Meta-analyses have revealed that the relative risk of hip fractures in patients with type 1 and type 2 diabetes mellitus is higher than that in non-diabetic subjects. The risk of fracture in patients with diabetes mellitus increases along with a decrease in bone mineral density (BMD) similarly to those in non-diabetic patients. However, the observed risk of fracture is higher than expected one by BMD in both type 1 and type 2 diabetic patients, indicating that precise estimation of bone fragility by BMD values in patients with diabetes is difficult. Bone strength consists of BMD and bone quality, for this reason, poor bone quality is a most suitable and explicable cause for elevated fracture risk in this population. This bone fragility observed in patients with diabetes mellitus is caused by unique pathogenesis in diabetes, suggesting that osteoporosis in diabetic patients may be one of the diabetic complications and that specific diagnostic criteria for this osteoporosis is required. Bone quality indicators closely related to bone fragility are required to be identified to establish a diagnostic method for osteoporosis in patients with diabetes mellitus.

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Obesity is associated with increased risk of developing numerous adverse health conditions. Cathepsin k (CTSK) is highly expressed in adipose tissues of obese patients and animal models. Although CTSK has been demonstrated to promote adipocyte differentiation in 3T3-L1 cells, the effects of CTSK selective inhibitor (CKSI) on weight gain and insulin resistance have not been well examined. High-fat diet (HFD) induced obese male C57BL/6 mice were fed a diet with or without CKSI for 8 weeks. The HFD induced increase in adipose tissue weight gain, increase in homeostasis model assessment (HOMA) index as well as accumulation of large adipocytes. After CKSI treatment, all these effects were blunted compared with the HFD control group. A study of the mechanism demonstrated a role for CKSI in significantly down-regulating the expression of two key transcription factors, peroxisome proliferators-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), which are markers of adipogenic differentiation. These results indicated that the CKSI possesses an anti-obesity effect, possibly involving the inhibition of adipocyte differentiation. CTSK is likely to be a new target of therapeutic intervention for the treatment of obesity.

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We retrospectively detected overt diabetes during pregnancy (ODMP) using a modified IADPSG definition and assessed whether ODMP increases the risk of developing maternal and neonatal complications and postpartum diabetes in Korean pregnant women. According to the definition of IADPSG, ODMP pregnant women were defined and 71 ODMP, 1781 gestational diabetes mellitus (GDM) and and 463 non-GDM pregnant women were included in a hospital-based study. Their blood glucose levels were tightly regulated by modifying lifestyles and insulin treatment. The pregnancy outcomes and postpartum glucose tolerances were determined among the non-GDM, GDM and ODMP groups. The ODMP women had higher plasma glucose levels after overnight-fasting and at 2 h after 100 g OGTT challenge as well as higher overnight-fasted plasma insulin and HbA_1c levels than GDM women. HbA_1c levels at delivery were close to the normal range in both GDM and ODMP groups. Most pregnancy outcomes such as Apgar score and the rate of preterm delivery were not significantly different among three groups. Only the rate of large for gestational age (LGA) was greater in the ODMP group than other groups. However, about 73% of ODMP women remained diabetic at 6-8 week postpartum as compared to 4.3% of GDM. The development of postpartum diabetes was also associated with postpartum waist circumferences and duration of breast feeding. In conclusion, ODMP women in this study maintained tight control of glucose homeostasis and did not experience serious adverse outcomes except for LGA infants; however most ODMP women still had postpartum glucose dysregulation.

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Pancreatic beta-cell mass contributes to glucose tolerance. The aim of this study was to evaluate the relationships between human beta-cell mass and various clinical parameters, including insulin secretory capacity. The study included 32 Japanese patients who underwent pancreatectomy and were naive to oral hypoglycemic agents and insulin. They were classified into those with normal glucose tolerance (n=13), impaired glucose tolerance (n=9) and diabetes (n=10), and their insulin secretory capacity and insulin resistance were evaluated. Immunohistochemistry was used to determine relative beta-cell area (%) which represented the proportion of insulin-positive cell area to whole pancreatic section. Increment of C-peptide immunoreactivity level by glucagon test (ΔC-peptide, increment of serum C-peptide [nmol/L] at 6 min after intravenous injection of 1-mg glucagon; r=0.64, p=0.002), homeostasis model assessment of beta-cell function (HOMA-beta, fasting immunoreactive insulin [μIU/mL] x 20 / (fasting plasma glucose [mmol/L] - 3.5); r=0.50, p=0.003), C-peptide index (CPI, fasting C-peptide [nmol/L] / fasting plasma glucose [mmol/L]; r=0.36, p=0.042), and fasting immunoreactive insulin (F-IRI [pmol/L]; r=0.36, p=0.044) correlated significantly and positively with the relative beta-cell area. The area under the curve of plasma glucose level from 0 to 120 min by 75 g-OGTT (AUC_0-120) also correlated significantly and inversely with the relative beta-cell area (r=-0.36, p=0.045). Stepwise multiple regression analysis identified ΔC-peptide as the only independent and significant determinant of the relative beta-cell area. We conclude that ΔC-peptide, HOMA-beta, CPI, F-IRI and AUC_0-120 correlated closely with the relative beta-cell area, and ΔC-peptide was the most valuable index for the prediction of the area.

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The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet β cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1β in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet β cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

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Insulinoma and insulin or insulin receptor (IR) autoantibodies are the main causes of hyperinsulinemic hypoglycemia in adults, but the exact cause in other cases remains obscure. This study is to determine the genetic basis of hyperinsulinemic hypoglycemia in two cases without the above abnormalities. Sequence analysis of IR gene in two patients with adult-onset hyperinsulinemic hypoglycemia and their relatives were performed, and the mutant gene observed in one case was analyzed. Both cases had normal levels of fasting plasma glucose (FPG), fasting hyperinsulinemia, low insulin sensitivity, and hypoglycemia with excessive insulin secretion during oral glucose tolerance test (OGTT). Both reported adult-onset postprandial hypoglycemic symptoms. In one patient, a missense mutation (Arg256Cys) was detected in both alleles of the IR gene, and his parents had the same mutation in only one allele but no hypoglycemia. The other had a novel nonsense mutation (Trp1273X) followed by a mutation (Gln1274Lys) in one allele, and his 9-year old son had the same mutation in one allele, together with hyperinsulinemic hypoglycemia during OGTT. Overexpression experiments of the mutant gene found in Case 1 in mammalian cells showed abnormal processing of the IR protein and demonstrated reduced function of Akt/Erk phosphorylation by insulin in the cells. In two cases of hyperinsulinemic hypoglycemia in adults, we found novel mutations in IR gene considered to be linked to hypoglycemia. We propose a disease entity of adult-onset hyperinsulinemic hypoglycemia syndrome associated with mutations in IR gene.

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Thyroid carcinoma with distant metastases at initial presentation, is uncommon. Skull metastases occur very rarely, with a reported incidence of 2.5-5.8%. Here we report two cases of follicular thyroid cancer with skull involvement, and describe the diagnostic and therapeutic approach to metastatic thyroid cancer. We present the cases of a 70-year-old female and a 74-year-old female who presented with painless, large slow-growing masses of the skull. The patients underwent surgical excision of the skull masses, which were histologically diagnosed as metastatic follicular thyroid cancer, and total thyroidectomy, which confirmed the diagnosis of follicular thyroid carcinoma. They were treated with radioiodine and suppressive levothyroxine, which achieved local control of the disease. Management of metastatic thyroid cancer, requires a multidisciplinary approach and multimodality treatment. Distant metastases should be surgically removed whenever possible. Initial aggressive treatment is crucial in the management of metastatic thyroid carcinoma, providing the best chance to prolong patient survival.

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We recently established 2 mouse lines with different susceptibilities (prone and resistant) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R], respectively). In the present study, we analyzed transgenerational changes in metabolic phenotypes in these 2 mouse colonies to explore how the distinct phenotypes have emerged through the repetitive selection. Using C57BL/6, C3H, and AKR as background strains, mice showing inferior and superior glucose tolerance after HFD feeding were selected and bred repetitively over 20 generations to produce SDG-P and SDG-R, respectively. In addition to the blood glucose levels, HFD intake and body weight were also measured over the selective breeding period. As the generations proceeded, SDG-P mice became more susceptible to HFD-induced glucose intolerance and body weight gain, whereas SDG-R mice had gradually reduced HFD intake. The differences in fasting and post-glucose challenge blood glucose levels, body weight, and HFD intake became more evident between the 2 colonies through the selective breeding, mainly due to the HFD-induced glucose metabolism impairment and body weight gain in SDG-P mice and the reduction of HFD intake in SDG-R mice. These transgenerational changes in the metabolic phenotypes suggest that the genetic loci associated with the quantitative traits have been selectively enriched in SDG-P and SDG-R.

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Agents that stimulate human pancreatic beta cell proliferation are needed to improve diabetes mellitus treatment. Recently, a small molecule, WS6, was observed to stimulate human beta cell proliferation. However, little is known about its other effects on human islets. To better understand the role of WS6 as a possible beta cell regenerative therapy, we carried out in-depth phenotypic analysis of WS6-treated human islets, exploring its effects on non-beta cell proliferation, beta cell differentiation, and islet cell viability. WS6 not only stimulated beta cell proliferation in cultured human islets (in agreement with previous reports), but also human alpha cell proliferation, indicating that WS6 is not a beta cell-specific mitogen. WS6 did not change the proportion of insulin-positive beta cells or the expression of beta cell-specific transcription factors, suggesting that WS6 does not alter beta cell differentiation, and WS6 had no effect on human islet cell apoptosis or viability. In conclusion, WS6 stimulates proliferation of both human beta and alpha cells while maintaining cellular viability and the beta cell differentiated phenotype. These findings expand the literature on WS6 and support the suggestion that WS6 may help increase human islet mass needed for successful treatment of diabetes.

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In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K⁺ (K_ATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 μL aliquot of 340 μM K_ATP channel opener diazoxide or 100 μM K_ATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the K_ATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered K_ATP channel activity.

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