INSR gene mutation masquerading as type 1 diabetes – A case report

INTRODUCTION

Type 1 diabetes (T1D) is the most common form of childhood diabetes, accounting for >90% cases.^[1] However, due to the predominance of T1D in the young population, important pointers such as family history or low/high insulin requirements indicative of possible non-dependence on insulin are often missed, leading to a delay in the diagnosis of monogenic diabetes. Possibility of other types of diabetes should be considered in a child or an adolescent with negative autoantibodies when there is a significant family history of diabetes in every generation, early onset (<6–12 months of age), and unusually high or low requirements of insulin, other syndromic features, or history of use of drugs such as glucocorticoids or tacrolimus.^[2]

Monogenic diabetes encompasses a group of rare genetic disorders characterized by diabetes due to one or more defects in a single gene or chromosome locus. Around the world, studies in the pediatric population have reported varying prevalence of monogenic diabetes between 0.6 and 4.2%;^[3] however, genetic testing is still underused/unavailable to estimate the exact prevalence of these cases. They are categorized into four important subtypes as neonatal diabetes mellitus (NDM), maturity onset diabetes of the young (MODY), diabetes associated with extra-pancreatic features, and monogenic insulin resistance (IR) diabetes.^[4]

Here, we present a case of an adolescent girl with a heterozygous missense mutation in the INSR gene, leading to IR and diabetes. She was initially diagnosed and treated as T1D for a significant period, highlighting the importance of careful history and examination in every child presenting with clinical features of diabetes.

CASE REPORT

A 16-year-9-month-old girl diagnosed with “Type 1 diabetes” was referred to the pediatric endocrine unit for very high insulin requirement (2 units/kg/day) and poor glycemic control. She was born to parents with third-degree consanguinity [Figure 1], had an uneventful birth (birth weight 3.2 kg), no admissions so far, and her intelligence was normal. She was diagnosed with T1D 3 years back due to symptoms of polyuria, polydipsia, weight loss, and a high hemoglobin A1C (HbA1c) of 9.7%. Her father had a history of type 2 diabetes (T2D) since 30 years of age and was on Tab Glimepiride (4 mg) and Tab Metformin (1000 mg) twice daily. She was initially put on pre-mixed insulin and later shifted to a basal bolus regimen consisting of glargine and regular insulin. She did not have any episodes of diabetic ketoacidosis so far.

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Figure 1:

Pedigree chart.

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On examination, she was timid and uncomfortable. Her weight was 42 kg (Z-score: −1.08), height 148 cm (Z-score: −1.56), BMI 19.17 kg/m² (Z-score: −0.45), and mid-parental height was 155 cm (Z-score: −0.47). She had a hoarse voice and hirsutism (Ferriman–Gallwey score: 27/36). She also had a dark complexion with mild acanthosis nigricans and lipohypertrophy on areas of insulin administration. Breast development was poor, stage 2, pubic hair stage 5, and axillary hair was stage 3. She had clitoromegaly 3 cm and had not achieved menarche yet. In view of significant hyperandrogenism, she had been evaluated for congenital adrenal hyperplasia (CAH); baseline 17-hydroxprogesterone 2.13 ng/mL; and adrenocorticotropic hormone stimulated levels 2.57 and 3.49 ng/mL at 1 and 2 h, respectively; and genetic testing for CAH did not identify any pathogenic mutations. Furthermore, a trial of spironolactone (50 mg/day) had been given with no response. Self-monitoring of glucose showed fasting blood glucose (BG) levels of 190 to 276 mg/dL and daytime BG levels ranging from 252 to 448 mg/dL. Androgens were elevated. Ultrasound evaluation revealed a uterus size of 45 × 17 × 25 mm with an endometrial thickness of 4.4 mm. Both ovaries were normal with peripherally situated small follicles (Right: 32 × 14 × 21 mm; Left: 29 × 14 × 25 mm). Laboratory investigations are summarized in Table 1.

IR syndrome was suspected, and blood samples were sent for genetic evaluation. She was started on oral metformin 500 mg/day, gradually increased to 2 g/day. Insulin requirement decreased and was stopped after 6 months. However, BG monitoring suggested asymptomatic pre-meal low BG levels in the range of 60–70 mg/dL and occasional postprandial hyperglycemia. She was advised to have balanced meals as well as low carbohydrate, protein/fat rich snacks in between meals. Analysis of the BG monitoring chart recorded by the patient showed BG with fasting BG levels ranging from 85 to 115 mg/dL and daytime BG levels from 68 to 180 mg/dL with occasional BG levels >250 mg/dL. Breast growth improved and is currently at stage B5 of development. Hoarseness of voice persists, but hirsutism has improved (she is also considering dermatology treatment for permanent removal). She experienced menarche 1 year after treatment; however, irregularities persisted, and she was subsequently put on combined hormonal pills (ethinyl estradiol 35 µg and cyproterone acetate 2 mg). At present, she has regular menstrual cycles of 30 days. Parents also report psycho-social improvement with her being more confident and attending school regularly. A timeline of major clinical milestones is summarized in Figure 2. Informed consent was obtained from the patient and parents for sharing anonymous clinical findings and laboratory investigations for publication.

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Figure 2:

Timeline of clinical milestones. CAH: Congenital adrenal hyperplasia.

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DISCUSSION

The current report highlights the presentation of an adolescent girl with severe IR resulting from a known heterozygous missense mutation (p.Arg1201Gln) in the INSR gene that led to significant clinical manifestations of hyperinsulinemia and hyperandrogenism. The INSR gene, located on chromosome 19p13.2, encodes for the heterotetrameric insulin receptor, a plasma membrane-associated receptor tyrosine kinase dimer formed of two α and two β sub-units. Insulin binds at β sub-units of the insulin receptor, stimulating the phosphorylation and tyrosine kinase activity in the β sub-units.^[6] This activates the insulin signaling pathways, activating glycogen, fatty acids, as well as protein synthesis, along with cell growth and differentiation.^[7] In contrast to the INSR gene, the INS gene is responsible for insulin biosynthesis, mutation of which can cause insulin-dependent forms of neonatal or later-onset monogenic diabetes.^[8]

The phenotype of IR syndromes depends on the effect of the mutation in the INSR gene on the signaling of the receptor. The most severe phenotypes of Donohue Syndrome and Rabson–Mendenhall syndrome occur due to homozygous or compound heterozygous mutations, respectively and present early in life with failure to thrive, severe acanthosis, hypertrichosis, and cardiomyopathy. They usually succumb to sepsis due to hyperglycemia in the first decade of life. Type A IR syndrome is the mildest, usually presenting in adolescence and happens due to dominant negative, heterozygous mutations. Over 150 genetic variants with homozygous as well as compound heterozygous mutations in INSR have been identified so far.^[5]

Clinically, IR syndromes are categorized into primary insulin pathway signaling defects (insulin receptor or post-receptor defects as in this child) and secondary adipose tissue abnormalities (like lipodystrophies). Unusually, high insulin requirement, often coupled with acanthosis nigricans and features of hyperandrogenism, is a typical finding of IR due to INSR defects.^[9] Clinicians are more familiar with the management of T2D or T1D; hence, the diagnosis of monogenic diabetes is often delayed. Management of monogenic diabetes varies significantly from other types of diabetes. Furthermore, the lack of availability/affordability of genetic testing impacts the diagnostic accuracy in such patients. Important clinical clues, including family history, can be missed, especially in a country like India, where T2D has a very high prevalence. The patient we encountered was on a basal-bolus insulin regimen for diabetes control, despite which the fasting BG and HbA1c levels were significantly high. Such elevated insulin levels lead to hyperpigmentation and acanthosis nigricans by promoting epidermal cell growth through insulin-like growth factor-1 (IGF-1) receptors. Hyperinsulinemia stimulates the secretion of gonadotropin-releasing hormone (GnRH), triggering excessive release of LH, causing premature theca cell differentiation and anovulation. It also increases LH-induced androgen production contributing to clinical signs of hyperandrogenism, such as hirsutism, hoarseness, clitoromegaly, and menstrual irregularities.^[10] Although the index case presented with primary feature of diabetes first, in females presenting with such polycystic ovarian syndrome like features, features of IR and extent of hyperglycemia should be carefully looked for. Although there are reports of IR syndromes detected in prepubertal children,^[11] it typically becomes more evident during puberty, reflecting the physiological state of IR during puberty,^[12] with the severity being more in females than in males.^[13] Heterozygous mutations in INSR gene have been associated with variable phenotypes within the same family.^[14]

In our case, the father carried the variant in a heterozygous condition, which led to him and the proband developing the disorder. She responded well to metformin, though occasional post-meal hyperglycemia persisted. Her subsequent HbA1c levels ranged between 6.5 and 7%. She still experiences asymptomatic hypoglycemia in the morning or before meals in the range of 60–70 mg/dL, possibly due to some functional insulin receptors. We could not use continuous glucose monitoring in our patient due to financial constraints, but it would be useful to understand the pattern and also for the family to understand how different meals with different glycemic index affect her BG levels.

While there are no established guidelines on optimal management of IR due to the rarity of the variant, a combination of lifestyle interventions including dietary modifications (low glycemic index diet), regular exercise, and pharmacological therapy (metformin monotherapy or combined with insulin) are the cornerstone of management.^[15] An 11-year-old Caucasian female from Australia responded to 500 mg sustained-release metformin, leading to reduction in HbA1c from 9.2% to 6% in 3 months.^[12] It may be combined with β-glucosidase inhibitors like acarbose with each meal to reduce the glycemic index of the food to prevent post-meal hypoglycemia. For hyperandrogenism and menstrual irregularities, a progestin with anti-androgen properties, such as cyproterone acetate or combined pills with estrogen, may be used.

CONCLUSION

The rarity of type A IR, combined with its variable clinical presentation and underlying genetic heterogeneity, highlights the need for greater awareness among clinicians to facilitate early recognition and appropriate management. This case underscores the importance of considering rare monogenic forms of diabetes in patients with severe IR, particularly when accompanied by features such as hyperandrogenism and acanthosis nigricans. Notably, regular BG monitoring – including fasting levels – is essential, as some patients, like ours, may exhibit fasting hypoglycemia despite IR. As our understanding of genotype–phenotype correlations evolves, further research is warranted to define optimal management strategies tailored to specific INSR gene mutations and to better understand the long-term outcomes in affected individuals.