Summary

Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia. Described here is a patient who within a few months after the onset of autoimmune type 1 diabetes increased her insulin requirements more than 20-fold; despite this she had considerable difficulty maintaining a plasma glucose value of <40–60 mmol/L (720–1100 mg/dL). On suspicion of TBIRS, the patient was started on tapering dose of glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect. Within days, insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L (126–144 mg/dL). The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays. After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses and immune column treatments with temporarily remarkable effect. Mixed and transient results were seen with rituximab, mycophenolic acid and bortezomib, but the glycemic status remained suboptimal. Lack of compliance and recurrent infections may have contributed to this.

Learning points:

• Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with acquired polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia.

• We describe here a young patient in whom, a few months after the onset of a regular autoimmune diabetes, insulin requirements in a short time increased more than 20-fold, but despite this, the plasma glucose level could be kept at <40–60 mmol/L only with considerable difficulty. Did this patient have TBIRS?

• On suspicion of TBIRS, the patient was started on tapering glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect; within days insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L.

• The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays.

  After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses with temporarily remarkable effect.

• TBIRS should be considered in diabetic patients whose glycemia and/or insulin requirements are inexplicably and dramatically increased.

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.

Learning points:

• Administration of beta-blockers in thyroid storm presenting with congestive cardiac failure may precipitate cardiovascular collapse due to inhibition of thyroid-induced hyperadrenergic compensation which maintains cardiac output.

• TPE can be an effective bridging therapy to emergency total thyroidectomy when conventional thyroid storm treatment is contraindicated.

• End-organ support using ECMO and CRRT can be combined with TPE effectively in the management of critically ill cases of thyroid storm.

• The effectiveness of plasma exchange in lowering thyroid hormones appears to wane after 44–48 h of therapy in this case, highlighting the importance early thyroidectomy.

Learning points:

• 11C-Methionine PET/CT and 18F-Fluorocholine PET/CT often visualizes the parathyroid adenoma in case of negative Tc-99m-MIBI SPECT/CT.

• A cold nodule in Tc-99m Pertechnetat thyroid scintigraphy with a negative Sestamibi scintigraphy has a very low probability of being malignant.

• However, the pretest likelihood of thyroid cancer in a cold nodule with increased Sestamibi uptake is low.

• 11C-Methionine PET might have a potential incremental value in increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake.

Learning points

• Anti-insulin antibodies may result in low levels of free insulin.

• Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.

• In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.

• It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.

• A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.