In this study, we describe the successful treatment of a patient with TBIR.
A 68-year-old Japanese man developed marked hyperglycemia and was hospitalized and diagnosed with TBIR. He had been diagnosed with type 2 diabetes at the age of 47 years and was treated with an oral hypoglycemic drug. The administration of sitagliptin (50 mg/day) was initiated at 6 months prior to hospitalization. The patient developed a cold (symptoms included chills and a runny nose) 1 week prior to hospitalization. Self-monitored blood glucose levels on the day before hospitalization were very high; thus, he visited our hospital.
The patient's medical history included meningioma, splenic infarction, colon cancer, and chronic renal failure. However, he had no history of mental illness. His family history was as follows: his father had diabetes, his mother had high blood pressure and chronic renal failure, and his sister had colon cancer. The oral medications included sitagliptin (50 mg/day), glimepiride (0.5 mg/day), irbesartan (50 mg/day), nifedipine (40 mg/day), furosemide (40 mg/day), spironolactone (25 mg/day), aspirin (100 mg/day), famotidine (20 mg/day), allopurinol (50 mg/day), and rosuvastatin (5 mg/day). He had not used insulin injection. His lifestyle history was as follows: he used to smoke 100 cigarettes per day from the age of 20 to 68 years but quit smoking after that. He consumed 750 mL of beer per day from the age of 20 to 65 years. He was unemployed.
Physical examination revealed a waist circumference of 107.0 cm and paralyzed left upper and lower limbs (due to sequela of meningioma surgery). The results of the examination showed a random blood glucose level of 587 mg/dL (32.6 mmol/L), immunoreactive insulin (IRI) level of 1340 muU/mL, and C-peptide (CPR) level of 15.7 ng/mL (5.20 nmol/L) (Because the blood glucose level was very high, IRI and CPR were tested using the same specimen.) (Table 1). The patient was hospitalized the next day to investigate and treat hyperglycemia and hyperinsulinemia.
On the day of hospitalization, the blood tests showed hemoglobin A1c (HbA1c) of 7.2% (55.2 mmol/mol) and glycoalbumin of 28.1% (Table 1). There was divergence between HbA1c and glycoalbumin values, suggesting a sharp increase in blood glucose levels. On the second day of hospitalization, the fasting blood glucose (FBG) levels were 538 mg/dL (29.9 mmol/L), and the fasting CPR levels were 10.3 ng/mL (3.4 nmol/L). It was impossible to measure the fasting IRI because it was of extremely high value and was affected by the influence of insulin antibody (Table 2).
Despite gradually increasing the use of insulin from 10 units/day to 170 units/day in 20 days after hospitalization, blood glucose levels did not decrease sufficiently. Differential diagnosis exhibiting marked insulin resistance is diverse. As a result, the possibility of obesity, chronic kidney disease, and insulin receptor abnormality remained positive in this case; the various physical findings and tests for other conditions were negative. Given that the patient was anti-insulin receptor antibody positive with a binding rate of 71.3%, he was diagnosed with TBIR.
We investigated the presence of comorbid disorders such as collagen diseases, including SLE. Physical findings did not indicate collagen diseases, and various autoantibodies were negative. Considering that antinuclear antibodies were positive only for cytoplasmic type, this did not enable the diagnosis of a specific disease. We also considered the possibility of malignant tumors. There were no significant findings in the chest X-ray examination, abdominal ultrasonography, whole-trunk computed tomography examination, and upper and lower gastrointestinal endoscopy. Endocrine disorders were also negative. H. pylori infection was negative.
 Figure 2 summarizes the clinical course. The administration of insulin-like growth factor-1 (IGF-1; 0.1 mg/kg = 8 mg/day) was initiated at the hospital on day 37. From the first day of administration, total blood glucose (taken four times per day) decreased by 163 mg/dL (9.06 mmol/L) (Table 3). IGF-1 was gradually increased to 0.125 mg/kg (10 mg/day) on hospital day 40. However, despite this decrease in blood glucose levels in response to IGF-1, blood glucose levels increased transiently following prednisolone administration 4 days after initiating IGF-1 administration. The administration of prednisolone (30 mg/day) was started at hospital day 41, and blood glucose, IRI, and CPR levels decreased sharply within 10 days. Given that prednisolone treatment was effective, IGF-1 administration was terminated on hospital day 59. The insulin receptor antibody was negative in the examination on day 23 after the initiation of prednisolone administration. The dose of prednisolone was gradually decreased, and a maintenance dose of 15 mg/day was set on hospital day 83. On hospital day 64, pioglitazone administration was started; however, FBG levels were sometimes as low as 60-70 mg/dL (3.33-3.89 mmol/L). Thus, pioglitazone was discontinued on hospital day 74. On hospital day 71, mitiglinide (10 mg) was administered prior to breakfast and lunch. Blood glucose levels improved with mitiglinide (20 mg/day) and prednisolone (15 mg/day) treatment, and the patient was discharged. Then, the dose of prednisolone was reduced to 10 mg/day and blood glucose control was good.
Regarding changes in body weight, during the first 40 days, body weight should have been reduced due to an energy-restricted diet, but the weight loss was moderate. The reason was considered to be an anabolic effect by administration of a large amount of insulin. Over the next 25 days, body weight was thought to have increased gradually because of increased body fluid volume due to the mineralocorticoid action of prednisolone. The rapid weight loss of about 10 kg in the last 25 days coincided with the gradual decline in the dosage of prednisolone. This was thought to be due to a decrease in mineralocorticoid action as well as due to the discontinuation of insulin.
There were no serious adverse or unanticipated events observed as well as no change in diet and exercise therapy from start to finish. Food energy intake was restricted to 1600 kcal/day after hospitalization.
In summary, the presence of autoimmune diseases at the time of diagnosis was not obvious in the present case. Acanthosis nigricans was not observed, and extreme or prolonged hypoglycemia was not found. The anti-insulin receptor antibody was positive, and the inhibition rate was 71.3%. Treatment with prednisolone and IGF-1 was effective.
We identified a case of TBIR that developed 6 months after sitagliptin administration, and the patient caught a cold immediately after this development. Examples of relapsed cases of this disease have also been reported, and it is necessary to continue the survey. The possibility of an association between DPP-4 inhibitor and autoimmune disease was reported, and it is not possible to rule out the involvement of sitagliptin in the onset of this disease. In addition, we considered that the effect of a viral infection ("cold") on immunity might have affected TBIR development. Therefore, further investigations are required.