Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to type 2 diabetes mellitus (T2DM) and insulin resistance (IR). We hypothesized that the difference in genotype may be one of the factors that affect the outcome of intervention. We genotyped 448 men with fasting glucose≥5.6 mM/L, including 371 in subjects with K allele (KK) (69 control group [CG]; and 302 intervention group [IG]) and 77 in subjects with Q allele (KQ+QQ) (13 CG and 64 IG). The web-based intervention based on a lifestyle modification was delivered by e-mail once a month for 10 months. In the KK, IG demonstrated significantly decreased levels of fasting serum insulin (FSI) as compared to CG and homeostasis model of assessment of insulin resistance (HOMA-IR). In the KQ+QQ IG group, hemoglobin A1c (HbA1c), FSI and HOMA-IR were significantly decreased, and showed further reduction in the HOMA-IR than KQ+QQ CG. After analysis of covariance, K121Q did significantly influence the change of HbA1c in CG after appropriate adjustment. In a multivariate model, BMI change predicted HOMA-IR change (adjusted β=0.801; P=0.022) in KK IG subjects with T2DM. ENPP1 K121Q did not influence the change in IR. However, individuals with T2DM carrying the K121 variant are very responsive to the effect of BMI reduction on HOMA-IR.Graphical Abstract

We report three cases of iron deficiency anemia due to long-time bloodletting using cupping. Case 1 was a 52-year-old man who sought evaluation at the Health Promotion Center in our hospital due to fatigue and dyspnea on exertion (DOE). There were no abnormal findings on his general health examination, except anemia. He has performed self-bloodletting for a long time with cupping on his back and extremities for fatigue, myalgias, or polyarthralgias. Case 2 was a 52-yearold woman with fatigue and DOE. The physical examination revealed a systolic murmur at her left lower anterior chest and pale conjunctiva. The initial hematocrit was 22.4% and the hemoglobin was 6.4 g/dL. She has self-bloodletted using cupping 2 to 3 times a week when she felt tired or had myalgias. Case 3 was a 35-year-old man with sudden onset fatigue and DOE. He had severe DOE during a challenging physical test. He frequently received bloodletting using cuppings on his back and extremities by a doctor of Oriental medicine. There were no abnormal findings on the general health examination, except anemia. All three patients were diagnosed with iron deficiency anemia due to chronic blood loss. We recommended stopping bloodletting using cupping and prescribed oral iron supplements.