Type B insulin resistance syndrome associated with gliptin-induced bullous pemphigoid: a case report in Abidjan

¹Department of Internal Medicine, University Hospital Center of Treichville, University of Felix Houphoüet Boigny, Abidjan, Côte d´Ivoire, ²Department of Internal Medicine, University Hospital Center of Angré, University of Felix, Houphoüet Boigny, Abidjan, Côte d´Ivoire

^&Corresponding author
Tiépé Rokia Ouattara, Department of Internal Medicine, University Hospital Center of Treichville, University of Felix Houphoüet Boigny, Abidjan, Côte d´Ivoire

Introduction    

Type B insulin resistance syndrome (TBIRS) is an especially rare autoimmune disorder with unknown prevalence, caused by immunoglobulin G polyclonal antibodies that act against the insulin receptor. It leads to abnormal cellular and metabolic responses to insulin, marked by elevated levels of circulating anti-insulin receptor antibodies. Type B insulin resistance syndrome (TBIRS) results in difficult-to-control diabetes, even with high doses of insulin, requiring long duration hospitalization and usually occurred in an immunocompromised context [1]. Its exact prevalence remains unknown because there have been no population-based studies to answer the question of disease prevalence. Since this is a rare condition, few articles in the literature have been devoted to this disease, especially in sub-Saharan Africa where auto-immune diseases are usually underdiagnosed. We report a case of type B insulin resistance occurring in a 52-year-old woman with bullous pemphigoid.

Patient and observation     

Patient information: Mrs G L, a 52-year-old woman from Cote d´Ivoire, was referred in the Department of Internal Medicine for the management of a hardly-controlled hyperglycemia. A history of type 2 diabetes for 10 years was treated initially by metformin and sulfonylurea, replaced with a combination of Metformin-Vildagliptin that she has been taking for two years.

Timeline of the current episode: March 2023: she was hospitalized in the dermatology department to diagnose and manage diffuse and intense pruritus with tense blisters. The diagnosis of bullous pemphigoid was confirmed based on clinical and histologic evidence. She was thus treated with 1mg/kg daily of prednisone and also steroid ointment. Few days later, glycemic disorder occurred and corticosteroids were thus stopped. She was then transferred to the Internal Medicine Department.

Clinical findings: her symptoms on admission were a significant weight loss (32 kilograms at her admission against 68 kilograms two months before hospitalization) associated with polyuria, polydypsia and polyphagia. Due to intense scratching, hypochromic lesions and post-bullous ulceration were observed (Figure 1).

Diagnostic approach: type B insulin resistance syndrome was suspected by a poorly controlled glycemia, requiring a daily titrated dose of insulin more than 4 UI/kg combined with oral medication: Glibenclamide 10mg and Metformin 2000 milligram daily. Multiple subcutaneous injection protocol was initiated using basal Insulin and rapid-acting insulin before meals and even before snacks since she had intense polyphagia. Progressive titration was done till 346 UI daily (Figure 2). The diagnosis was then confirmed with the presence of elevated levels of anti-insulin antibodies. The screening of autoimmune conditions revealed the positivity of DNA autoantibodies and direct Coombs test while antinuclear antibodies were negative (Table 1, Table 2).

Therapeutical intervention and follow-up: immunosuppressive therapy: mofetil mycophenolate (MMF) was administered. Local and oral corticosteroids were also re-administered due to bullous pemphigoid relapse.

Follow-up and outcome intervention: considerable changes were noticeable after three months of hospitalization with the gradual correction of diabetes and weight gain. The onset of recurrent hypoglycaemia had led to progressive reduction of insulin doses to 90 Units daily and she was then discharged from hospital.

Patient perspective: Mrs GL was comfortable with the treatment given its good tolerance, the absence of side effects and weight gain. She continued glucose monitoring at home. Fasting glucose levels were in range, but postprandial glucose levels remain difficult to control due to poor diet compliance. Figure 2 summarizes the therapeutic approach and the evolution of glycaemic controls.

Informed consent: it was obtained from the patient to publish this report by the journal's patient consent policy.

Discussion     

Type B insulin resistance is a rare condition, generally described in middle-aged people with female predominance. It generally occurred in a dysimmunity context such as connective tissue diseases mostly systemic lupus [2]. In some cases, there are no obvious auto-immune diseases diagnosed but abnormalities like antinuclear antibodies are often detected. In our patient case, TBIRS occurred in the context of bullous pemphigoid, the most common autoimmune blistering skin disease [3]. We found no other risk factors apart from the use of Gliptins. Dipeptydil peptidase IV (DPP4) inhibitors have been identified as a major risk factor for the development of Bullous pemphigoid but the molecular mechanisms that cause the association between DPP4 inhibitors and bullous pemphigoid are currently unclear [4]. Importantly, DPP4 inhibitors-induced bullous pemphigoid does not remit fully after withdrawal of DPP4 inhibitors, suggesting that it induces and aggravates the process of bullous pemphigoid rather than a reversible side effect. In our case apparently, the expression of DPP4 is significantly affected in different autoimmune conditions. It is presumed that the DPP4 inhibitor affects the action of CD26, a costimulatory molecule involved in T cell activation [5]. Therefore a direct link between TBIRS and the use of DPP4 inhibitor might be possible, as some cases were previously identified [6].

Regarding clinical aspects, clinical features may vary whether antibodies act like agonists at the insulin receptor or antagonists when at high titre. The most common presentation is extreme insulin resistance with hyperglycemia, acanthosis nigricans, and weight loss [1-7]. In our case, acanthosis nigricans was not observed, maybe because of diffuse blisters and scratching lesions. During the remission phase, patients can experience hypoglycaemic episodes when the titre decreases, also noticed by Klubo-Gwiezdzinska et al. which allowed to reduce insulin doses [8]. However, initial presentation with hypoglycaemic phase has also been noticed in 28% of cases [1]. Some authors reported a high prevalence of hypoglycemia in Asia, with a low prevalence of acanthosis nigricans [6].

When it comes to therapeutic aspects, it includes glycemic control measures and sometimes immunosuppression. The level of insulin required to attain these goals might be very high, more than 50000UI daily in rare cases [1]. In our case insulin doses used were combined with an oral drug like metformin and sulfonylurea. Although patients with type B insulin-resistance taking antidiabetic oral drugs exhibited uncontrolled blood glucose levels and persistent insulin-resistance [8], some authors experimented the use of lower doses of Insulin combined with antidiabetic oral drugs like thiazolidinediones [9].

Regarding immunosuppressive treatment, there is no standard immunosuppression protocol. In Martin's cohort, prednisone and cyclophosphamide were the most frequently used in the first phase. Azathioprine and mycophenolate mofetil were also used during the maintenance phase in this survey [1]. The combination of plasmapheresis, intravenous immunoglobulin and glucocorticoids also showed positive effects. Some authors highlighted the effectiveness of Rituximab in hypoglycaemic form of TBIRS [10] but spontaneous remission is also possible, noticed in twenty percent of cases [1]. In our case, blood glucose levels gradually decreased over five months of treatment with the combination of insulin, antidiabetic oral drug, and immunosuppressive treatment. However, it seems difficult to decide between a spontaneous remission of the disease and the efficacy of immunosuppressive treatment.

Conclusion     

Type B insulin resistance is a rare cause of diabetes, under-recognized in our areas. It mostly results in a hardly-controlled diabetes requiring high doses of insulin, into a dysimmunity context. The treatment is not yet standardized, the combination of an antidiabetic drug and immunosuppressive treatment generally leads to remission even though spontaneous remission is also possible. Our case is specific because it happened in an autoimmunity context, probably mediated by DPP4 inhibitors that are important risk factors of bullous pemphigoid and some other immune diseases. Due to its effects on lymphocytosis activation, inflammation and antibody production, a direct link between the use of DPP4 inhibitor and TBIRS might be possible.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Data collection: Tiépé Rokia Ouattara, Ingrid Balmaken, N´guessan Michel Konan, and Georges Stéphane Koffi. Drafting the manuscript: Tiépé Rokia Ouattara, and Ingrid Balmaken. Revising the manuscript: Tiépé Rokia Ouattara, N´guessan Michel Konan, Georges Stéphane Koffi, Fiacre Abbe, Ingrid Balmaken, Chantal Assy, Alain Djoman, Yacouba Kone, Ubrich Venceslas Acko and Jacques Kacou. All the authors have read and approved the final version of the manuscript.

Tables and figures     

Table 1: biological assessment of Mrs GL

Table 2: immunological assessment of Mrs GL

Figure 1: hypochromic lesion after intense scratching and rupture of blisters in context of bullous pemphigoid

Figure 2: evolution of glycaemic ranges and treatment of Mrs GL

References