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Abstract
A 42 year-old Caribbean woman with, known type 2 diabetes, was admitted with worsening fatigue, arthritis and rashes. She was diagnosed with multisystem systemic lupus erythematosus and was initially treated with systemic steroids. During this admission, she had persistently elevated capillary glucose levels with insulin requirements over 8 U/kg/day that still did not control her blood glucose levels. Due to her profound hyperglycaemia, serum samples of fasting insulin, C-peptide, paired with blood glucose were analysed, which confirmed significant hyperinsulinaemia. Further analysis confirmed the presence of insulin receptor antibodies consistent with type B insulin resistance.
She was started on intravenous cyclophosphamide (Euro-Lupus regimen) along with continuous glucose monitoring system. After completing her six cycles of cyclophosphamide, she no longer required insulin treatment. The goal of therapy for our patient with confirmed type B insulin resistance was to manage hyperglycaemia with high doses of insulin until autoantibodies were eliminated with immunosuppressive therapy.
- systemic lupus erythematosus
- diabetes
- metabolic disorders
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Background
According to the National Diabetes inpatient audit report from 2019, around one in six hospital beds in England are occupied by a patient with diabetes. Of the 11 hospital sites that participated in the audit, one-quarter of inpatients had diabetes highlighting the scale of the problem and the need to address complications related to diabetes.1 Considering the widespread prevalence of various types of diabetes in the inpatient population, uncontrolled hyperglycaemia is the most common cause of referral to diabetes specialist teams. Uncontrolled hyperglycaemia is defined as two or more capillary blood glucose values >11 mmol/L within 24 hours.
Of the many causes of hyperglycaemia, type B insulin resistance remains a rare cause yet essential to diagnose. It is an autoimmune disorder that could present with either hypoglycaemia or hyperglycaemia depending on antibody titres. Apart from using insulin to treat hyperglycaemic, immunosuppression is the mainstay of treatment.
This case highlights the association between type B insulin resistance and autoimmune rheumatic diseases, its diagnostic workup and management.
Case presentation
We present a case of a 42 year-old Caribbean woman with a 12-month history of marked constitutional symptoms (anorexia, 15 kg weight loss, night sweats), fatigue, generalised weakness, arthralgia and rashes. During the summer of 2020, she was referred to haematology as routine blood tests with the general practitioner revealed anaemia and neutropaenia. She had a bone marrow biopsy which was reactive and consistent with anaemia of chronic disease. Her GP also organised a blood test to check her creatine kinase, as she reported ongoing muscle weakness. This was more than 3000 IU/L and she was admitted to her local hospital for further investigations.
She was diagnosed with type 2 diabetes in February 2020 and there was no other relevant medical history. There was no clinical or biochemical evidence of diabetes related complications. Her glycated hemoglobin (HbA1C) was 99 mM/M (11.2%) at diagnosis. She was initially started on metformin 1 g two times per day, but insulin was needed to optimise her diabetes control, and she was treated with a combination of once daily long-acting insulin and quick acting insulin with three meals. There was a strong family history of autoimmune conditions; her older sister had Sjogren’s syndrome and her younger sister had systemic lupus erythematosus (SLE). There was no family history of diabetes in first-degree relatives.
On admission, her HbA1C was 88 mM/M (10.2%) indicative of suboptimal control despite metformin and insulin. Further questioning revealed intermittent chest pain, and her troponin T was more than 400 ng/L. She had lymphopaenia, hypergammaglobulinaemia and a raised erythrocyte sedimentation rate (ESR), in keeping with a likely diagnosis of multisystem SLE. Due to suspicion of myocarditis on a background of newly diagnosed SLE, she was transferred to our hospital under the rheumatology team for ongoing investigations and management. She received three doses of intravenous methylprednisolone 500 mg before the transfer for multisystem SLE.
Her immunology was strongly positive, with an ANA (anti-nuclear antibody) of 1/10240, speckle pattern and ribonucleoprotein was positive. Her myositis panel demonstrated equivocal Ro-52, and her complements were normal. MRI of femurs and a cardiac MRI confirmed myositis and myocarditis, respectively.
Her urine dipstick revealed proteinuria and her urine protein-creatinine ratio was markedly elevated at 442 mg/mmol (normal range: 0–15 mg protein/mmol creatinine) with normal renal function. A renal biopsy was not performed as the renal team did not feel that this will change the management of her SLE in view of known myositis and myocarditis.
These investigations were consistent with a new diagnosis of multisystem SLE with myositis, myocarditis and likely lupus nephritis. She was started on intravenous cyclophosphamide (Euro-Lupus regimen) with background prednisolone.
Her body mass index was 21 kg/m2: height 162 cm and weight 55 kg. Her diabetes remained very poorly controlled with persistent hyperglycaemic throughout this time, and she required insulin doses above 100 IU/day. Initially, this was attributed to steroid use, but she required higher than usually administered insulin doses with steroid treatment. On clinical examination, she had mild acanthosis nigricans. There were no clinical signs of androgen excess or pseudoacromegaly, or evidence of lipodystrophy. Her long-acting insulin and prandial insulin doses were more than doubled, but despite that, she remained hyperglycaemic. She required intravenous insulin several times during the admission, with the maximum dose being 17 units/hour, but her capillary blood glucose remained persistently >20 mmol/L and at times were unrecordable. She was put on a flash blood glucose monitoring system.
Several weeks into her admission, her blood glucose remained uncontrolled despite insulin requirements of over 8 U/kg/day (figure 1). Her intermittently scanned continuous glucose monitoring profile suggested worsening hyperglycaemic during the day, which was attributed to the usual pattern seen with steroid-induced hyperglycaemic.
Intermittently scanned continuous glucose monitoring data precyclophosphamide.
She remained remarkably well despite this and never developed ketonaemia during her admission. She had two infusions of cyclophosphamide during her admission, following which she was discharged home. On discharge, the flash glucose monitoring system was changed to continuous glucose monitoring as it provided alarms to alert about hypoglycaemia. At discharge she was on 1 g two times per day of metformin, once daily intermediate acting insulin, twice a day basal insulin and three injections of quick acting insulin with food. Her total daily dose of insulin on discharge was 124 units per day.
Investigations
Due to her persistent profound hyperglycaemia, she was under close review by the Diabetes team.
Fasting insulin, C-peptide paired with blood glucose were analysed. C-peptide levels were elevated at 848 pmol/L (N: 370–1470 pmol/L), with a fasting blood glucose of 14.5 mmol/L. Insulin was also abnormally raised at 2172 pmol/L (N: 18–173 pmol/L). These results confirmed extreme hyperinsulinaemia in the presence of elevated blood glucose readings. The patient had an adiponectin level of 17.7 µg/mL (reference range for women with body mass index <25 kg/m2: 4.4–17.7) and triglycerides were 1.98 mmol/L (fasting triglycerides >1.70 mmol/L are associated with increased cardiovascular risk).
In view of her new diagnosis of SLE and marked insulin resistance, a decision to test for insulin antibodies and insulin receptor (INSR)-blocking antibodies was made. Insulin antibodies were not detected. Analysis using immunoprecipitation and western blotting confirmed the presence of INSR-blocking antibodies.
Differential diagnosis
Differential diagnosis of uncontrolled hyperglycaemia in a known person with diabetes includes the following:
Inappropriate insulin type/regimen/incorrect timings of administration/insufficient dosing.
Infrequent self-administration of antidiabetes treatment.
Concomitant steroid use.
Administering enteral feeds via nasogastric tube or parenteral nutrition.
Injecting into areas of lipohypertrophy/old surgical scars leading to impaired absorption of subcutaneous insulin.
Peripheral insulin resistance usually seen in obese individuals.
Insulin resistance syndromes such as exogenous insulin antibody syndrome (EIAS), type A and type B insulin resistance.
Glucotoxicity after a period of hyperglycaemia due to pancreatic beta cell dysfunction.
Treatment
The blood glucose control started to improve after two doses of intravenous cyclophosphamide. The patient had four more infusions of cyclophosphamide every 2 weeks after discharge from the hospital. We noticed an improvement in glycaemic control on the continuous glucose monitoring data as she was treated with cyclophosphamide, with gradual reduction in her insulin requirements (figure 2).
Continuous glucose monitoring data post six cyclophosphamide infusions.
The therapy goals for type B insulin resistance are to reverse the hypercatabolic state, usually with high doses of insulin and to eliminate the autoantibodies with immunosuppressive therapy. Elimination of autoantibodies has been attempted using plasmapheresis, plasma exchange, intravenous immunoglobulins or immunosuppressive agents, including mycophenolate mofetil, cyclophosphamide, cyclosporine, azathioprine and glucocorticoids.2 It is essential to titrate insulin to avoid severe hypoglycaemia once immunosuppressive treatments are initiated; hence, a decision was made to use a continuous glucose monitoring system concomitantly.
Outcome and follow-up
After receiving six infusions of cyclophosphamide, she did not require insulin to maintain normoglycaemia and she was able to stop insulin completely (figure 3).
Timeline of reduction of total daily insulin use and cyclophosphamide infusions.
Her creatine kinase, troponin, urine protein-creatinine ratio and ESR all improved with intravenous cyclophosphamide, demonstrating improvement in her SLE and her prednisolone was weaned.
She remains under rheumatology and diabetes teams follow-up. She continues on metformin for pre-existing diabetes. A recent oral glucose test showed a fasting blood glucose of 6.1 mmol and a 2-hour reading of 16.9 mmol; this confirms that she has pre-existing type 2 diabetes.
Discussion
Our case was complicated to manage; during the earlier phase of her admission when she was still being investigated for SLE, her blood glucose was increasingly challenging to manage. Initially, her hyperglycaemia was thought to be steroid induced. Later, the high insulin demands were also attributed to glucotoxicity seen after a prolonged period of hyperglycaemia. Glucose toxicity is a well-established entity that has been shown to contribute to the development of insulin resistance and impaired insulin secretion. In type 2 diabetes, a considerable body of evidence has accumulated indicating that a chronic physiological increment in the plasma glucose concentration leads to progressive impairment in insulin secretion and may contribute to insulin resistance as well.3
However, as she started to require higher insulin doses, we initiated investigations for the presence of insulin resistance.
In patients with uncontrolled hyperglycaemia despite escalating doses of insulin, it is imperative to investigate for rare causes of insulin resistance. EIAS, type A and type B insulin resistance have been defined in the literature, and various case reports have been published to illustrate their phenotype better.
The use of purified and recombinant human insulin preparations has markedly reduced the incidence of insulin antibodies (IAs) but not wholly suppressed it. IAs induced by exogenous insulin in patients with diabetes is associated with clinical events; this is named EIAS. Patients with type 2 diabetes receiving long-term recombinant human insulin treatment who have unexplained high plasma glucose or frequent recurrence of hypoglycaemia should be investigated for the presence of EIAS.4
Type A insulin resistance, on the other hand, is a rare form of severe congenital insulin resistance that is frequently caused by heterozygous mutations in the INSR gene and a different entity from type B insulin resistance.5
Our patient had confirmed type B insulin resistance with the presence of insulin-receptor blocking antibodies. It was first described at the National Institutes of Health in a series of publications from 1975 to 1976. Type B insulin resistance is a sporadic autoimmune disorder caused by a highly specific polyclonal autoantibody against the cell surface INSR. The autoantibody acts as a partial agonist to the INSR. It elicits a hypoglycaemic response at low titres, but at higher titres, it decreases the cellular response to insulin, resulting in refractory hyperglycaemic.6
The exact prevalence of type B insulin resistance is unknown because epidemiological data are based predominantly on case reports and case series. To the best of our knowledge, over 100 cases of type B insulin resistance have been reported in the literature to date. Type B insulin resistance is most commonly observed in women and African Americans, followed by Asians and Caucasians.7 Affected patients typically present with a hypercatabolic state with dramatic weight loss, hyperglycaemic with or without ketoacidosis, and unusually widespread acanthosis nigricans. Less common presentations include hypoglycaemia or virilisation in women. The syndrome usually occurs in patients with a background of autoimmune rheumatological diseases, such as SLE, Sjogren’s syndrome or mixed connective tissue disease. However, it may also occur as a paraneoplastic manifestation of lymphoma or multiple myeloma. The biochemical signature of type B insulin resistance includes markedly elevated fasting insulin concentrations with high insulin-to-C-peptide ratio, hyperadiponectinaemia and low/average fasting triglyceride concentrations with normal to increased HDL (High-density lipoprotein) cholesterol.2
Learning points
Ensure hyperglycaemia is investigated and managed appropriately.
Do not hesitate to involve diabetes specialist teams in cases that are difficult to manage.
Usual insulin requirements are 0.3–0.6 U/Kg/day.
Consider type B insulin resistance in patients with a history of autoimmune conditions and higher than usual insulin needs.
Beware of the reduction of insulin dose when the underlying condition is treated with immunosuppression and the risk of hypoglycaemia in patients with high insulin needs and ensure safe monitoring and follow-up is in place.
Ethics statements
Acknowledgments
We will like to thanks Professor Stephen O’Rahilly, Director, Metabolic Research Laboratories in Cambridge, where the special Insulin Receptor antibody test was conducted. And Dr Stephen Thomas who is the Clinical Director of Diabetes and Endocrinology at Guys and St Thomas NHS Foundation trust for his clinical insight and help with management of the case.
Footnotes
Twitter @Aaisha_Saqib
Contributors AS and YM: contributed to the management of the case and coauthored the case report. RI: contributed to the management of the case, revised initial draft and got patient consent. DK: lead the management of the case and revised the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.