FRAX (Australia) scores in women with impaired fasting glucose and diabetes.

BACKGROUND: Diabetes is associated with higher fracture risk despite higher bone mineral density (BMD), with FRAX® underestimating risk. This study aimed to investigate FRAX score with and without BMD for women with normoglycaemia, impaired fasting glucose (IFG) and diabetes. METHODS: Among 566 women, aged 40-90 years, enrolled in the Geelong Osteoporosis Study, IFG was defined as fasting plasma glucose (FPG) ≥5.5 mmol/L and diabetes as FPG ≥ 7.0 mmol/L, use of antihyperglycaemic medication and/or self-report. FRAX (Australia) 10-year probabilities of major osteoporotic (MOF) and hip fracture were calculated, with and without BMD, producing four FRAX scores per participant. Kruskal-Wallis test for non-parametric data was used to examine differences between the three glycaemia groups. Fractures over 10 years were ascertained using radiological reports. The number of fractures predicted by FRAX was compared with the number of fractures observed using Chi-square tests. RESULTS: For MOF FRAX calculated without BMD, women with diabetes (n = 67) tended to have a higher median score 7.1 (IQR 2.7-12.0) than normoglycaemia (n = 252) (4.3 (IQR 1.9-9.9) and IFG (n = 247) (5.1 (IQR 2.2-9.6)). For hip FRAX without BMD, diabetes tended to have a higher score (2.5 (IQR 06-4.3)) than normoglycaemia (1.2 (IQR 0.3-4.1)) and IFG (1.3 (IQR 0.3-4.1)). In the normoglycaemia and IFG groups, MOFs were underestimated; 15 predicted vs 28 observed, p = 0.038; and 16 predicted vs 31 observed, p = 0.021, respectively. Fractures were accurately estimated in all other groups.When including BMD, the association with diabetes was non-significant for both MOF FRAX (normoglycaemia 3.7 (IQR 1.9-8.0), IFG 4.3 (IQR 2.2-8.1) and diabetes 5.3 (IQR 2.7-9.4)) and hip FRAX scores (normoglycaemia 0.6 (IQR 0.2-2.5), IFG 0.8 (IQR 0.2-2.7) and diabetes 1.0 (IQR 0.3-3.0)). For normoglycaemia and IFG, MOFs were underestimated (normoglycaemia: 13 predicted vs 28 observed and IFG: 13 vs 31). For diabetes, both MOFs and hip fractures tended to be underestimated by FRAX with BMD (MOF: 4 predicted vs 11 observed, p = 0.055, hip: 1 predicted vs 6 observed, p = 0.052). Hip fractures were accurately estimated in the normoglycaemia and IFG groups. CONCLUSIONS: Compared with women who had normoglycaemia or IFG, women with diabetes tended to have a higher FRAX score for both MOF and hip fractures when BMD was not included. When BMD was included, there was no difference. Fractures in diabetes tended to be underestimated by FRAX with BMD. This suggests that FRAX calculations including BMD may not be accurate for estimating fractures in those with diabetes.

Association between area-level socioeconomic status, accessibility and diabetes-related hospitalisations: a cross-sectional analysis of data from Western Victoria, Australia.

OBJECTIVE: Hospitalisation rates for many chronic conditions are higher in socioeconomically disadvantaged and less accessible areas. We aimed to map diabetes hospitalisation rates by local government area (LGA) across Western Victoria, Australia, and investigate their association with socioeconomic status (SES) and accessibility/remoteness. DESIGN: Cross-sectional study METHODS: Data were acquired from the Victorian Admitted Episodes Dataset for all hospitalisations (public and private) with a diagnosis of type 1 or type 2 diabetes mellitus during 2011-2014. Crude and age-standardised hospitalisation rates (per 1000 population per year) were calculated by LGA for men, women and combined data. Associations between accessibility (Accessibility/Remoteness Index of Australia, ARIA), SES (Index of Relative Socioeconomic Advantage and Disadvantage, IRSAD) and diabetes hospitalisation were investigated using Poisson regression analyses. RESULTS: Higher LGA-level accessibility and SES were associated with higher rates of type 1 and type 2 diabetes hospitalisation, overall and for each sex. For type 1 diabetes, higher accessibility (ARIA category) was associated with higher hospitalisation rates (men incidence rate ratio [IRR]=2.14, 95% CI 1.64 to 2.80; women IRR=2.45, 95% CI 1.87 to 3.19; combined IRR=2.30, 95% CI 1.69 to 3.13; all p<0.05). Higher socioeconomic advantage (IRSAD decile) was also associated with higher hospitalisation rates (men IRR=1.25, 95% CI 1.09 to 1.43; women IRR=1.32, 95% CI 1.16 to 1.51; combined IRR=1.23, 95% CI 1.07 to 1.42; all p<0.05). Similarly, for type 2 diabetes, higher accessibility (ARIA category) was associated with higher hospitalisation rates (men IRR=2.49, 95% CI 1.81 to 3.43; women IRR=2.34, 95% CI 1.69 to 3.25; combined IRR=2.32, 95% CI 1.66 to 3.25; all p<0.05) and higher socioeconomic advantage (IRSAD decile) was also associated with higher hospitalisation rates (men IRR=1.15, 95% CI 1.02 to 1.30; women IRR=1.14, 95% CI 1.01 to 1.28; combined IRR=1.13, 95% CI 1.00 to 1.27; all p<0.05). CONCLUSION: Our observations could indicate self-motivated treatment seeking, and better specialist and hospital services availability in the advantaged and accessible areas in the study region. The determinants for such variations in hospitalisation rates, however, are multifaceted and warrant further research.

Bone Turnover Markers in Men and Women with Impaired Fasting Glucose and Diabetes.

Bone turnover markers (BTMs) are reduced in diabetes, but whether BTM changes occur in impaired fasting glucose (IFG) is unknown. The aim of this study was to investigate whether BTMs are altered in IFG and diabetes compared to normoglycaemia. For men and women (n = 2222) in the Geelong Osteoporosis Study, IFG was defined as fasting plasma glucose (FPG) 5.5-6.9 mmol/L and diabetes as FPG ≥ 7.0 mmol/L, use of antihyperglycemic medication and/or self-report. Serum C-terminal telopeptide (CTx) and procollagen type 1 N-terminal propeptide (P1NP) were measured. After natural log transformation to normalise the data, multivariable regression was used to examine the relationship between glycaemia status and bone turnover markers (BTMs), before and after adjusting for other confounders. There were 643 men and 682 women with normoglycaemia, 355 men and 391 women with IFG and 97 men and 54 women with diabetes. Men with IFG or diabetes had lower adjusted ln(CTx) and ln(P1NP) compared to normoglycaemia (all p < 0.05). Women with IFG or diabetes had lower adjusted ln(CTx) and ln(P1NP) (all p < 0.05) except for ln(P1NP) when comparing diabetes with normoglycaemia, which showed a trend for lower ln(P1NP) (p = 0.053). In both sexes, an age * glycaemia interaction term indicated between-group differences in BTMs diminished with increasing age. No other confounders were identified. Bone turnover was lower in those with either IFG or diabetes compared to normoglycaemia.

Fracture Risk in Women with Dysglycaemia: Assessing Effects of Baseline and Time-Varying Risk Factors.

Although individuals with diabetes appear to have a higher fracture risk compared to those without diabetes, fracture risk in impaired fasting glucose (IFG) has not been thoroughly explored. This study determined associations between glycaemia status and fracture risk. Women (n = 575, aged 50 + years) enrolled in the Geelong Osteoporosis Study, were followed from baseline (1993-1997), to date of first fracture, death or December 31, 2010, whichever occurred first (median 13.7 years, IQR 7.4-14.8). Hazard ratios (HRs) for any fracture (excluding fingers, toes, skull/face), as well as major osteoporotic fracture (MOF, clinical spine, hip, proximal humerus, wrist), in diabetes (n = 69), IFG (n = 250) and normoglycaemia (n = 256), were calculated using a Cox proportional hazards model. Normoglycaemia was set as the reference category. A Cox proportional hazards model with time-varying covariates was also used to assess change in baseline risk factors at the 10-year follow-up visit (2004-2008). During follow-up (6433 person-years), 162 women sustained any fracture and 104 had a MOF. Unadjusted fracture risk was higher in diabetes (HR 1.64; 95% CI 1.02-2.63) compared to normoglycaemia, but IFG and normoglycaemia had similar risk (HR 1.06; 95% CI 0.76-1.47). Age- and BMD-adjusted any-fracture risk in diabetes compared to normoglycaemia was greater (HR 1.59; 95% CI 0.98-2.58); IFG was similar to normoglycaemia (HR 1.01; 95% CI 0.72-1.41). For MOF, unadjusted and age- and BMD-adjusted fracture risk in IFG was similar to normoglycaemia HR 1.02; 95% CI 0.74-1.40 and HR 0.95; 95% CI 0.69-1.32, respectively, but diabetes was higher compared to normoglycaemia (unadjusted HR 1.64; 95% CI 1.04-2.60; adjusted HR 1.57; 95% CI 0.98-2.51). In the time-varying model, there was no difference between IFG in either the unadjusted or adjusted models, for both any fracture and MOF (p > 0.05). For diabetes, there was a significant difference between normoglycaemia in the adjusted model for any fracture (p = 0.046), but not for MOF (p = 0.103). An increased risk of fracture for women with diabetes was observed after accounting for time-varying risk factors. There was no difference in fracture risk detected for women with IFG.

Comparison of incidence, rate and length of all-cause hospital admissions between adults with normoglycaemia, impaired fasting glucose and diabetes: a retrospective cohort study in Geelong, Australia.

OBJECTIVE: To determine whether adults with normoglycaemia, impaired fasting glucose (IFG) and diabetes differed according to the incidence, rate, length and primary reasons for hospital admission. DESIGN: Retrospective cohort study. SETTING: Barwon Statistical Division, Geelong, Australia. PARTICIPANTS: Cohort included 971 men and 924 women, aged 20+ years, participating in the Geelong Osteoporosis Study. Glycaemic status was assessed at cohort entry using fasting plasma glucose, use of antihyperglycaemic medication and/or self-report. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was any admission to the major tertiary public hospital in the study region over the follow-up period. Secondary outcome measures were admission rate and length (days). RESULTS: Over a median follow-up of 7.4 years (IQR 5.3-9.6), participants with diabetes, compared with those with normoglycaemia, were two times as likely to be hospitalised (OR 2.07, 95% CI 1.42 to 3.02), had a higher admission rate (incidence rate ratio 1.61, 95% CI 1.17 to 2.23) and longer hospital stay (third quartile difference 7.7, 95% CI 1.3 to 14.1 and ninth decile difference 16.2, 95% CI 4.2 to 28.3). IFG group was similar to normoglycaemia for the incidence, rate and length of admission. Cardiovascular disease-related diagnoses were the most common primary reasons for hospitalisation across all glycaemic categories. CONCLUSIONS: Our results show increased incidence, rate and length of all-cause hospital admission in adults with diabetes as compared with normoglycaemia; however, we did not detect any associations for IFG. Interventions should focus on preventing IFG-to-diabetes progression and reducing cardiovascular risk in IFG and diabetes.

Trabecular Bone Score in Men and Women with Impaired Fasting Glucose and Diabetes.

Diabetes is associated with increased skeletal fragility, despite higher bone mineral density (BMD). Alternative measures are necessary to more accurately determine fracture risk in individuals with diabetes. Therefore, we aimed to describe the relationship between trabecular bone score (TBS) and normoglycaemia, impaired fasting glucose (IFG) and diabetes and determine whether TBS-adjusted FRAX (Aus) score differed between these groups. This study included 555 men (68.7 ± 12.2 years) and 514 women (62.0 ± 12.0 years), enrolled in the observational Geelong Osteoporosis Study. IFG was considered as fasting plasma glucose (FPG) ≥ 5.5 mmol/L and diabetes as FPG ≥ 7.0 mmol/L, with the use of antihyperglycaemic medication and/or self-report. Using multivariable regression, the relationship between groups and TBS was determined. Men and women (all ages) with diabetes had lower mean TBS compared to those with normoglycaemia, in models adjusted for age, height and weight/waist circumference (all p < 0.05). Men with IFG had lower mean TBS in the age-adjusted models only (all p < 0.05). The addition of TBS to the FRAX score improved the discrimination between glycaemia groups, particularly for younger women (< 65 years). There was no difference in TBS detected between normoglycaemia and IFG; however, those with diabetes had lower TBS. Thus, the increased fracture risk in men and women with diabetes may be a result of BMD-independent bone deterioration. TBS adjustment of FRAX scores may be useful for younger women (< 65 years) with diabetes. This suggests that halting or reversing progression from IFG to diabetes could be important to prevent skeletal fragility in diabetes.

All-Cause Mortality Risk in Australian Women with Impaired Fasting Glucose and Diabetes.

AIMS: Impaired fasting glucose (IFG) and diabetes are increasing in prevalence worldwide and lead to serious health problems. The aim of this longitudinal study was to investigate the association between impaired fasting glucose or diabetes and mortality over a 10-year period in Australian women. METHODS: This study included 1167 women (ages 20-94 yr) enrolled in the Geelong Osteoporosis Study. Hazard ratios for all-cause mortality in diabetes, IFG, and normoglycaemia were calculated using a Cox proportional hazards model. RESULTS: Women with diabetes were older and had higher measures of adiposity, LDL cholesterol, and triglycerides compared to the IFG and normoglycaemia groups (all p < 0.001). Mortality rate was greater in women with diabetes compared to both the IFG and normoglycaemia groups (HR 1.8; 95% CI 1.3-2.7). Mortality was not different in women with IFG compared to those with normoglycaemia (HR 1.0; 95% CI 0.7-1.4). CONCLUSIONS: This study reports an association between diabetes and all-cause mortality. However, no association was detected between IFG and all-cause mortality. We also showed that mortality in Australian women with diabetes continues to be elevated and women with IFG are a valuable target for prevention of premature mortality associated with diabetes.

Topiramate treatment improves hypothalamic insulin and leptin signaling and action and reduces obesity in mice.

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator α and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity.

Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial.

BACKGROUND: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. OBJECTIVE: The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. RESEARCH DESIGN AND METHODS: We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. RESULTS AND CONCLUSIONS: Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01295177.

Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice.

Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKß-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other immunological disorders.