Serum 25-hydroxyvitamin D cutoffs for functional bone measures in postmenopausal osteoporosis.

This study sought to determine the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health in postmenopausal women with low bone mass. A serum 25(OH)D concentration of 20 ng/mL rather than 30 ng/mL was appropriate for bone health. INTRODUCTION: There is no consensus on the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health. The aim of this study was to investigate the relationship between 25(OH)D measured via liquid chromatography-mass spectrometry (LC-MS/MS), which is the current gold standard, and biochemical markers of bone turnover, PTH, and bone mineral densitometry (BMD). METHODS: The medical records of 750 postmenopausal women newly diagnosed with osteoporosis or osteopenia at Samsung Medical Center from 2009 to 2014 were investigated. Subjects were divided into four groups according to serum 25(OH)D concentration: <10, 10-20, 20-30, and ≥30 ng/mL. Serum concentrations of bone-specific alkaline phosphatase (BS-ALP), carboxy-terminal cross-linking telopeptide of type 1 collagen (CTx), intact PTH (iPTH), and BMD were compared among the four groups using analysis of covariance. Thresholds of 25(OH)D were then assessed using spline plots and locally weighted regression smoothing (LOESS) plots. RESULTS: 25(OH)D was negatively correlated with serum BS-ALP, CTx, and iPTH. Only femur neck and total femur BMD had significant positive relationships with 25(OH)D. Cutoff values of 11.9 and 9.7 ng/mL were estimated from the spline plots of femur neck and total femur BMD, respectively. For iPTH, the LOESS plot showed a steep decrease to a serum 25(OH)D concentration of about 20 ng/mL, followed by a plateau. CONCLUSIONS: According to this study, a serum 25(OH)D concentration of 20 ng/mL, rather than 30 ng/mL, was appropriate for bone health.

Effect of high dietary sodium on bone turnover markers and urinary calcium excretion in Korean postmenopausal women with low bone mass.

BACKGROUND/OBJECTIVES: High salt intake is a well-recognized risk factor of osteoporosis for its modulating effect on calcium metabolism. To understand the effect of dietary sodium on bone turnover, we evaluated the association between urinary sodium excretion and bone turnover markers in Korean postmenopausal women with low bone mass. SUBJECTS/METHODS: A retrospective review of medical records at a single institution identified 537 postmenopausal women who were first diagnosed with osteopenia or osteoporosis between 2008 and 2013. Subjects were stratified by low (<2 g/day, n=77), moderate (2-4.4 g/day, n=354) and high (⩾4.4 g/day, n=106) sodium excretion. A 24-h urine was collected to estimate sodium, calcium and creatinine. Bone turnover markers and calciotropic hormones were measured in serum. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry. RESULTS: Sodium intake was positively associated with urinary sodium excretion (P=0.006, r=0.29). Bone turnover markers were significantly higher in the moderate-to-high urinary sodium excretion group (⩾2 g/day) than in the low urinary sodium excretion group (<2 g/day); CTX-I (C-telopeptides of type I collagen) was 21.3% higher (P=0.001) and osteocalcin (OC) was 15.7% higher (P=0.004). Calciotropic hormones and BMD were not significantly different across the sodium excretion groups. CONCLUSIONS: High urinary sodium excretion (⩾2 g/day) increased bone turnover markers in Korean postmenopausal women, suggesting that excessive sodium intake might accelerate bone turnover.

Association between the extent of urinary albumin excretion and glycaemic variability indices measured by continuous glucose monitoring.

AIMS: The contribution of glycaemic variability to the microvascular complication of diabetes has not been established. We examined whether there is an independent association between indices of glycaemic variability in continuous glucose monitoring and extent of albuminuria. METHODS: A total of 173 patients with Type 2 diabetes (without insulin therapy, n = 96; with insulin therapy, n = 77) who had unexplained large fluctuations in blood glucose values underwent three-day continuous glucose monitoring. We used a multinomial logistic regression model to determine whether the indices of glycaemic variability independently affected the odds of having a spot urine albumin/creatinine ratio of 30-299 mg/g and ≥ 300 mg/g. RESULTS: Higher standard deviation (P = 0.002), mean of daily differences (P = 0.023) and mean amplitude of glycaemic excursion (P = 0.043) significantly increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g. In multivariable analysis, only higher standard deviation, but not mean amplitude of glycaemic excursion and mean of daily differences, independently increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g (P = 0.025). Coefficient of variation (sd/mean) was not associated with the odds of having a urine albumin/creatinine ratio of 30-299 or ≥ 300 mg/g. CONCLUSIONS: The independent association between standard deviation and the extent of albuminuria was lost when the measures were normalized by mean glucose level. At least in terms of relative measures of glycaemic variability, we failed to demonstrate an independent association between glycaemic variability and albuminuria extent in patients with inadequately controlled Type 2 diabetes.

Gastric bypass in Type 2 diabetes with BMI < 30: weight and weight loss have a major influence on outcomes.

AIM: To assess factors influencing glycaemic control following gastric bypass surgery in patients with Type 2 diabetes and BMI< 30 kg/m(2) . METHODS: Prospective longitudinal study of 103 patients with inadequate glycaemic control who underwent gastric bypass surgery at Soonchunhyang University, Seoul, Korea (n = 66) and Min-Sheng General Hospital, Taipei, Taiwan (n = 37). Procedures were performed August 2009 to January 2011. Key outcome measures were excellent glycaemic control of Type 2 diabetes defined as HbA1c < 42 mmol/mol (≤6%); inadequate response defined as HbA1c > 53 mmol/mol (> 7%). Analysis was conducted using binary logistic regression, and cut-points obtained from receiver operator characteristics. RESULTS: Excellent glycaemic control was achieved in 31 (30%) at 1 year. Diabetes duration of < 7 years and BMI > 27 kg/m(2) provided independent predictors and useful cut-points. Likelihood of excellent glycaemic control for an individual could be estimated using loge (Odds) = -6.7 + (0.26 × BMI) + (-1.2 × diabetes duration). Baseline BMI of < 27 kg/m(2) and baseline C-peptide of < 2.0ng/ml, best predicted a poor glycaemic response. In those with favourable baseline characteristics percentage weight loss (%WL) had a dominant influence on glycaemic outcomes. Baseline C-peptide (> 2.4 ng/ml) and subsequent percentage weight loss (> 16%) were associated with excellent glycaemic control. Higher BMI was associated with greater percentage weight loss. CONCLUSION: In patients with Type 2 diabetes and BMI < 30 kg/m(2) , glycaemic response to gastric bypass is predicted by higher baseline BMI, shorter disease duration and higher fasting C-peptide. Post-surgery weight loss has a dominant effect. Baseline BMI and weight loss have a major influence on outcomes.

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice.

AIMS/HYPOTHESIS: The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes. METHODS: Rat insulin promoter (RIP)-Cre(+);autophagy-related 7 (Atg7)(F/W) mice were bred with ob/w mice to derive RIP-Cre(+);Atg7(F/F)-ob/ob mice and to induce ER stress in vivo. GFP-LC3(+)-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine. RESULTS: Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85ß regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced. CONCLUSIONS/INTERPRETATION: These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

Role of autophagy in ß-cell function and mass.

Type 2 diabetes (T2D) is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in pancreatic ß-cell mass and/or function. Apoptosis, oxidative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress responses including JNK activation have been suggested as mechanisms for the changes of pancreatic ß-cells in T2D; however, the underlying causes were not clearly elucidated. Autophagy is an intracellular process that plays crucial roles in cellular homeostasis through degradation and recycling of organelles. We have reported increased apoptosis and decreased proliferation of ß-cells with resultant reduction in the ß-cell mass in ß-cell-specific autophagy-deficient mice. Morphological analysis of ß-cells revealed accumulation of ubiquitinated proteins, swollen mitochondria and distended ER. Insulin secretory function ex vivo was also impaired. As a result, ß-cell-specific autophagy-deficient mice showed hypoinsulinaemia and hyperglycaemia. These results suggested that autophagy is necessary to maintain the structure, mass and function of pancreatic ß-cells. In addition, as autophagy may play a protective role against ER stress and rejuvenates organelle function, impaired autophagy may lead to mitochondrial dysfunction and ER stress, which have been implicated as potential causes of insulin resistance. Therefore, in addition to ß-cell homeostasis, dysregulated autophagy may possibly be involved in diverse aspects of the pathogenesis of diabetes.