Diabetes associated with concurrent INSR and KLF11 (MODY7) mutations: a case report

Abstract

IntroductionAdvances in the understanding of glucose metabolism and insulin signaling have revealed that diabetes mellitus develops through diverse and complex pathogenic mechanisms. As molecular diagnostics evolve, the traditional classification of diabetes is increasingly challenged by genetically defined subtypes with overlapping clinical features.Case PresentationWe present two diagnostically challenging cases that illustrate the expanding spectrum of monogenic and genetically influenced dysglycemia. The first case involves an adult patient with a heterozygous insulin receptor (INSR) gene mutation presenting with hypoglycemia, impaired glucose tolerance, compensatory hyperinsulinemia, and persistent ketonuria—an atypical phenotype for insulin resistance syndromes. The second case describes a patient with persistent pancreatic autoantibody positivity but preserved β-cell function, in whom genetic analysis revealed a Krüppel-like factor 11 (KLF11) mutation consistent with maturity-onset diabetes of the young (MODY)7.ConclusionThese cases emphasize that diabetes pathogenesis extends beyond classical paradigms, highlighting the importance of genetic evaluation in unexplained metabolic disorders.

Keywords

Introduction

Mutations in the insulin receptor (INSR) gene are classically associated with severe insulin resistance syndromes. Homozygous or compound heterozygous mutations result in severe phenotypes such as Donohue and Rabson–Mendenhall syndromes, whereas heterozygous mutations typically cause milder or atypical metabolic presentations.¹
However, adult-onset presentations without classical stigmata of insulin resistance remain rare and diagnostically challenging. Similarly, monogenic diabetes forms such as maturity-onset diabetes of the young (MODY) may clinically overlap with both type 1 and type 2 diabetes, particularly when autoimmune markers coexist.
Here, we report two cases that broaden the phenotypic spectrum of INSR mutation and MODY7 and underscore the clinical value of genetic testing in atypical glycometabolic disorders.

Case Presentation

Heterozygous INSR Mutation Presenting With Hypoglycemia and Persistent KetonuriaA 44-year-old man presented with a one-year history of tremor and weakness, mainly during fasting. He had no comorbidities or family history of diabetes. Examination showed a normal body mass index (BMI) (22 kg/m²) without signs of insulin resistance.
Laboratory tests revealed impaired fasting glucose and persistent ketonuria (+++). The oral glucose tolerance test (OGTT) showed marked hyperinsulinemia (271 μU/mL) with postprandial hyperglycemia, indicating severe insulin resistance. During fasting, glucose was 52 mg/dL with low insulin and connecting peptide (C-peptide), meeting borderline insulinoma criteria.³ Imaging was normal, and autoimmune markers were negative. Genetic testing confirmed a heterozygous INSR mutation. All results and autoimmune markers were listed in the relevant tables. (Supplementary Tables 1, 2 and Tables 1, 2 and 3).ImagingContrast-enhanced pancreatic CT and endoscopic ultrasonography showed no mass, excluding insulinoma.Genetic AnalysisA heterozygous INSR variant (c.2100dup, p.E701, exon 10) was identified. The case represents a rare adult-onset INSR-related disease characterized by hypoglycemia, compensatory hyperinsulinemia, impaired glucose tolerance, and persistent ketonuria.ManagementThe patient was initially treated with acarbose (50 mg three times daily) and metformin (500 mg twice daily, later increased to 1000 mg twice daily). However, both were poorly tolerated due to gastrointestinal side effects and hypoglycemic symptoms. A structured six-meal diet was introduced, and metformin was later reintroduced cautiously. No standardized treatment exists for heterozygous INSR mutations; therefore, management remains individualized, with insulin sensitizers used empirically.Paradox of Hyperinsulinemia and DysglycemiaThe most notable finding was marked postprandial hyperglycemia (267 mg/dL) during OGTT despite extreme hyperinsulinemia (271 μU/mL), reflecting severe peripheral insulin resistance due to an INSR defect. The worsening response on repeat testing suggests progressive receptor dysfunction. Hypoglycemia in heterozygous INSR mutations may result from tissue-specific insulin sensitivity, where skeletal muscle is profoundly resistant while hepatic sensitivity persists, leading to excessive suppression of hepatic glucose output. This paradox can mimic insulinoma, making genetic testing essential in severe unexplained dysglycemia.²Metabolic Dysregulation and Persistent KetonuriaPersistent ketonuria indicated impaired insulin signaling in adipose tissue. Despite hyperinsulinemia, defective receptor function fails to suppress lipolysis and ketogenesis. This selective resistance differs from diabetic ketoacidosis, as ketosis persists despite high insulin levels, suggesting significant metabolic dysregulation and potential cardiovascular risk.²Genetic Variability and Clinical PresentationINSR mutations affect receptor biosynthesis, trafficking, ligand binding, or kinase activity. Heterozygous variants usually cause partial dysfunction, with hypoglycemia being rare and mainly reported in pediatric cases.^2,8 The absence of acanthosis nigricans in this adult case further highlights phenotypic variability.Therapeutic ChallengesThere is no standardized treatment for INSR mutations. While insulin sensitizers such as metformin are commonly used, intolerance often limits therapy. Management relies on dietary modification, including low-carbohydrate intake and frequent meals, to stabilize glycemia and reduce ketonuria.
This case illustrates a rare combination of hypoglycemia, impaired glucose tolerance, and persistent ketonuria due to an atypical INSR mutation, underscoring the importance of genetic evaluation in extreme metabolic phenotypes.Autoantibody-Positive Diabetes With Preserved β-Cell Function and KLF11 (MODY7) MutationA 38-year-old woman presented with hyperglycemia detected during fatigue evaluation. She had no comorbidities, medication use, or family history of diabetes. Physical examination showed BMI 22.3 kg/m² with no signs of insulin resistance.
Initial labs showed preserved β-cell function (fasting C-peptide 1.83 ng/mL; postprandial 6.43 ng/mL) with positive anti-glutamic acid decarboxylase (GAD) antibodies. Other autoantibodies were initially negative but later became positive, while C-peptide levels remained stable over two years. Given this atypical course, genetic testing was performed, identifying a KLF11 variant consistent with MODY7 (Supplementary Table 3).Variants IdentifiedKLF11 (NM_003597.5) heterozygous c.781C > T (p.Pro261Ser), along with heterozygous variants in SLC26A4, IL17RA, and GNRHR, and HLA-DQB1 positivity. The KLF11 variant is consistent with MODY7. KLF11 encodes a pancreatic transcription factor regulating insulin gene expression. Some variants have been reported as benign or with limited impact on diabetes risk. For example, the Q62R polymorphism has been associated with type 2 diabetes, although its effect appears modest, while other variants (A347S, T220M) alter function in vitro but show no strong association with diabetes in population studies.ManagementInsulin therapy was initiated, given positivity for pancreatic β-cell autoantibodies. However, severe hypoglycemia prompted a dose adjustment to low-dose insulin (glargine 2 U/day) in conjunction with metformin (1000 mg/day).Mechanistic Insights Into MODY7Maturity-Onset Diabetes of the Young (MODY) represents a group of autosomal dominant forms of monogenic diabetes characterized by early onset, preserved β-cell function, and low insulin resistance.⁴ The KLF11 gene is a zinc-finger transcription factor that regulates insulin expression through PDX-1 interaction in a p300-dependent manner.⁵ KLF11 loss-of-function mutations decrease insulin promoter activity and reduce β-cell function.⁷ These variants also display incomplete penetrance and variable expressivity, and associated phenotypes include early-onset diabetes and increased vascular risk.^6-7Clinical Presentation and Diagnostic ComplexityDespite persistent autoantibody positivity, the clinical course was atypical for type 1 diabetes, as C-peptide levels were preserved, there was no absolute insulin deficiency, and the patient maintained good glycemic control with oral therapy. A KLF11 mutation indicates β-cell impairment independent of autoimmunity and may drive disease progression. This overlap highlights the limitations of antibody-based classification alone and underscores the need for genetic testing in atypical diabetes to ensure an accurate diagnosis and guide targeted therapies, as associated genotypes may differ in their responses to glucose.Ethical ApprovalAs this is a case report involving a single patient and based on clinical data, ethical approval was not required by the institution's review board.
This case report was prepared in accordance with the CARE guidelines.

Discussion

Modern diabetology is shifting from phenotype-based classification toward precision, genotype-guided approaches. Heterozygous INSR mutations and MODY7 (KLF11) highlight the limitations of traditional type 1 and type 2 diabetes frameworks and emphasize the importance of genetic testing when clinical findings are atypical.^1-2
Red flags for genetic evaluation include unexplained hypoglycemia, discordant insulin–glucose profiles, persistent ketonuria, preserved C-peptide despite autoantibody positivity, and atypical metabolic progression in adulthood.³
INSR mutations may present paradoxically in adults. Although typically linked to insulin resistance, they can cause hypoglycemia, marked hyperinsulinemia, and ketosis.^1-2 Early recognition is essential for preventing complications and guiding management.
MODY7 (KLF11) is an autosomal dominant form of diabetes caused by mutations in a β-cell transcription factor.⁴ KLF11 regulates insulin gene expression, oxidative stress responses, and vascular integrity. Mutations impair insulin secretion, reduce antioxidant capacity, and may increase susceptibility to vascular complications.^5-7
Clinically, MODY7 demonstrates variable expression and incomplete penetrance.⁶ In the presented case, the coexistence of autoimmune markers with a KLF11 mutation created diagnostic complexity. Despite antibody positivity, preserved insulin secretion suggested modification of classical autoimmune progression.
Therapeutically, identifying MODY7 is important, as patients may respond to lifestyle modification and oral agents such as metformin or sulfonylureas rather than insulin.⁴ These findings underscore the value of integrating genetic data into clinical decision-making (Table 4).

Limitations

There are several limitations that should be considered. First, this study includes only two cases, limiting generalizability despite expanding the phenotypic spectrum of heterozygous INSR mutations and MODY7 (KLF11). Second, the identified variants were not functionally characterized; although previously reported, the absence of in vitro or in vivo assays restricts conclusions about causality and underlying mechanisms. Third, long-term follow-up is limited, and the progression of metabolic complications, treatment durability, and outcomes in these conditions remains unclear, highlighting the need for longitudinal data beyond one year. Additionally, the coexistence of autoimmune markers and a monogenic mutation in one case complicates interpretation, as their relative contributions to the phenotype cannot be clearly distinguished. Finally, treatment approaches were individualized due to the lack of established clinical guidelines for these rare conditions, which may limit the generalizability of therapeutic responses.

Conclusion

Rare variants in INSR and KLF11 produce phenotypes that overlap with insulinoma and T1D/T2D. As molecular diagnostics advance, recognizing these entities is vital for precision diagnosis, targeted therapy, and accurate genetic counseling.

Declarations

Abbreviations

References

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