Linear and Non-linear Correlations Between Serum Phosphate Level and Bone Mineral Density in Type 2 Diabetes.

Introduction: Serum phosphate plays an important role in bone mineralization and might be a risk factor for many bone diseases. Patients with T2D usually have low serum phosphate level due to diet control, osmotic diuresis, and insulin stimulation. Current studies have discussed the linear association between serum phosphate and bone mineral density (BMD). Objective: We aimed to analyze both the linear and non-linear correlations between serum phosphate and BMD in patients with type 2 diabetes (T2D). Methods: We included 1,469 patients with T2D and obtained their basic information, laboratory measurements, and BMD data. Multivariate adjusted linear regression was used to analyze the linear associations, and we applied a two-piecewise linear regression model using a smoothing function to examine the non-linear association. Results: No linear correlation was found between serum phosphate and BMD in patients with T2D. In women with T2D, we found a non-linear correlation between serum phosphate level and femur neck or total hip BMD. When serum phosphate was <1.3 mmol/L, it was positively associated with femur neck and total hip BMD, whereas when phosphate was >1.3 mmol/L, it was negatively associated with femur neck BMD. Conclusions: In men with T2D, serum phosphate level was not associated with BMD. However, in women with T2D, we found a non-linear correlation between serum phosphate and femur neck or total hip BMD.

Prospect of Sodium-Glucose Co-transporter 2 Inhibitors Combined With Insulin for the Treatment of Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new family of antidiabetic drugs that reduce blood glucose independent of insulin. In this review, we present the advantages and adverse effects of SGLT2 inhibitors plus insulin therapy as a treatment regimen for patients with type 2 diabetes (T2D). Compared with placebo, SGLT2 inhibitors plus insulin therapy could significantly decrease fasting blood glucose and HbA1c, thereby reducing the daily required dose of insulin. A reduction in body weight and improvements in insulin resistance and ß-cell function have also been widely reported with this therapy, and other potential advantages, including the reduction in blood pressure, adverse cardiovascular outcomes, and visceral adipose tissue volume, have been revealed. SGLT2 inhibitors cause a greater reduction than dipeptidyl peptidase-4 (DPP-4) inhibitors in body weight and the risk of cardiovascular disease. Furthermore, compared with glucagon-like peptide-1 (GLP-1) agonists, SGLT2 inhibitors reduce blood pressure, and heart failure. As this therapy is an oral preparation, an improvement in patient compliance is also achieved. Despite these advantages, however, combination therapy with SGLT2 inhibitors and insulin has several risks. Although no difference has been found in the incidence of hypoglycemic events and urinary tract infection between the administration of this combination and that of placebo, the risk of genital tract infections was reported to increase with the combination therapy. Additionally, bone adverse effects, euglycemic diabetic ketoacidosis, and volume depletion-and osmotic diuresis-related adverse effects have been observed. Altogether, we could conclude that SGLT2 inhibitors plus insulin therapy is an efficient treatment option for patients with T2D, especially those requiring high daily insulin doses and those with insulin resistance, obesity, and a high risk of cardiovascular events. However, careful monitoring of the adverse effects of this combination is also warranted.

A retrospective cohort study of preoperative lipid indices and their impact on new-onset diabetes after liver transplantation.

BACKGROUND: The correlation between preoperative lipid profiles and new-onset diabetes after transplantation (NODAT) remains relatively unexplored in liver transplant recipients (LTRs). Thus, we aimed to investigate the preoperative lipid profiles in Chinese LTRs and evaluate the different influences of preoperative total cholesterol, total triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol on the development of NODAT in both sexes. METHODS: A total of 767 Chinese LTRs from Zhongshan Hospital were retrospectively evaluated. NODAT was defined according to the American Diabetes Association guidelines; the relationship between each preoperative lipid index and NODAT development was analyzed separately in men and women. RESULTS: Pretransplant hypotriglyceridemia was observed in 35.72% of the total LTRs. In men, only the preoperative TG level was significantly associated with incident NODAT after adjusting for potential confounders (hazard ratio 1.37, 95% confidence interval 1.13-1.66, P = .001). There was a nonlinear relationship between the preoperative TG level and NODAT risk. The risk of NODAT significantly increased with preoperative a TG level above 0.54 mmol/L (log-likelihood ratio test, P = .043). In women, no significant association was observed. CONCLUSION: Among male LTRs, a higher preoperative TG level, even at a low level within the normal range, was significantly and nonlinearly associated with an increased risk of NODAT.

Association between serum levels of bone turnover markers and bone mineral density in men and women with type 2 diabetes mellitus.

BACKGROUND: In patients with type 2 diabetes mellitus (T2DM), higher risks of impaired bone metabolism are widely reported. To evaluate bone metabolism, bone mineral density (BMD) and bone turnover levels should be included. In this article, we analyzed the relationship between them in T2DM. METHODS: We conducted a hospital-based cross-sectional study enrolling 1499 patients hospitalized for T2DM between October 2009 and January 2013. Multivariate linear regression models were used to identify the relationship between bone turnover markers (BTMs) and BMD levels. A two-sided P-value < .05 was considered statistically significant. RESULTS: After adjusting for confounding factors, osteocalcin (OC) showed a negative relationship with total lumbar, femur neck, and total hip BMD in men and women. N-terminal propeptides of type I collagen (P1NP) and alkaline phosphatase (ALP) showed a negative association with BMD at three sites in men and total lumbar BMD in women, whereas in the femur neck and total hip in women, the relationship was only found for P1NP with total hip. For ß-C-terminal telopeptides of type I collagen (ß-CTX), a negative relationship was also found in all three sites for BMD in men and total lumbar BMD in women, whereas ß-CTX was not associated in the femoral neck and total hip in women. CONCLUSION: In patients with T2DM, serum levels of OC, P1NP, ß-CTX, and ALP were negatively correlated with BMD levels in men in three sites and with total lumbar BMD in women. The relationship varied in femur neck and total hip BMD in women.

Effects of preoperative hepatitis B virus infection, hepatitis C virus infection, and coinfection on the development of new-onset diabetes after kidney transplantation.

BACKGROUND: The effects of preoperative hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and HBV plus HCV coinfection on the development of new-onset diabetes after transplantation (NODAT) remain unexplored in kidney transplant recipients (KTRs). This study examined the association between preoperative viral status (i.e., HBV, HCV, and HBC + HCV infection) and incident NODAT in a large population of Chinese KTRs. METHODS: This population-based retrospective cohort study enrolled 557 subjects who underwent kidney transplantation between 1993 and 2014 at Zhongshan Hospital. Pre-, peri-, and postoperative data were extracted and analyzed. Viral status was defined by serological results for hepatitis B surface antigen and anti-HCV antibody. The cumulative incidence of NODAT was compared across four groups of KTRs with different viral status. Multivariate Cox regression models were used to estimate the effects of HBV, HCV, and HBC + HCV infection on incident NODAT after adjusting for important confounders. RESULTS: Patients seropositive for HCV (both HCV monoinfection and HBC + HCV coinfection) had a significantly higher cumulative incidence of NODAT than KTRs who were not infected with HCV (P < 0.05 for both). However, only HCV infection alone was found to be a risk factor for NODAT, increasing the NODAT risk 3.03-fold (95% confidence interval 1.77-5.18; P < 0.001). There was no independent correlation between HBV infection (alone or combined with HCV) and incident NODAT in KTRs. CONCLUSIONS: Preoperative HCV infection significantly increased the risk of NODAT in Chinese KTRs, whereas HBV infection and HBC + HCV coinfection were not correlated with NODAT development.

Association Between Bone Mineral Density, Bone Turnover Markers, and Serum Cholesterol Levels in Type 2 Diabetes.

Purpose: The association between bone mineral density (BMD), bone turnover markers, and serum cholesterol in healthy population has already been proved. However, in patients with type 2 diabetes mellitus (T2D), it has not been adequately analyzed. In this study, we investigated the correlation between BMD, bone turnover markers, and serum cholesterol levels in people with T2D. Methods: We enrolled 1,040 men and 735 women with T2D from Zhongshan Hospital between October 2009 and January 2013. Their general condition, history of diseases and medication, serum markers, and BMD data were collected. We used logistic regression analysis to identify the association between serum cholesterol levels and BMD as well as bone turnover markers. Results: In multivariate regression analysis, we observed that in men with T2D, high high-density lipoprotein-cholesterol and total cholesterol levels were significantly associated with low total lumbar, femur neck, and total hip BMD, while low-density lipoprotein-cholesterol level was only inversely associated with total lumbar and femur neck BMD. Total cholesterol and low-density lipoprotein-cholesterol levels were also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and ß-crosslaps. In women with T2D, high-density lipoprotein-cholesterol level was observed to be negatively correlated with total lumbar, femur neck, and total hip BMD, while total cholesterol and low-density lipoprotein-cholesterol levels were only associated with BMD at the total lumbar. Furthermore, total cholesterol was also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and ß-crosslaps; high-density lipoprotein-cholesterol was only related to osteocalcin and parathyroid hormone, while low-density lipoprotein-cholesterol was only related to ß-crosslaps in women. Conclusion: Our study suggests a significantly negative correlation between serum cholesterol levels and BMD in both men and women with T2D. The associations between serum cholesterol levels and bone turnover markers were also observed in T2D patients.

Interleukin-2 receptor antagonists: Protective factors against new-onset diabetes after renal transplantation.

BACKGROUND: The aim of the present study was to examine the association between interleukin-2 receptor antagonists (IL-2Ra) and new-onset diabetes after transplantation (NODAT) among renal transplant recipients (RTRs). METHODS: Between January 1993 and March 2014, 915 patients underwent renal transplantation at Zhongshan Hospital. In all, 557 RTRs were included in the present retrospective cohort study. The incidence of NODAT in this cohort was determined and multivariate Cox regression analysis was used to evaluate the risk factors for NODAT and to show the association between IL-2Ra use and NODAT development among RTRs. The cumulative incidence of NODAT was compared between groups treated with or without IL-2Ra. RESULTS: The mean ±SD postoperative follow-up was 5.08 ±3.17 years. The incidence of NODAT at the end of follow-up was 20.3%. After adjusting for potential confounders in the multivariate logistic regression (i.e. age, sex, body mass index, history of smoking, family history of diabetes, duration of dialysis, type of dialysis, donor type, recovery of graft function, acute rejection, hepatitis B or C or cytomegalovirus infection, fasting plasma glucose levels before and 1 week after transplantation, preoperative total cholesterol and triglyceride levels, daily dose of glucocorticoid, immunosuppressive regimen type, and immunosuppressant concentration after transplantation), IL-2Ra use was found to be related to a reduced incidence of NODAT. CONCLUSIONS: Use of IL-2Ra is associated with protection against the development of NODAT in RTRs.

Effect of Sodium-Glucose Co-transporter 2 Inhibitors on Bone Metabolism and Fracture Risk.

The effect of anti-diabetic medications on bone metabolism has received increasing attention, considering that type 2 diabetes mellitus is a common metabolic disorder with adverse effects on bone metabolism. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel anti-diabetic medications that prevent glucose resorption at the proximal convoluted tubules in the kidney, increasing urinary glucose excretion, and decreasing the blood glucose level. The superiority of SGLT2 inhibitors shows in reducing the glucose level independent of insulin secretion, lowering the risk of hypoglycemia, and improving cardiovascular outcomes. SGLT2 inhibitors have been associated with genital mycotic infections, increased risk of acute kidney injury, dehydration, orthostatic hypotension, and ketoacidosis. Moreover, the effect of SGLT2 inhibitors on bone metabolism and fracture risk has been widely taken into consideration. Our review summarizes the results of current studies investigating the effects of SGLT2 inhibitors on bone metabolism (possibly including increased bone turnover, disrupted bone microarchitecture, and reduced bone mineral density). Several mechanisms are probably involved, such as bone mineral losses due to the disturbed calcium and phosphate homeostasis, as confirmed by an increase in fibroblast growth factor 23 and parathyroid hormone levels and a decrease in 1,25-dihydroxyvitamin D levels. SGLT2 inhibitors might indirectly increase bone turnover by weight loss. Lowering the blood glucose level might ameliorate bone metabolism impairment in diabetes. The effect of SGLT2 inhibitors on bone fractures remains unclear. Evidence indicating the direct effect of SGLT2 inhibitors on fracture risk is lacking and increased falls probably contribute to fractures.

Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms.

Diabetes mellitus has been demonstrated to be closely associated with osteoporosis. Accordingly, hypoglycemic therapy is considered effective in treating metabolic bone disease. Recently, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors, a new type of antidiabetic drug, on bone metabolism have been widely studied. This review mainly describes the effects of DPP-4 inhibitors on bone metabolism, including their effects on bone mineral density, bone quality, and fracture risk. In addition, the potential underlying mechanisms are discussed. Based on the current progress in this research field, DPP-4 inhibitors have been proved to reduce fracture risk. In addition, sitagliptin, a strong and highly selective DPP-4 inhibitor, showed its beneficial effects on bone metabolism by improving bone mineral density, bone quality, and bone markers. With regard to the potential underlying mechanisms, DPP-4 inhibitors may promote bone formation and reduce bone resorption through DPP-4 substrates and DPP-4-related energy metabolism. Vitamin D and other related signaling pathways also play a role in affecting bone metabolism. Although these assumptions are controversial, they provide a translational pharmacology approach for the clinical use of DPP-4 inhibitors in the treatment of metabolic diseases. Prior to the use of these drugs in clinic, further studies should be conducted to determine the appropriate type of DPP-4 inhibitor, the people who would benefit the most from this therapy, appropriate dose and duration, and the effects of the treatment.

The Impact of Glucagon-Like Peptide-1 on Bone Metabolism and Its Possible Mechanisms.

The impact of antidiabetic drugs on bone metabolism is drawing increasing attention due to the discovery of a correlation between type 2 diabetes mellitus (T2DM) and osteoporosis. Glucagon-like peptide-1 (GLP-1) receptor agonists are a novel and promising class of drugs for T2DM, which may also have clinical applications in bone tissue disorders. This review examines the impact of GLP-1 on bone metabolism, including enhancement of bone mineral density and improvement of bone quality. However, the precise effect of GLP-1 on fracture risk has not been unambiguously defined. This review also summarizes our current understanding of the mechanisms by which GLP-1 affects bone metabolism. GLP-1 may act on bone by promoting bone formation, inhibiting bone resorption, and affecting the coordination of the two processes. We describe molecular pathways and proteins, such as Wnt and calcitonin, that are associated with GLP-1 and bone tissue. The specific processes and related molecular mechanisms of the effects of GLP-1 on bone metabolism need to be further explored and clarified.

Donor liver steatosis: A risk factor for early new-onset diabetes after liver transplantation.

AIMS/INTRODUCTION: To investigate whether donor liver steatosis increases the incidence of new-onset diabetes after transplantation (NODAT) in liver transplant recipients. MATERIALS AND METHODS: We retrospectively analyzed liver transplant recipients at Zhongshan Hospital, Shanghai, China, from April 2001 to December 2014. The final analysis involved 763 patients. The cumulative incidence of NODAT at 1, 3, 5 and 10 years after liver transplantation was investigated. Furthermore, according to the findings of donor liver biopsy before transplantation, patients were divided into steatotic and non-steatotic donor liver groups, and NODAT incidence was compared between these groups. Multivariate Cox regression was used to explore the risk factors for NODAT in the patients. RESULTS: Of the 763 donors, 309 (40.5%) had liver steatosis. At the end of follow up, 130 (42.1%) patients in the steatotic donor liver group developed NODAT, an incidence that exceeded that in the non-steatotic donor liver group (P = 0.001). The cumulative incidence of NODAT among all patients at 1, 3, 5, and 10 years after transplantation was 33, 43, 50 and 56%, respectively. The cumulative incidences of NODAT at 1, 3, 5 and 10 years in the steatotic donor liver group were significantly higher than those in the non-steatotic donor liver group (P = 0.003). Multivariate Cox regression analyses showed that donor liver steatosis was an independent risk factor for NODAT among liver transplant recipients, after other potential risk factors were adjusted for (hazard ratio 1.774, 95% confidence interval: 1.025-3.073; P = 0.041). CONCLUSIONS: Donor liver steatosis increases NODAT incidence among liver transplant recipients.