Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes caused by autosomal dominant mutations in a single gene that impair pancreatic β-cell function. Mechanistically, MODY differs from type 2 diabetes mellitus (T2DM) in that it involves the impaired synthesis and secretion of insulin rather than insulin resistance. MODY accounts for 1-2% of all diabetes cases in Europe (1). However, in China, improvements in genetic screening and clinical diagnostics have increased the diagnostic rate of MODY to ~9% (2). MODY is currently classified into 14 genetic subtypes due to mutations in the following genes: Hepatocyte nuclear factor 4a (HNF4A), HNF1A, HNF1B, glucokinase (GCK), pancreatic and duodenal homeobox 1, neuronal differentiation 1, KLF transcription factor 11, carboxyl ester lipase, paired box 4, insulin, B lymphocyte kinase, ATP-binding cassette subfamily C member 8 (ABCC8), potassium inwardly rectifying channel subfamily J member 11 and adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1. Among the various subtypes, HNF1A-MODY, GCK-MODY, HNF4A-MODY and HNF1B-MODY are the most commonly diagnosed (3). In 2011, Fajans and Bell (4) formally described the onset of MODY as occurring during childhood or early adolescence, typically in patients aged 9-14 years, although it may present even earlier. Previous studies have estimated that MODY accounts for ~1-5% of all diabetes cases in Western countries, such as Europe, North America and Australia. However, in Asian populations, including China, owing to differences in screening intensity and genetic architecture, the true prevalence of MODY may fall below or exceed this interval (5,6). Over time, MODY can lead to chronic complications affecting the eyes, kidneys, nerves and blood vessels (6).

The diagnostic criteria for MODY, proposed by Tattersall and Fajans (7) in 1975, comprise: i) Onset of diabetes before age 25 years; ii) diabetes in at least three family members across successive generations, indicating autosomal dominant inheritance; iii) presentation as non-insulin-dependent diabetes mellitus (NIDDM); iv) absence of obesity; and v) no history of diabetic ketoacidosis (DKA). Despite these diagnostic definitions, MODY remains rare and is frequently misdiagnosed as T2DM (8).

The present study describes a MODY-12 pedigree carrying a heterozygous pathogenic variant in the ABCC8 gene, segregating in an autosomal dominant pattern. The index patient is a 22-year-old woman with a body mass index within the normal range (18.5-24.9 kg/m²). Contrary to the classical diagnostic criteria for MODY, the patient experienced three episodes DKA within 10 months of diagnosis, along with a transient but rapid decline in renal function. While most patients with MODY-12 are currently managed with sulfonylureas, emerging evidence suggests that sodium-glucose transporter 2 inhibitors (SGLT2is) can be used in combination with sulfonylureas as an alternative treatment approach for MODY (9).

Among all monogenic forms of diabetes, MODY is the most prevalent. However, despite the diversity of its subtypes, the overall occurrence of MODY in clinical practice remains relatively low, particularly for the rarer subtypes, including MODY-4 and MODY-6 to MODY-14(1). The ABCC8 gene is associated with MODY-12. As of April 2023, the HGMD had cataloged 737 distinct mutations in ABCC8, highlighting high genetic heterogeneity. Of these, missense and nonsense mutations are the most common, accounting for 502 cases. Other reported mutation types include splicing mutations (100 cases), small deletions (81 cases), small insertions (25 cases), gross deletions (16 cases), small indels (5 cases), gross insertions/duplications (5 cases), complex rearrangements (2 cases) and regulatory mutations (1 case).

In the present study, NGS and Sanger sequencing revealed that all affected individuals in the pedigree with MODY-12 harbored the ABCC8 c.2500C>T (p.Arg834Cys) mutation. To assess the potential structural impact of this variant, the SWISS-MODEL server was employed to construct the three-dimensional structure of the mutant protein. This demonstrated that the genetic mutation results in the substitution of arginine at residue 834 with cysteine, which induces spatial conformational changes, primarily due to changes in local electrostatic interactions and steric effects. The most fundamental difference between the mutant and wild-type protein is in the properties of the amino acid side chains; the substitution of the positively charged, elongated side chain of Arg834 by the neutral, shorter side chain of Cys834 disrupts the local electrostatic potential and markedly diminishes steric hindrance. In addition, the hydrogen bonding network is critical for the structural integrity of the protein. However, following the mutation, an additional hydrogen bond is predicted to form between the residue at position 834 and Ser830, altering both the number and orientation of hydrogen bonds. This restricts the conformational flexibility of these residues and ultimately distorts the secondary structure of the 830-834 region. In addition, the reduction in steric hindrance may lead to an adaptive displacement of adjacent amino acid side chains, thereby compromising the stability of local hydrophobic residues. Furthermore, Cys834 has the potential to form disulfide bonds under oxidative conditions, which could promote aberrant dimerization (14). Disulfide bond formation may also interfere with the normal folding process of the SUR1 protein, as observed by 200-nsec molecular dynamics simulations and documented in K_ATP channelopathies (15). Collectively, these structural alterations are predicted to lead to a pronounced conformational rearrangement of the ATP-binding domain, disrupting key residue interactions essential for ATPase activity and compromising the regulatory function of the protein.

A comprehensive review of the LitVar database indicates that ABCC8 mutations are associated with numerous disorders, including congenital hyperinsulinemia, neonatal diabetes and MODY-12 (16,17). For patients harboring these mutations, particularly those leading to SUR1 subunit dysfunction, clinical management with oral sulfonylureas has demonstrated short-term efficacy and safety, as evidenced by significant reductions in glycated hemoglobin levels within 3 months. However, careful monitoring and the individualized adjustment of sulfonylurea dosage is essential to optimize treatment outcomes (18). In addition, a review of the literature on ABCC8 gene mutations reveals several molecular mechanisms underlying MODY, as summarized in Fig. 3A (19,20). Mutations in the ABCC8 gene primarily impair the expression and function of the K_ATP channel, which is essential for the release of insulin by pancreatic β cells. The K_ATP channel is an octamer composed of four Kir6.x pore-forming units and four regulatory SUR1 subunits (Fig. 3B). ABCC8 mutations markedly reduce the surface expression of SUR1, thereby decreasing the overall abundance of functional K_ATP channels and disrupting glucose-stimulated insulin secretion (21). Furthermore, ABCC8 modulates multiple facets of K_ATP channel activity, including ATP and Mg²⁺ sensitivity, β-cell membrane excitability and the function of voltage-dependent Ca²⁺ channels (22). Notably, certain ABCC8 mutations have been shown to reduce the ATP sensitivity of K_ATP channels by ~4-fold. Consequently, even under hyperglycemic conditions with compensatory changes in β cells that maintain normal intracellular ATP levels and ATP/ADP ratios, the closure of K_ATP channels is delayed, ultimately delaying the triggering of insulin secretion. The electrical activity of pancreatic β cells is essential for insulin exocytosis (19). However, when K_ATP channel function is compromised, β cells fail to depolarize normally, likely due to diminished K⁺ efflux. This prevents the proper opening of voltage-dependent Ca²⁺ channels and reduces intracellular Ca²⁺ concentrations, thereby impairing Ca²⁺-dependent insulin exocytosis (23). These findings have been substantiated by quantitative experiments using patch-clamp and calcium imaging techniques. Furthermore, the K_ATP channel contains two nucleotide-binding sites, NBF1 and NBF2, on the SUR1 subunit. NBF1 lacks ATPase activity and functions independently of Mg²⁺, whereas NBF2 exhibits ATPase activity and is highly dependent on Mg²⁺, particularly in pancreatic β cells (22). Certain ABCC8 gene mutations increase the Mg²⁺ dependence of NBF2, thereby enhancing overall potassium currents (20), impairing K_ATP channel inhibition and ultimately suppressing insulin secretion.

SGLT-2is are widely used to manage hyperglycemia in patients with diabetes. They primarily function by inhibiting glucose reabsorption in the proximal renal tubules, thereby increasing urinary glucose excretion. This induces osmotic diuresis, resulting in a notable loss of body fluids (24). In its 2018 consensus report, the American Diabetes Association and the European Association for the Study of Diabetes emphasized the clinical value of SGLT-2is, recommending their use, supported by high-level evidence, in patients with chronic kidney disease (CKD) and heart failure (25). A 2022 meta-analysis of cardiovascular and renal outcomes further demonstrated that SGLT-2is not only confer cardio-renal benefits but also effectively reduce mortality in patients with T2DM and diabetic kidney disease. However, the meta-analysis excluded patients with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m², a subgroup that may respond differently to treatment, thus limiting the generalizability of its findings (26).

The long-term renal protection provided by SGLT-2is is attributed not only to their beneficial effects on cardiovascular risk factors, such as the lowering of blood pressure and improvement of glycemic control, but also to direct renal mechanisms, including the reduction of intraglomerular pressure and anti-fibrotic effects. These combined actions have been associated with a slower decline in eGFR and reduced proteinuria in clinical studies (27). Investigation of the potential cardiorenal protective benefits of SGLT-2is in patients with heart disease has revealed that the osmotic diuresis induced by these agents may exacerbate a hyperosmolar state and increase the risk of urinary retention (28). Several mechanisms may account for the occurrence of AKI in patients treated with SGLT-2is. First, these agents induce osmotic diuresis, leading to dehydration and a subsequent reduction in blood volume (29). Second, increased delivery of sodium to the distal nephron activates tubuloglomerular feedback, resulting in afferent arteriolar constriction. Third, SGLT-2is may promote renal artery vasoconstriction, further compromising renal blood flow. These hemodynamic alterations can collectively lead to a gradual decline in eGFR (30). Furthermore, SGLT2is may exacerbate hypoxia in the renal medulla by reducing local oxygen availability and increasing metabolic demand. This hypoxic state stabilizes hypoxia-inducible factor (31), resulting in its upregulation, which in turn elevates plasma erythropoietin levels and promotes reticulocytosis (32).

Pseudo-AKI is a clinical phenomenon characterized by transient increases in serum creatinine or reductions in eGFR caused by extrarenal factors, rather than intrinsic damage to the renal parenchyma (33). Pseudo-AKI in patients with MODY-12 is particularly complex. In addition to the transient eGFR reductions induced by SGLT2i therapy, recurrent DKA episodes and various comorbidities act as critical triggers. Firstly, recurrent DKA can impair renal function through two main mechanisms: i) Severe dehydration and a reduction in effective circulating blood volume may lead to prerenal AKI (29) and ii) metabolic acidosis may trigger renal vasoconstriction, further decreasing renal perfusion and the eGFR (34). Additionally, CKD reduces the intrinsic resilience of the kidney to acute insults by inducing structural damage and impairing adaptive repair mechanisms, with reported odds ratios indicating a significantly increased risk. Furthermore, cardiovascular diseases, such as heart failure, reduce cardiac output below critical thresholds, thereby diminishing renal perfusion and imposing additional hemodynamic stress on the kidneys. The use of nephrotoxic agents further exacerbates renal impairment (35), for example, non-steroidal anti-inflammatory drugs inhibit cyclooxygenase-2, leading to a reduction in the production of prostaglandin E₂, which is essential for tubular repair (36). Similarly, contrast agents can trigger oxidative stress, as evidenced by increased malondialdehyde levels, thereby inducing cellular injury (37). Genetic factors also contribute to renal vulnerability. Specific mutations in the ABCC8 gene, such as p.Arg834Cys, disrupt the function of K_ATP channels in β-cells, resulting in abnormal lipolysis and elevated free fatty acid levels. These metabolic disturbances can overwhelm the capacity of the kidney to adapt, further destabilizing renal function. In the present study, it was hypothesized that the pseudo-AKI observed in this pedigree may result from a synergistic interaction between pharmacological and genetic factors. Specifically, treatment with SGLT2is increases sodium excretion, potentially reducing the effective circulating volume and altering renal tubular dynamics, thereby mimicking AKI. Concurrently, the ABCC8 c.2500C>T (p.Arg834Cys) mutation may impair K_ATP channel function, leading to metabolic disturbances that increase susceptibility to renal dysfunction. Together, these factors may contribute synergistically to the development of pseudo-AKI. A schematic summary of the study is presented in Fig. 4.

There are several limitations in the present study. First, the small sample size limits the ability to perform a comprehensive analysis of the heterogeneity of renal complications in MODY-12. To address this, a dedicated MODY-12 disease database is under development and multi-center cooperative studies with a larger cohort are planned, thereby increasing statistical power and improving the generalizability of the findings. Second, although the structure of the mutant ABCC8-encoded protein was preliminarily predicted using Swiss-Model, the impact of the mutation on the dynamic conformation of the protein was not thoroughly investigated. In future studies, molecular dynamics simulation software, such as Gromacs, Sybyl or Discovery Studio, will be employed to simulate and analyze the wild-type and mutant proteins over an extended time scale. This approach will help to reveal mutation-induced conformational changes, alterations in the free energy landscape, and modifications in the interaction network of key residues. These future studies will provide deeper insights into the molecular mechanisms underlying the functional impact of the ABCC8 mutation and lay a theoretical foundation for the development of precise treatment strategies.