., “A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes,” EMBO Reports, vol. 9, no. 7, pp. 648–654, 2008.
View at: Publisher Site | Google Scholar
D. Ortiz, P. Voyvodic, L. Gossack, U. Quast, and J. Bryan, “Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2,” The Journal of Biological Chemistry, vol. 287, no. 22, pp. 17985–17995, 2012.
View at: Publisher Site | Google Scholar
D. Ortiz and J. Bryan, “Neonatal diabetes and congenital hyperinsulinism caused by mutations in ABCC8/SUR1 are associated with altered and opposite affinities for ATP and ADP,” Frontiers in Endocrinology, vol. 6, p. 48, 2015.
View at: Publisher Site | Google Scholar
M. Abdulhadi-Atwan, J. Bushman, S. Tornovsky-Babaey et al., “Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence,” Diabetes, vol. 57, no. 7, pp. 1935–1940, 2008.
View at: Publisher Site | Google Scholar
K. Shimomura, M. Tusa, M. Iberl et al., “A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1,” Diabetes, vol. 62, no. 11, pp. 3797–3806, 2013.
View at: Publisher Site | Google Scholar
S. Harel, A. S. Cohen, K. Hussain et al., “Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 28, no. 3-4, pp. 345–351, 2015.
View at: Publisher Site | Google Scholar
L. J. Baier, Y. L. Muller, M. S. Remedi et al., “ABCC8 R1420H loss-of-function variant in a Southwest American Indian community: association with increased birth weight and doubled risk of type 2 diabetes,” Diabetes, vol. 64, no. 12, pp. 4322–4332, 2015.
View at: Publisher Site | Google Scholar
H. Huopio, T. Otonkoski, I. Vauhkonen, F. Reimann, F. M. Ashcroft, and M. Laakso, “A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1,” The Lancet, vol. 361, no. 9354, pp. 301–307, 2003.
View at: Publisher Site | Google Scholar
G. Romanisio, A. Salina, C. Aloi, M. C. Schiaffino, A. Virgone, and G. d'Annunzio, “A mild impairment of K⁺ATP channel function caused by two different ABCC8 defects in an Italian newborn,” Acta Diabetologica, vol. 55, no. 2, pp. 201–203, 2018.
View at: Publisher Site | Google Scholar
M. Karatojima and H. Furuta, “A family in which people with a heterozygous ABCC8 gene mutation (p.Lys1385Gln) have progressed from hyperinsulinemic hypoglycemia to hyperglycemia,” Journal of Diabetes, vol. 12, no. 1, pp. 21–24, 2019.
View at: Publisher Site | Google Scholar
N. Matsutani, H. Furuta, S. Matsuno et al., “Identification of a compound heterozygous inactivating ABCC8 gene mutation responsible for young-onset diabetes with exome sequencing,” Journal of diabetes investigation, vol. 11, no. 2, pp. 333–336, 2020.
View at: Publisher Site | Google Scholar
S. H. Kwak, C. H. Jung, C. H. Ahn et al., “Clinical whole exome sequencing in early onset diabetes patients,” Diabetes Research and Clinical Practice, vol. 122, pp. 71–77, 2016.
View at: Publisher Site | Google Scholar
A. K. Ovsyannikova, O. D. Rymar, E. V. Shakhtshneider et al., “ABCC8-related maturity-onset diabetes of the young (MODY12): clinical features and treatment perspective,” Diabetes therapy : research, treatment and education of diabetes and related disorders, vol. 7, no. 3, pp. 591–600, 2016.
View at: Publisher Site | Google Scholar
F. Reilly, B. Sanchez-Lechuga, S. Clinton et al., “Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy,” Diabetic medicine : a journal of the British Diabetic Association, vol. 37, no. 5, pp. 876–884, 2020.
View at: Publisher Site | Google Scholar
J. Bryan, A. Crane, W. H. Vila-Carriles, A. P. Babenko, and L. Aguilar-Bryan, “Insulin secretagogues, sulfonylurea receptors and K(ATP) channels,” Current Pharmaceutical Design, vol. 11, no. 21, pp. 2699–2716, 2005.
View at: Publisher Site | Google Scholar
P. Proks, A. L. Arnold, J. Bruining et al., “A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes,” Human Molecular Genetics, vol. 15, no. 11, pp. 1793–1800, 2006.
View at: Publisher Site | Google Scholar
A. P. Babenko, M. Polak, H. Cavé et al., “Activating mutations in theABCC8Gene in neonatal diabetes mellitus,” The New England Journal of Medicine, vol. 355, no. 5, pp. 456–466, 2006.
View at: Publisher Site | Google Scholar
C. Li, A. M. Ackermann, K. E. Boodhansingh et al., “Functional and metabolomic consequences of KATPChannel inactivation in human islets,” Diabetes, vol. 66, no. 7, pp. 1901–1913, 2017.
View at: Publisher Site | Google Scholar
T. Miki, F. Tashiro, T. Iwanaga et al., “Abnormalities of pancreatic islets by targeted expression of a dominant-negative K_ATP channel,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 22, pp. 11969–11973, 1997.
View at: Publisher Site | Google Scholar
H. Huopio, F. Reimann, R. Ashfield et al., “Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1,” The Journal of Clinical Investigation, vol. 106, no. 7, pp. 897–906, 2000.
View at: Publisher Site | Google Scholar
Y. de Marinis, M. Cai, P. Bompada et al., “Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney,” Kidney International, vol. 89, no. 2, pp. 342–353, 2016.
View at: Publisher Site | Google Scholar
Q. Li and D. G. Puro, “Adenosine activates ATP-sensitive K⁺ currents in pericytes of rat retinal microvessels: role of A₁ and A_2a receptors,” Brain Research, vol. 907, no. 1-2, pp. 93–99, 2001.
View at: Publisher Site | Google Scholar
P. Jeppesen, C. Aalkjaer, and T. Bek, “Adenosine relaxation in small retinal arterioles requires functional Na-K pumps and K(ATP) channels,” Current Eye Research, vol. 25, no. 1, pp. 23–28, 2002.
View at: Publisher Site | Google Scholar
J. M. Simard, V. Yurovsky, N. Tsymbalyuk, L. Melnichenko, S. Ivanova, and V. Gerzanich, “Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke,” Stroke, vol. 40, no. 2, pp. 604–609, 2009.
View at: Publisher Site | Google Scholar
P. Proks, J. F. Antcliff, J. Lippiat, A. L. Gloyn, A. T. Hattersley, and F. M. Ashcroft, “Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 50, pp. 17539–17544, 2004.
View at: Publisher Site | Google Scholar
P. Proks, C. Girard, S. Haider et al., “A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome,” EMBO Reports, vol. 6, no. 5, pp. 470–475, 2005.
View at: Publisher Site | Google Scholar
P. Proks, “Neonatal diabetes caused by activating mutations in the sulphonylurea receptor,” Diabetes and Metabolism Journal, vol. 37, no. 3, pp. 157–164, 2013.
View at: Publisher Site | Google Scholar
P. Proks, K. Shimomura, T. J. Craig, C. A. Girard, and F. M. Ashcroft, “Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome,” Human Molecular Genetics, vol. 16, no. 16, pp. 2011–2019, 2007.
View at: Publisher Site | Google Scholar
Y. Hashimoto, S. Dateki, M. Hirose et al., “Molecular and clinical features of KATP-channel neonatal diabetes mellitus in Japan,” Pediatric Diabetes, vol. 18, no. 7, pp. 532–539, 2017.
View at: Publisher Site | Google Scholar
D. Katanic, I. Vorgučin, A. Hattersley et al., “A successful transition to sulfonylurea treatment in male infant with neonatal diabetes caused by the novel abcc8 gene mutation and three years follow-up,” Diabetes Research and Clinical Practice, vol. 129, pp. 59–61, 2017.
View at: Publisher Site | Google Scholar
E. Ozsu, D. Giri, G. S. Karabulut, and S. Senniappan, “Successful transition to sulfonylurea therapy in two Iraqi siblings with neonatal diabetes mellitus and iDEND syndrome due to ABCC8 mutation,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 29, no. 12, pp. 1403–1406, 2016.
View at: Publisher Site | Google Scholar
M. B. Lemelman, L. Letourneau, and S. A. W. Greeley, “Neonatal diabetes mellitus: an update on diagnosis and management,” Clinics in Perinatology, vol. 45, no. 1, pp. 41–59, 2018.
View at: Publisher Site | Google Scholar
E. R. Pearson, I. Flechtner, P. R. Njølstad et al., “Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations,” The New England Journal of Medicine, vol. 355, no. 5, pp. 467–477, 2006.
View at: Publisher Site | Google Scholar
H. Zhang, X. Zhong, Z. Huang, C. Huang, T. Liu, and Y. Qiu, “Sulfonylurea for the treatment of neonatal diabetes owing to K(ATP)-channel mutations: a systematic review and meta-analysis,” Oncotarget, vol. 8, no. 64, pp. 108274–108285, 2017.
View at: Publisher Site | Google Scholar
M. Rafiq, S. E. Flanagan, A. M. Patch, B. M. Shields, S. Ellard, and A. T. Hattersley, “Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations,” Diabetes Care, vol. 31, no. 2, pp. 204–209, 2008.
View at: Publisher Site | Google Scholar
A. M. Patch, S. E. Flanagan, C. Boustred, A. T. Hattersley, and S. Ellard, “Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period,” Diabetes, obesity & metabolism, vol. 9, Supplement 2, pp. 28–39, 2007.
View at: Publisher Site | Google Scholar
S. Suzuki, Y. Makita, T. Mukai, K. Matsuo, O. Ueda, and K. Fujieda, “Molecular basis of neonatal diabetes in Japanese patients,” The Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 10, pp. 3979–3985, 2007.
View at: Publisher Site | Google Scholar
S. Jahnavi, V. Poovazhagi, V. Mohan et al., “Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children,” Clinical Genetics, vol. 83, no. 5, pp. 439–445, 2013.
View at: Publisher Site | Google Scholar
M. A. Abujbara, M. I. Liswi, M. S. El-Khateeb, S. E. Flanagan, S. Ellard, and K. M. Ajlouni, “Permanent neonatal diabetes mellitus in Jordan,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 27, no. 9-10, pp. 879–883, 2014.
View at: Publisher Site | Google Scholar
T. Klupa, I. Kowalska, K. Wyka et al., “Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype,” Clinical Endocrinology, vol. 71, no. 3, pp. 358–362, 2009.
View at: Publisher Site | Google Scholar
S. Ellard, S. E. Flanagan, C. A. Girard et al., “Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects,” American Journal of Human Genetics, vol. 81, no. 2, pp. 375–382, 2007.
View at: Publisher Site | Google Scholar
E. Globa, N. Zelinska, D. J. Mackay et al., “Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 28, no. 11-12, pp. 1279–1286, 2015.
View at: Publisher Site | Google Scholar
M. Zhang, X. Chen, S. Shen et al., “Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 28, no. 7-8, pp. 877–884, 2015.
View at: Publisher Site | Google Scholar
J. P. Shield, S. E. Flanagan, D. J. Mackay et al., “Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy,” Diabetes, vol. 57, no. 1, pp. 255–258, 2008.
View at: Publisher Site | Google Scholar
B. Cao, C. Gong, D. Wu et al., “Genetic analysis and follow-up of 25 neonatal diabetes mellitus patients in China,” Journal of Diabetes Research, vol. 2016, Article ID 6314368, 9 pages, 2016.
View at: Publisher Site | Google Scholar
S. E. Flanagan, E. de Franco, H. Lango Allen et al., “Analysis of Transcription Factors Key for Mouse Pancreatic Development Establishes _NKX2-2_ and _MNX1_ Mutations as Causes of Neonatal Diabetes in Man,” Cell Metabolism, vol. 19, no. 1, pp. 146–154, 2014.
View at: Publisher Site | Google Scholar
S. E. Flanagan, A. M. Patch, D. J. Mackay et al., “Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood,” Diabetes, vol. 56, no. 7, pp. 1930–1937, 2007.
View at: Publisher Site | Google Scholar
J. Støy, S. A. Greeley, V. P. Paz et al., “Diagnosis and treatment of neonatal diabetes: a United States experience,” Pediatric Diabetes, vol. 9, no. 5, pp. 450–459, 2008.
View at: Publisher Site | Google Scholar
L. Fanciullo, B. Iovane, D. Gkliati et al., “Sulfonylurea-responsive neonatal diabetes mellitus diagnosed through molecular genetics in two children and in one adult after a long period of insulin treatment,” Acta bio-medica : Atenei Parmensis, vol. 83, no. 1, pp. 56–61, 2012.
View at: Google Scholar
the ISPED Early Diabetes Study Group, L. Russo, D. Iafusco et al., “Permanent diabetes during the first year of life: multiple gene screening in 54 patients,” Diabetologia, vol. 54, no. 7, pp. 1693–1701, 2011.
View at: Publisher Site | Google Scholar
M. Takagi, R. Takeda, H. Yagi, D. Ariyasu, R. Fukuzawa, and T. Hasegawa, “A case of transient neonatal diabetes due to a novel mutation in ABCC8,” Clinical Pediatric Endocrinology, vol. 25, no. 4, pp. 139–141, 2016.
View at: Publisher Site | Google Scholar
X. Li, A. Xu, H. Sheng et al., “Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: Experience from China,” Experience from China., vol. 19, no. 2, pp. 251–258, 2018.
View at: Publisher Site | Google Scholar
The Early Diabetes Study Group of ISPED, D. Iafusco, O. Massa et al., “Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births,” Acta Diabetologica, vol. 49, no. 5, pp. 405–408, 2012.
View at: Publisher Site | Google Scholar
A. Bonnefond, E. Durand, O. Sand et al., “Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome,” PLoS One, vol. 5, no. 10, article e13630, 2010.
View at: Publisher Site | Google Scholar
A. Deeb, A. Habeb, W. Kaplan et al., “Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates,” American Journal of Medical Genetics Part A, vol. 170, no. 3, pp. 602–609, 2016.
View at: Publisher Site | Google Scholar
A. Anık, G. Çatlı, A. Abacı et al., “A novel activating ABCC8 mutation underlying neonatal diabetes mellitus in an infant presenting with cerebral sinovenous thrombosis,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 27, no. 5-6, pp. 533–537, 2014.
View at: Publisher Site | Google Scholar
A. Hartemann-Heurtier, A. Simon, C. Bellanné-Chantelot et al., “Des mutations du gene _ABCC8_ peuvent etre a l'origine d'un diabete insulinodependant non auto-immun,” Diabetes & Metabolism, vol. 35, no. 3, pp. 233–235, 2009.
View at: Publisher Site | Google Scholar
R. Takeda, M. Takagi, K. Miyai et al., “A case of a Japanese patient with neonatal diabetes mellitus caused by a novel mutation in the ABCC8 gene and successfully controlled with oral glibenclamide,” Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, vol. 24, no. 4, pp. 191–193, 2015.
View at: Publisher Site | Google Scholar
N. N. Dalvi, S. T. Shaikh, V. K. Shivane, A. R. Lila, T. R. Bandgar, and N. S. Shah, “Genetically confirmed neonatal diabetes: a single centre experience,” Indian Journal of Pediatrics, vol. 84, no. 1, pp. 86–88, 2017.
View at: Publisher Site | Google Scholar
K. R. Shima, R. Usuda, T. Futatani et al., “Heterogeneous nature of diabetes in a family with a gain-of-function mutation in the ATP-binding cassette subfamily C member 8 (ABCC8) gene,” Endocrine journal., vol. 65, no. 10, pp. 1055–1059, 2018.
View at: Publisher Site | Google Scholar
M. Yamazaki, H. Sugie, M. Oguma, T. Yorifuji, T. Tajima, and T. Yamagata, “Sulfonylurea treatment in an infant with transient neonatal diabetes mellitus caused by an adenosine triphosphate binding cassette subfamily C member 8 gene mutation,” Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, vol. 26, no. 3, pp. 165–169, 2017.
View at: Publisher Site | Google Scholar
P. Klee, C. Bellanne-Chantelot, G. Depret, J. P. Llano, C. Paget, and M. Nicolino, “A novel ABCC8 mutation illustrates the variability of the diabetes phenotypes associated with a single mutation,” Diabetes & Metabolism, vol. 38, no. 2, pp. 179–182, 2012.
View at: Publisher Site | Google Scholar
H. Chen, R. Chen, X. Yuan, X. Yang, and S. Chen, “ABCC8 gene analysis, treatment and follow-up of an infant with neonatal diabetes mellitus,” Zhonghua Yi Xue Yi Chuan Xue Za Zhi, vol. 34, no. 4, pp. 571–575, 2017.
View at: Publisher Site | Google Scholar
B. Piccini, C. Coviello, L. Drovandi et al., “Transient neonatal diabetes mellitus in a very preterm infant due to ABCC8 mutation,” AJP reports, vol. 8, no. 1, pp. e39–e42, 2018.
View at: Publisher Site | Google Scholar
S. E. Flanagan, V. C. Dung, J. A. L. Houghton et al., “An ABCC8 nonsense mutation causing neonatal diabetes through altered transcript expression,” Journal of Clinical Research in Pediatric Endocrinology, vol. 9, no. 3, pp. 260–264, 2017.
View at: Publisher Site | Google Scholar
J. Sikimic, T. S. McMillen, C. Bleile et al., “ATP binding without hydrolysis switches sulfonylurea receptor 1 (SUR1) to outward-facing conformations that activate K_ATP channels,” The Journal of Biological Chemistry, vol. 294, no. 10, pp. 3707–3719, 2019.
View at: Publisher Site | Google Scholar
J. H. Kong and J. B. Kim, “Transient neonatal diabetes mellitus caused by a de novoABCC8 gene mutation,” Korean Journal of Pediatrics, vol. 54, no. 4, pp. 179–182, 2011.
View at: Publisher Site | Google Scholar
C. M. Batra, N. Gupta, G. Atwal, and V. Gupta, “Transient neonatal diabetes due to activating mutation in the ABCC8 gene encoding SUR1,” Indian Journal of Pediatrics, vol. 76, no. 11, pp. 1169–1172, 2009.
View at: Publisher Site | Google Scholar
R. F. Vasanwala, S. H. Lim, S. Ellard, and F. Yap, “Neonatal diabetes in a Singapore children’s hospital: molecular diagnoses of four cases,” Annals of the Academy of Medicine, Singapore, vol. 43, no. 6, pp. 314–319, 2014.
View at: Google Scholar
N. Abraham, A. Ahamed, A. G. Unnikrishnan, H. Kumar, and S. Ellard, “Permanent neonatal diabetes mellitus due to an ABCC8 mutation: a case report,” Journal of the pancreas, vol. 15, no. 2, pp. 198–200, 2014.
View at: Publisher Site | Google Scholar
O. Oztekin, E. Durmaz, S. Kalay, S. E. Flanagan, S. Ellard, and I. Bircan, “Successful sulfonylurea treatment of a neonate with neonatal diabetes mellitus due to a novel missense mutation, p.P1199L, in the ABCC8 gene,” Journal of perinatology : official journal of the California Perinatal Association, vol. 32, no. 8, pp. 645–647, 2012.
View at: Publisher Site | Google Scholar
T. Takagi, H. Furuta, M. Miyawaki et al., “Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus,” Journal of diabetes investigation, vol. 4, no. 3, pp. 269–273, 2013.
View at: Publisher Site | Google Scholar
A. Cattoni, C. Jackson, M. Bain, J. Houghton, and C. Wei, “Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation,” Pediatric Diabetes, vol. 20, no. 4, pp. 482–485, 2019.
View at: Publisher Site | Google Scholar
C. M. Mak, C. Y. Lee, C. W. Lam, W. K. Siu, V. C. Hung, and A. Y. Chan, “Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation,” Diagnostic molecular pathology : the American journal of surgical pathology, part B, vol. 21, no. 1, pp. 56–59, 2012.
View at: Publisher Site | Google Scholar
A. N. Thakkar, M. N. Muranjan, S. Karande, and N. S. Shah, “Neonatal diabetes mellitus due to a novel ABCC8 gene mutation mimicking an organic acidemia,” Indian Journal of Pediatrics, vol. 81, no. 7, pp. 702–704, 2014.
View at: Publisher Site | Google Scholar
S. Sood, H. Landreth, J. Bustinza, L. Chalmers, and R. Thukaram, “Neonatal diabetes: case report of a 9-week-old presenting diabetic ketoacidosis due to an activating ABCC8 gene mutation,” Journal of Investigative Medicine High Impact Case Reports, vol. 5, no. 1, p. 2324709617698718, 2017.
View at: Publisher Site | Google Scholar
H. de Wet, M. G. Rees, K. Shimomura et al., “Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 48, pp. 18988–18992, 2007.
View at: Publisher Site | Google Scholar
P. Taberner, S. E. Flanagan, D. J. Mackay, S. Ellard, M. J. Taverna, and M. Ferraro, “Clinical and genetic features of Argentinian children with diabetes-onset before 12 months of age: successful transfer from insulin to oral sulfonylurea,” Diabetes Research and Clinical Practice, vol. 117, pp. 104–110, 2016.
View at: Publisher Site | Google Scholar
R. Masia, D. D. De Leon, C. MacMullen, H. McKnight, C. A. Stanley, and C. G. Nichols, “A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM),” Diabetes, vol. 56, no. 5, pp. 1357–1362, 2007.
View at: Publisher Site | Google Scholar
O. Rubio-Cabezas, S. E. Flanagan, A. Damhuis, A. T. Hattersley, and S. Ellard, “KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life,” Pediatric Diabetes, vol. 13, no. 4, pp. 322–325, 2012.
View at: Publisher Site | Google Scholar
B. Shah, E. Breidbart, M. Pawelczak, L. Lam, M. Kessler, and B. Franklin, “Improved long-term glucose control in neonatal diabetes mellitus after early sulfonylurea allergy,” Journal of pediatric endocrinology & metabolism : JPEM, vol. 25, no. 3-4, pp. 353–356, 2012.
View at: Publisher Site | Google Scholar
Y. W. Lin, A. Akrouh, Y. Hsu, N. Hughes, C. G. Nichols, and D. D. De Leon, “Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits,” Channels (Austin, Tex), vol. 6, no. 2, pp. 133–138, 2012.
View at: Publisher Site | Google Scholar
J. O. Day, S. E. Flanagan, M. H. Shepherd et al., “Hyperglycaemia-related complications at the time of diagnosis can cause permanent neurological disability in children with neonatal diabetes,” Diabetic medicine : a journal of the British Diabetic Association, vol. 34, no. 7, pp. 1000–1004, 2017.
View at: Publisher Site | Google Scholar
G. Alkorta-Aranburu, D. Carmody, Y. W. Cheng et al., “Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach,” Molecular Genetics and Metabolism, vol. 113, no. 4, pp. 315–320, 2014.
View at: Publisher Site | Google Scholar
V. Jain, A. Satapathy, J. Yadav et al., “Clinical and molecular characterization of children with neonatal diabetes mellitus at a tertiary care center in northern India,” Indian Pediatrics, vol. 54, no. 6, pp. 467–471, 2017.
View at: Publisher Site | Google Scholar
V. Jain, S. E. Flanagan, and S. Ellard, “Permanent neonatal diabetes caused by a novel mutation,” Indian Pediatrics, vol. 49, no. 6, pp. 486–488, 2012.
View at: Google Scholar
L. Gonsorcikova, M. Vaxillaire, S. Pruhova et al., “Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations,” Pediatric Diabetes, vol. 12, 3 part 2, pp. 266–269, 2011.
View at: Publisher Site | Google Scholar
L. S. de Santana and L. A. Caetano, “Targeted sequencing identifies novel variants in common and rare MODY genes,” Molecular Genetics & Genomic Medicine, vol. 7, no. 12, article e962, 2019.
View at: Publisher Site | Google Scholar
E. Isik, H. Demirbilek, J. A. L. Houghton, S. Ellard, S. E. Flanagan, and K. Hussain, “Congenital hyperinsulinism and evolution to sulfonylurea-responsive diabetes later in life due to a novel homozygous p.L171F ABCC8 mutation,” Journal of Clinical Research in Pediatric Endocrinology, vol. 11, no. 1, pp. 82–87, 2018.
View at: Publisher Site | Google Scholar
V. Bansal, J. Gassenhuber, T. Phillips et al., “Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals,” BMC Medicine, vol. 15, no. 1, p. 213, 2017.
View at: Publisher Site | Google Scholar
A. Ando, S. Nagasaka, and S. Ishibashi, “A case with relapsed transient neonatal diabetes mellitus treated with sulfonylurea, ending chronic insulin requirement,” Endocrinology, diabetes & metabolism case reports, vol. 2018, 2018.
View at: Publisher Site | Google Scholar
O. Bourron, F. Chebbi, M. Halbron et al., “Incretin effect of glucagon-like peptide 1 receptor agonist is preserved in presence of ABCC8/SUR1 mutation in Cell,” Diabetes Care, vol. 35, no. 11, article e76, 2012.
View at: Publisher Site | Google Scholar
E. B. Tatsi, C. Kanaka-Gantenbein, A. Scorilas, G. P. Chrousos, and A. Sertedaki, “Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy,” Pediatric Diabetes, vol. 21, no. 1, pp. 28–39, 2019.
View at: Publisher Site | Google Scholar
S. Pezzilli, O. Ludovico, T. Biagini et al., “Insights from molecular characterization of adult patients of families with multigenerational diabetes,” Diabetes, vol. 67, no. 1, pp. 137–145, 2018.
View at: Publisher Site | Google Scholar
V. Mohan, V. Radha, T. T. Nguyen et al., “Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India,” BMC Medical Genetics, vol. 19, no. 1, p. 22, 2018.
View at: Publisher Site | Google Scholar
C. B. P. Lenfant, P. Baz, A. Degavre et al., “Juvenile-onset diabetes and congenital cataract: “double-gene” mutations mimicking a syndromic diabetes presentation,” Genes, vol. 8, no. 11, p. 309, 2017.
View at: Publisher Site | Google Scholar
H. Dallali, S. Pezzilli, M. Hechmi et al., “Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing,” MODY patients in Tunisia by targeted next-generation sequencing., vol. 56, no. 5, pp. 515–523, 2019.
View at: Publisher Site | Google Scholar
S. Uraki, H. Furuta, M. Miyawaki et al., “Neonatal diabetes caused by the heterozygous Pro1198Leu mutation in the ABCC8 gene in a male infant: 6-year clinical course,” Journal of diabetes investigation, vol. 11, no. 2, pp. 502–505, 2020.
View at: Publisher Site | Google Scholar
S. R. Johnson, P. Leo, L. S. Conwell, M. Harris, M. A. Brown, and E. L. Duncan, “Clinical usefulness of comprehensive genetic screening in maturity onset diabetes of the young (MODY): a novel ABCC8 mutation in a previously screened family,” Journal of Diabetes, vol. 10, no. 9, pp. 764–767, 2018.
View at: Publisher Site | Google Scholar
R. R. Kapoor, S. E. Flanagan, C. T. James et al., “Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations,” Diabetologia, vol. 54, no. 10, pp. 2575–2583, 2011.
View at: Publisher Site | Google Scholar
S. F. Ang, S. C. Lim, C. Tan et al., “A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians,” Diabetes Research and Clinical Practice, vol. 119, pp. 13–22, 2016.
View at: Publisher Site | Google Scholar
T. C. Vieira, C. S. Bergamin, L. C. Gurgel, and R. S. Moises, “Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation,” Pediatric Diabetes, vol. 11, no. 7, pp. 505–508, 2010.
View at: Publisher Site | Google Scholar
O. S. Glotov, E. A. Serebryakova, M. E. Turkunova et al., “Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes,” Molecular Medicine Reports, vol. 20, no. 6, pp. 4905–4914, 2019.
View at: Publisher Site | Google Scholar
T. Koufakis, A. Sertedaki, E. B. Tatsi et al., “First report of diabetes phenotype due to a loss-of-function ABCC8 mutation previously known to cause congenital hyperinsulinism,” Case reports in genetics, vol. 2019, Article ID 3654618, 5 pages, 2019.
View at: Publisher Site | Google Scholar
A. Saito-Hakoda, T. Yorifuji, J. Kanno, S. Kure, and I. Fujiwara, “Nateglinide is effective for diabetes mellitus with reactive hypoglycemia in a child with a compound heterozygous ABCC8 mutation,” Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, vol. 21, no. 3, pp. 45–52, 2012.
View at: Publisher Site | Google Scholar
M. Gussinyer, M. Clemente, R. Cebrian, D. Yeste, M. Albisu, and A. Carrascosa, “Glucose intolerance and diabetes are observed in the long-term follow-up of nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene,” Diabetes Care, vol. 31, no. 6, pp. 1257–1259, 2008.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2021 Meng Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1393

Downloads

975

Citations