A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation.

Summary: A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 µU/mL; 60 min: 953 µU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother's diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years. Learning points: Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance. Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed. Clinical courses may differ even if the same genetic mutation is found in a family.

Associations of Infant Feeding with Body Composition and Cardiometabolic Health in Young Female University Students.

Background: We assessed the association of infant feeding with body composition and cardiometabolic health at 20 years in a setting where infant feeding is not associated with socioeconomic status. Materials and methods: Body size trajectory since birth, current body composition measured using whole-body dual-energy X-ray absorptiometry, and a broad range of cardiometabolic risk factors were compared cross-sectionally among young female university students who were ever breastfed (n = 158, 120 exclusively, and 38 mainly), mixed fed (n = 124), and formula fed (n = 15, 10 mainly, and 5 exclusively) Results: Compared with breastfed and mixed fed women, formula fed women had higher serum total and low-density lipoprotein (LDL) cholesterol although fat mass, fat distribution, fasting glucose, and insulin and high-density lipoprotein cholesterol did not differ. In addition, resting heart rates were higher in formula fed women compared with the other two groups of women although systolic and diastolic blood pressure did not differ. Further, formula fed women had higher adiponectin while serum leptin did not differ. There was no difference in birthweight, weight and height in childhood and adolescence, and glucose tolerance. On multivariate logistic regression analysis, formula feeding was associated with resting heart rates (odds ratio [OR]: 1.06, confidence interval [95% CI]; 1.01-1.12, p = 0.01) and adiponectin (OR: 1.3, 95% CI; 1.1-1.5, p < 0.001) independently of serum total and LDL cholesterol. Conclusions: Breastfeeding may be associated with favorable lipid profile and autonomic nervous function in young adults through mechanisms unrelated to adiposity, implicating potential long-term benefits of breastfeeding for cardiovascular health. Higher adiponectin in nonbreastfed women warrants further studies.

Serum Orosomucoid Is Associated with Serum Adiponectin, Adipose Tissue Insulin Resistance Index, and a Family History of Type 2 Diabetes in Young Normal Weight Japanese Women.

INTRODUCTION: Adipose tissue (AT) expandability may be facilitated by adiponectin and suppressed by orosomucoid, and reduced AT expandability may be associated with first-degree relatives of type 2 diabetes. We tested the hypothesis that orosomucoid may be associated not only with adiponectin and adipose tissue insulin resistance but also with a family history of type 2 diabetes (FHD). Research Design and Methods. Anthropometric and metabolic variables, adipokines, and measures of inflammatory and insulin resistance were cross-sectionally investigated in 153 young normal weight Japanese women. Stepwise multivariate linear regression analyses were used to identify the most important determinants of orosomucoid. RESULTS: Orosomucoid was higher in women with positive (n = 57) compared to women with negative FHD and was associated positively with FHD (both p = 0.01). Orosomucoid also showed positive associations with fasting glucose (p < 0.001), free fatty acids (p = 0.001), and HbA1c (p = 0.007), whereas there was no association with fasting insulin and serum lipids. In addition, orosomucoid was associated inversely with adiponectin (p = 0.02) and positively with adipose tissue-insulin resistance index (AT-IR, the product of fasting insulin and free fatty acids; p = 0.001) but not with homeostasis model assessment-insulin resistance, leptin, and high-sensitivity C-reactive protein. In multivariate analyses, AT-IR (standardized ß, 0.22; p = 0.003), serum adiponectin (standardized ß, -0.163; p = 0.032), FHD+ (standardized ß, 0.178; p = 0.029), and HbA1c (standardized ß, 0.213; p = 0.005) emerged as independent determinants of orosomucoid and explained 15.2% of its variability. CONCLUSIONS: These results are the first to demonstrate that orosomucoid is associated not only with adipose tissue-insulin resistance and adiponectin but also with FHD.

Accuracy of a Professional Continuous Glucose Monitoring Device in Individuals with Type 2 Diabetes Mellitus.

Among continuous glucose monitoring (CGM) devices, which continuously measure glucose concentration in subcutaneous interstitial fluid for comprehensive monitoring of blood glucose profile, only FreeStyle Libre Pro® (Abbott Diabetes Care) is currently available in Japan as a professional system. FreeStyle Libre Pro® is easy to use because it does not require calibration by self-monitoring of blood glucose (SMBG), but information on its accuracy has been insufficient. To evaluate the measurement accuracy of FreeStyle Libre Pro®, we have now compared blood glucose levels determined by this device with those measured by SMBG in 40 individuals with type 2 diabetes mellitus. The mean absolute relative difference (MARD) for FreeStyle Libre Pro® measurements compared with SMBG measurements was calculated as an index of CGM accuracy. Overall blood glucose values measured by SMBG were 167.0 ± 60.1 mg/dL, and those determined by FreeStyle Libre Pro® were 155.0 ± 60.7 mg/dL, with this difference being statistically significant. The MARD for FreeStyle Libre Pro® relative to SMBG was 12.7 ± 9.3%. It was substantially higher in 2 of the 40 patients, at 49.2% and 47.5%, than in the other 38 individuals. MARD values did not differ significantly between before and 2 h after meals. However, the MARD was significantly higher for SMBG values of <100 mg/dL than for those of ≥250 mg/dL. Our results thus indicate that the measurement accuracy of FreeStyle Libre Pro® is relatively good, but that some cases in which values determined by the device deviate from SMBG values require caution in interpretation.

Epidemic Myalgia Associated with Human Parechovirus Type 3 Infection.

A 42-year-old man was hospitalized due to a fever, orchiodynia, and extremely severe myalgia predominantly in the extremities, which made it difficult for him to stand or walk. He had a history of contact with his son who had acute upper respiratory infection. Based on the characteristic clinical symptoms and detection of the partial sequence of human parechovirus type 3 (HPeV3) in throat swabs as well as stool and serum samples, he was diagnosed with epidemic myalgia associated with HPeV3 infection. Because HPeV3 infection is widespread among children in Japan, HPeV3-associated myalgia should be considered when adult patients manifest such distinguishing clinical characteristics.

A case of pulmonary tuberculosis diagnosed in a patient with manifestations of haemophagocytic lymphohistiocytosis.

An 80-year-old woman was admitted with continuous fever, hepatic dysfunction and cytopaenia. The presence of hepatosplenomegaly, hyperferritinaemia, hypofibrinogenaemia and phagocytosis by macrophages in the bone marrow was consistent with a diagnosis of haemophagocytic lymphohistiocytosis (HLH). We suspected that HLH was induced by pre-existing tuberculosis, and antitubercular agents were started. Positive nucleic acid amplification and sputum culture for Mycobacterium tuberculosis resulted in a diagnosis of pulmonary tuberculosis. The patient improved with three months of treatment. In this patient, manifestations of HLH preceded those of pulmonary tuberculosis. A diagnosis of HLH should increase suspicion of disseminated tuberculosis and thus contribute to early detection.