Diagnosis and Treatment > Signs and Symptoms
Search for other papers by Agnieszka Łebkowska in
Google Scholar
PubMed
Search for other papers by Anna Krentowska in
Google Scholar
PubMed
Search for other papers by Agnieszka Adamska in
Google Scholar
PubMed
Search for other papers by Danuta Lipińska in
Google Scholar
PubMed
Search for other papers by Beata Piasecka in
Google Scholar
PubMed
Search for other papers by Otylia Kowal-Bielecka in
Google Scholar
PubMed
Search for other papers by Maria Górska in
Google Scholar
PubMed
Search for other papers by Robert K Semple in
Google Scholar
PubMed
Search for other papers by Irina Kowalska in
Google Scholar
PubMed
Summary
Type B insulin resistance syndrome (TBIR) is characterised by the rapid onset of severe insulin resistance due to circulating anti-insulin receptor antibodies (AIRAs). Widespread acanthosis nigricans is normally seen, and co-occurrence with other autoimmune diseases is common. We report a 27-year-old Caucasian man with psoriasis and connective tissue disease who presented with unexplained rapid weight loss, severe acanthosis nigricans, and hyperglycaemia punctuated by fasting hypoglycaemia. Severe insulin resistance was confirmed by hyperinsulinaemic euglycaemic clamping, and immunoprecipitation assay demonstrated AIRAs, confirming TBIR. Treatment with corticosteroids, metformin and hydroxychloroquine allowed withdrawal of insulin therapy, with stabilisation of glycaemia and diminished signs of insulin resistance; however, morning fasting hypoglycaemic episodes persisted. Over three years of follow-up, metabolic control remained satisfactory on a regimen of metformin, hydroxychloroquine and methotrexate; however, psoriatic arthritis developed. This case illustrates TBIR as a rare but severe form of acquired insulin resistance and describes an effective multidisciplinary approach to treatment.
Learning points:
-
We describe an unusual case of type B insulin resistance syndrome (TBIR) in association with mixed connective tissue disease and psoriasis.
-
Clinical evidence of severe insulin resistance was corroborated by euglycaemic hyperinsulinaemic clamp, and anti-insulin receptor autoantibodies were confirmed by immunoprecipitation assay.
-
Treatment with metformin, hydroxychloroquine and methotrexate ameliorated extreme insulin resistance.
Division of Endocrinology and Metabolism, Dokuz Eylul University, Izmir, Turkey
Search for other papers by Baris Akinci in
Google Scholar
PubMed
Search for other papers by Rasimcan Meral in
Google Scholar
PubMed
Search for other papers by Diana Rus in
Google Scholar
PubMed
Search for other papers by Rita Hench in
Google Scholar
PubMed
Search for other papers by Adam H Neidert in
Google Scholar
PubMed
Search for other papers by Frank DiPaola in
Google Scholar
PubMed
Search for other papers by Maria Westerhoff in
Google Scholar
PubMed
Search for other papers by Simeon I Taylor in
Google Scholar
PubMed
Search for other papers by Elif A Oral in
Google Scholar
PubMed
Summary
A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.
Learning points:
-
A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.
-
Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.
-
The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.
-
Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.
-
Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.
Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan
Asahina Shinryoujo, Fujieda, Shizuoka, Japan
Search for other papers by Masato Kotani in
Google Scholar
PubMed
Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan
Search for other papers by Naohisa Tamura in
Google Scholar
PubMed
Search for other papers by Tatsuhide Inoue in
Google Scholar
PubMed
Search for other papers by Issei Tanaka in
Google Scholar
PubMed
Summary
Type B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings.
Learning points:
-
Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors.
-
This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents.
-
Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.
Search for other papers by Eline van der Valk in
Google Scholar
PubMed
Search for other papers by Tom Tobe in
Google Scholar
PubMed
Search for other papers by Aline Stades in
Google Scholar
PubMed
Search for other papers by Alex Muller in
Google Scholar
PubMed
Summary
A 53-year-old male presented with recurrent calcium oxalate kidney stones as a first sign of underlying acromegaly, which vanished when his acromegaly was controlled. The exact mechanism behind hypercalciuria and urolithiasis in acromegaly is not yet clear. By discussing this case, a short overview of the pathophysiology of hypercalciuria in acromegaly and practical insights are given.
Learning points
-
Hypercalciuria is a common finding in acromegaly.
-
There are only few reports describing hypercalciuric kidney stones in acromegaly.
-
We assume that in acromegaly there is a primary role of IGF1-mediated, PTH-independent increase in calcitriol synthesis resulting in hypercalciuric kidney stones.
