There is controversy regarding the roles of bone marrow (BM)-derived cells in pancreatic β-cell regeneration. To examine these roles in vivo, mice were treated with streptozotocin (STZ), followed by bone marrow transplantation (BMT; lethal irradiation and subsequent BM cell infusion) from green fluorescence protein transgenic mice. BMT improved STZ-induced hyperglycemia, nearly normalizing glucose levels, with partially restored pancreatic islet number and size, whereas simple BM cell infusion without preirradiation had no effects. In post-BMT mice, most islets were located near pancreatic ducts and substantial numbers of bromodeoxyuridine-positive cells were detected in islets and ducts. Importantly, green fluorescence protein-positive, i.e. BM-derived, cells were detected around islets and were CD45 positive but not insulin positive. Then to examine whether BM-derived cell mobilization contributes to this process, we used Nos3−/− mice as a model of impaired BM-derived cell mobilization. In streptozotocin-treated Nos3−/− mice, the effects of BMT on blood glucose, islet number, bromodeoxyuridine-positive cells in islets, and CD45-positive cells around islets were much smaller than those in streptozotocin-treated Nos3+/+ controls. A series of BMT experiments using Nos3+/+ and Nos3−/− mice showed hyperglycemia-improving effects of BMT to correlate inversely with the severity of myelosuppression and delay of peripheral white blood cell recovery. Thus, mobilization of BM-derived cells is critical for BMT-induced β-cell regeneration after injury. The present results suggest that homing of donor BM-derived cells in BM and subsequent mobilization into the injured periphery are required for BMT-induced regeneration of recipient pancreatic β-cells.

Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nε-(carboxymethyl) lysine and 3-deoxyglucosone. Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects.

Pharmacological treatments to decrease low-density lipoprotein (LDL) cholesterol (LDL-C) have limited effects on patients with homozygous familial hypercholesterolemia (HoFH). Since LDL receptors are located mainly in the liver, liver transplantation is considered to be the only way to correct the hepatic cholesterol metabolism abnormalities in HoFH. Liver transplantations, including those combined with heart transplantation, for HoFH have been increasing since 1984, making this a globally established therapeutic option for HoFH. Plasma LDL-C is reported to be dramatically lowered, by 80%, after transplantation, with the rapid regression of cutaneous and tendinous xanthomas. However, long-term cardiovascular benefits remain unclear. The major concerns about liver transplantation include surgical complications, the need for lifelong immunosuppressive therapy, and rejection. In addition, organ transplantations from deceased donors are extremely rare in Japan. We experienced two pediatric siblings with HoFH who received living-donor liver transplantations from their heterozygous parents. Their plasma LDL-C levels decreased immediately and stabilized at approximately 200 mg/dL. Both developed normally with the administration of lipid-lowering medications and have been free of severe problems for more than 10 years, to date, since transplantation. In Japan, where the shortage of deceased donors is critical, the combination of living-donor liver transplant from a heterozygous donor, that is, usually a parent, and medication is regarded as a valid therapeutic option for HoFH. Further studies and clinical experience are required to establish liver transplantation as a safe and effective treatment for HoFH.

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

This study aimed to assess the relationship between the metabolic effect after laparoscopic sleeve gastrectomy (LSG) in morbidly obese Japanese patients, with or without type 2 diabetes mellitus (T2DM), and improved pancreatic steatosis (PS). The study enrolled 27 morbidly obese Japanese patients who were undergoing LSG. Their clinical and metabolic effects were evaluated at baseline and six months after LSG. Pancreas volume (PV), pancreatic attenuation (PA), and splenic attenuation (SA) were measured using a 64-row computed tomography (CT). Changes in PV, PA-SA, and PA/SA were evaluated. The mean body-weight loss, body mass index loss, and percentage of excess weight loss (%EWL) were -34.4 kg (p < 0.001), -11.0 kg/m2 (p < 0.001), and 43.7%, respectively. The mean PV was 96.7 mL at baseline, and it decreased six months after LSG (-16.3mL, p < 0.001). The mean PA significantly increased six months after LSG (9.5 HU, p < 0.001). PA-SA (-23.2 HU vs. -13.3 HU, p = 0.003), and PA/SA (0.54 vs. 0.73, p < 0.001) also significantly increased six months after LSG. In T2DM patients, decreased PV correlated with decreased fasting blood sugar, decreased insulin, and reduced liver volume. In conclusion, PV significantly decreased after LSG in morbidly obese Japanese patients, and that decrease correlated with improvements in PS. In addition, PS plays an important role of development and progression of insulin resistance and T2DM.