A case of drug-induced hypersensitivity syndrome complicated with fulminant type 1 diabetes and type 2 myocardial infarction.

Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of drug eruption that causes multiorgan disorders after the administration of certain drugs such as anticonvulsants. Herein, we report the case of a 66-year-old man with DiHS/DRESS complicated by fulminant type 1 diabetes (FT1D), shock, and cardiac involvement who was treated conservatively without systemic corticosteroid administration. He had taken carbamazepine for trigeminal neuralgia for 7 weeks until he noticed eruptions on his trunk. Two days after admission, he developed diabetic ketoacidosis, resulting in hypovolemic shock. The patient was diagnosed with FT1D, and insulin was administered. Additionally, the patient had a fever over 38°C, elevated white blood cells (>20 000/µL), liver dysfunction, atypical lymphocytes, and lymphadenopathy, but no evidence of viral reactivation. The lymphocyte transformation test for carbamazepine was positive, and human leukocyte antigen typing revealed the A31:01 haplotype, a risk factor for carbamazepine-induced cutaneous adverse drug reactions. Collectively, a diagnosis of atypical DiHS and a definitive case of DRESS was made. Moreover, myocardial dysfunction wall motion was observed. A close examination revealed mild coronary artery stenosis, leading to a diagnosis of type 2 myocardial infarction due to relative ischemia. The patient was carefully monitored without systemic corticosteroid administration because both clinical findings and laboratory data peaked on the same day. The patient's eruption and general condition improved, and he was discharged 4 weeks later. While most cases of DiHS/DRESS with cardiac involvement present with myocarditis, the possibility of ischemic heart disease should be considered in patients with cardiac involvement under shock.

Dupilumab-related type 1 diabetes in a patient with atopic dermatitis: a case report.

Dupilumab, a humanized monoclonal antibody that inhibits both interleukin (IL)-4 and IL-13 signals, is used as a treatment for a variety of allergic diseases including atopic dermatitis. We experienced a case of dupilumab-related type 1 diabetes in a patient with atopic dermatitis. An 18-year-old female presented with thirst and polydipsia seven months after initiating dupilumab therapy for atopic dermatitis and was found to have marked hyperglycemia with ketosis. She was positive for anti-glutamic acid decarboxylase antibody, leading to the diagnosis of type 1 diabetes. She carried human leukocyte antigen (HLA) genes associated with type 1 diabetes. Most type 1 diabetes is considered a T-helper (Th) 1 type autoimmune disease, whereas IL-4 and IL-13, which are Th2 cytokines, play inhibitory roles in the pathogenesis of type 1 diabetes. This case implies that dupilumab might contribute to the development of type 1 diabetes in individuals with a genetic background of type 1 diabetes via relative Th1 dominance. To our knowledge, this is the first case of the development of type 1 diabetes during dupilumab therapy. As dupilumab therapy might accelerate the development of type 1 diabetes, it is important to note cases like this case to clarify the pathogenic mechanisms underlying dupilumab-related type 1 diabetes.

A Case Report of Graves' Disease Induced by the Anti-Human Programmed Cell Death-1 Monoclonal Antibody Pembrolizumab in a Bladder Cancer Patient.

Immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1), have been widely used in the treatment of malignancies. However, these drugs can cause immune-related adverse events resembling autoimmune diseases. There are some reports of Graves' disease (GD) induced by anti-cytotoxic T-lymphocyte-associated antigen 4 antibodies, but reports which discussed GD induced by anti-PD-1 antibodies are very rare. We report the case of a 61-year-old man with bladder cancer who presented with severe diarrhea, fatigue, palpitation, body weight loss, and hyperthyroidism after the fifth treatment with the anti-PD-1 monoclonal antibody pembrolizumab. His thyroid function prior to pembrolizumab administration had been subclinical hyperthyroidism, despite a negative thyroid-stimulating hormone receptor antibody (TRAb) level. On admission, pembrolizumab administration was discontinued. Graves' disease was diagnosed based on a positive TRAb test result and the ultrasonographic finding of increased blood flow in the superior thyroid artery. Based on colonoscopy findings, the cause of diarrhea was diagnosed as active colitis. His diarrhea was improved with prednisolone, and thyroid function was treated with potassium iodide and thiamazole. This case report of GD with positive TRAb induced by the anti-PD-1 antibody pembrolizumab may contribute to the understanding of the mechanism underlying the association between GD and autoimmune activation via PD-1.

First case report of thyroid abscess caused by Helicobacter cinaedi presenting with thyroid storm.

BACKGROUND: Helicobacter cinaedi is a microaerobic Gram-negative spiral-shaped bacterium that causes enteritis, cellulitis, and bacteremia in both immunocompromised and immunocompetent patients. While there have been increasing numbers of reported H. cinaedi infections recently, there has been no thyroid abscess case caused by H. cinaedi presenting with thyroid storm. CASE PRESENTATION: A 50-year-old Japanese man presented with a 9-day history of high fever associated with palpitations, dry cough, and chronic diarrhea. The patient had a history of Basedow's disease that had been treated with thiamazole in the past. During the current episode, the patient was diagnosed with thyroid storm and treated accordingly. The blood culture taken on admission was positive for H. cinaedi. This finding was confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOFMS). A systemic computed tomography (CT) scan revealed a thyroid abscess as the site of infection and cause of the bacteremia. The 16S rRNA gene sequencing identified the pathogen of thyroid abscess as H. cinaedi. Clinical symptoms and laboratory data normalized on admission day 7 after treatment with both effective antibiotics and antithyroid drugs. CONCLUSIONS: The case study described a patient with a history of Basedow's disease that presented with a thyroid abscess caused by H. cinaedi with symptoms similar to those of thyroid storm. While this bacterium has been implicated in other infections, we believe this is the first time the bacteria has been documented to have caused a thyroid abscess.

CD4+ T cell-dominant insulitis in acute-onset Type 1 diabetes mellitus associated with intraductal papillary mucinous adenoma.

The loss of insulin-producing pancreatic ß-cells in Type 1 diabetes mellitus (DM) is presumably the result of a T cell-mediated process. In general, CD8+ T cells are the predominant lymphocytes in the insulitis lesions, and CD4+ T cell-dominant insulitis is very rare. We present a case of a 72-year-old woman presented with excessive thirst and a 3-month history of weight loss. She was in a state of ketosis, and her plasma glucose concentration and HbA1c value were elevated. Moreover, anti-islet autoantibodies were positive, thus acute-onset Type 1 DM was diagnosed. At the time of diagnosis, a tumour was detected in the pancreas; total pancreatectomy was carried out 2 months later. The pathological diagnosis was intraductal papillary mucinous adenoma. Immunohistochemical staining of a sample of non-tumorous pancreatic tissue revealed 13 insulitis lesions infiltrated by both CD4+ and CD8+ T cells, and interestingly there were more CD4+ T cells than CD8+ T cells in the lesions. Moreover, B cells and macrophages had also infiltrated the lesions, and these two cell frequencies were both positively correlated with CD4+ as well as CD8+ T cell frequencies. This was a rare case with acute-onset Type 1 DM characterized by CD4+ T cell-dominant insulitis. Proinflammatory cytokines that can promote ß-cell apoptosis or CD8+ T cell function are reported to be secreted from CD4+ T cells. Thus, together with B cells and macrophages, CD4+ T cell-associated immune responses may have, directly and/or indirectly, played a role in the pathogenesis of the Type 1 DM in this patient.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes.

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

One-minute mental status examination for category fluency is more useful than mini-mental state examination to evaluate the reliability of insulin self-injection in elderly diabetic patients.

AIMS/INTRODUCTION: We investigated the factors associated with the reliability of insulin self-injection in elderly diabetic patients receiving insulin therapy. MATERIALS AND METHODS: We enrolled diabetic patients aged ≥65 years and receiving insulin therapy, and assessed their cognitive function by the mini-mental state examination and 1-min mental status examination for category fluency. We also observed their technique of insulin self-injection, and evaluated whether or not patients were able to inject insulin by themselves according to nine defined details in terms of insulin self-injection. The predictive factors for the reliability of insulin self-injection were determined by univariate and multivariate logistic regression analysis. There were 278 participants (135 males, 143 females) enrolled in the present study. RESULTS: According to multivariate logistic regression analysis, only the 1-min mental status examination score was found to be a significant independent predictor of the reliability of insulin self-injection (odds ratio 0.75; 95% confidence interval 0.62-0.90; P = 0.002). CONCLUSIONS: The 1-min mental status examination for category fluency can be considered more useful than mini-mental state examination to evaluate the reliability of insulin self-injection in elderly diabetic patients receiving insulin therapy.

[A questionnaire survey on current status of anti-diabetic therapy for diabetic patients with dementia].

AIM: It is important to establish treatment goals and optimal anti-diabetic therapy for diabetic patients with dementia. However, there are currently no established treatment guidelines. Recently, the West Tokyo Diabetes Association has established the Diabetes and Dementia Study Group to investigate the status of anti-diabetic therapy for diabetic patients with dementia. Here, we assessed the current status of such patients by a questionnaire survey. METHODS: In November 2011, we conducted a mailed survey to the clinics and hospitals affiliated with Kita-Tama, Hachioji and Tachikawa Medical Associations in Tokyo, Japan. The survey evaluated the most suitable anti-diabetic therapy for elderly diabetic patients or diabetic patients with dementia, combined anti-diabetic therapy, insulin therapy for elderly diabetic patients and diabetic patients with dementia, combination therapy of insulin and oral anti-diabetic agents for diabetic patients with dementia, factors that make it difficult for diabetic patients with dementia to continue insulin therapy, and selection of treatment or care for diabetic patients with dementia. RESULTS: The responses indicated that the anti-diabetic agents appropriate for diabetic patients with dementia are dipeptidyl peptidase-4 inhibitors. Those inappropriate for the same patients are metformin and insulin. Family support was a major factor for insulin therapy continuation for diabetic patients with dementia. Moreover, anti-diabetic agents for these patients are selected according to their ease of use and compatibility with available familial and social resources. CONCLUSION: Our survey results can be utilized for the creation of new guidelines and educational resources for the anti-diabetic therapy of diabetic patients with dementia.

Effect on the atherogenic marker plasminogen activator inhibitor type-1 of addition of the ACE inhibitor imidapril to angiotensin II type 1 receptor antagonist therapy in hypertensive patients with abnormal glucose metabolism: a prospective cohort study in primary care.

BACKGROUND AND OBJECTIVE: Renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are recommended by the American Diabetes Association for blood pressure control and prevention or management of cardiovascular disease in patients with diabetes mellitus. However, some investigators have suggested that ARBs may increase the risk of myocardial infarction in hypertensive patients. Activation of the RAS is associated with an increased risk of ischaemic events. Angiotensin II stimulates the production of plasminogen activator inhibitor type-1 (PAI-1), a powerful predictor of cardiovascular disease. ACE inhibitors are reported to reduce PAI-1 levels and activity, while ARBs do not reduce or may even elevate levels of this atherogenic marker. The objective of this study was to determine whether the ACE inhibitor imidapril reduces PAI-1 levels in hypertensive patients already being treated with an ARB. METHODS: This was a prospective cohort study carried out in primary care with a follow-up period of 6 months. Estimating the alpha error (p-value) at 0.05, the power of the test as 80%, and the difference in PAI-1 levels as 10 + or - 15 ng/mL, the required sample size was calculated to be 40. Participants were hypertensive patients taking ARBs for more than 8 weeks, and having dyslipidaemia, obesity or abnormal glucose metabolism. Imidapril 5-10 mg/day was prescribed for 6 months to reduce blood pressure to <130/80 mmHg. The main outcome measure, PAI-1 level, was measured before and 6 months after the addition of imidapril to ARBs in 21 subjects (13 men, eight women), all with abnormal glucose metabolism, nine with dyslipidaemia, and six who were obese. Bodyweight, body mass index, blood pressure, homeostasis model assessment of insulin resistance, glycosylated haemoglobin, creatinine, potassium, high sensitivity C-reactive protein (hs-CRP), and high molecular weight adiponectin levels were measured as secondary outcomes. RESULTS: PAI-1 level was not significantly changed overall. Hs-CRP level was also not significantly changed; however, the high molecular weight adiponectin level was significantly increased (p = 0.044), especially in men (p = 0.026). There were no significant changes in the other outcomes measured. CONCLUSION: The current study showed that imidapril added to ARBs did not decrease PAI-1 levels in hypertensive patients with abnormal glucose metabolism; however, this combination therapy significantly increased high molecular weight adiponectin levels in men.

Effect of combination therapy of a rapid-acting insulin secretagogue (glinide) with premixed insulin in type 2 diabetes mellitus.

AIM: The effect of rapid-acting insulin secretagogues (glinides) on glycemic control when included with insulin therapy for type 2 diabetes remains uncertain. To examine this, we added glinide once a day to twice daily injections of premixed insulin. RESEARCH DESIGN AND METHODS: Seventy-four type 2 diabetic patients, taking twice daily injections of premixed insulin and whose diabetic control was stable, were registered at 6 independent institutions. After a 3-month observation period, 60 patients were administered 10 mg mitiglinide or 90 mg nateglinide at lunchtime without changing their insulin regimen. After 12 weeks, administration of glinide was discontinued and observation was continued. HbA1c levels were measured at the start of glinide administration, after 12 weeks of glinide , and at 12 weeks after discontinuation. RESULTS: HbA1c improved from 7.72+/-0.66% to 7.55+/-0.71% (p <0.01) at Week 12 of glinide administration. Twelve weeks after discontinuation, HbA1c returned to the baseline level (7.72+/-0.81%). CONCLUSION: This study indicates that the addition of glinide once a day at lunchtime to twice daily injections of premixed insulin is effective for the treatment of type 2 diabetes.

"Low dose" metformin improves hyperglycemia better than acarbose in type 2 diabetics.

OBJECTIVES: "High dose" metformin therapy (2,550 mg/day) is reported to improve glycemic control in type 2 diabetic patients with obesity (body mass index (BMI) > or = 30). Some have reported that metformin therapy, even in low doses (500-750 mg/day), improves glycemic control in non-obese type 2 diabetic patients (BMI approximately 25). However, it is unclear whether "low dose" metformin improves glycemic control better than acarbose in non-obese type 2 diabetic patients, which has been shown to improve glycemic control in type 2 diabetes with obesity. METHODS: We randomly divided 22 non-obese type 2 diabetic patients (mean BMI approximately 25) into two groups (A = 11, B = 11). Group A was treated with "low dose" metformin (500-750 mg/day) for 3 months, and switched to acarbose (150-300 mg/day) for another 3 months. Group B was treated with acarbose first, and then switched to "low dose" metformin. RESULTS: "Low dose" metformin significantly decreased the fasting plasma glucose (FPG) and HbA1c level in both groups A and B, whereas acarbose decreased HbA1c levels in group B but not in group A. Overall, "low dose" metformin significantly decreased HbA1c (p=0.0165) levels as compared to acarbose. CONCLUSION: In conclusion, "low dose" metformin therapy improved glycemic control better than acarbose in non-obese diabetics.

Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice.

Although peroxisome proliferator-activated receptor (PPAR)gamma agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARgamma agonist, pioglitazone, and a PPARalpha agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARgamma agonist-treated groups. Also, PPARgamma agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARgamma and -alpha agonists. We conclude that combination therapy with PPARgamma and PPARalpha agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.