Association between hyperglycaemia and fracture risk in non-diabetic middle-aged and older Australians : a national, population-based prospective study (AusDiab)

Summary : The association between pre-diabetes and fracture risk remains unclear. In this large cohort of middle-aged and older Australian men and women without diabetes, elevated 2-h plasma glucose and pre-diabetes were associated with a reduced 5-year risk of low trauma and all fractures in women, independently of BMI, fasting insulin and other lifestyle factors.

Introduction : We aimed to (1) examine associations between fasting and 2-h plasma glucose (FPG and 2-h PG), fasting insulin and risk of low trauma and all fractures in non-diabetic adults and (2) compare fracture risk between adults with pre-diabetes (impaired glucose tolerance or impaired fasting glucose) and those with normal glucose tolerance (NGT).

Methods : Six thousand two hundred fifty-five non-diabetic men and women aged ≥40 years with NGT (n = 4,855) and pre-diabetes (n = 1,400) were followed for 5 years in the AusDiab Study. Fractures were self-reported.

Results : Five hundred thirty-nine participants suffered at least one fracture (368 women, 171 men), of which the majority (318) occurred after a low-energy trauma (258 women, 60 men). In women, a 2-h PG ≥7.2 mmol/L (highest quartile) was associated with a decreased risk of low trauma and all fractures independent of age and BMI [OR (95% CI) for low trauma fractures, 0.59 (0.40–0.88)], but also fasting insulin, smoking, physical activity, history of fracture, dietary calcium and alcohol intake or menopausal status. There was no effect of 2-h PG on fracture risk in men [OR (95% CI), 1.39 (0.60–3.26)] or any relationship between fracture risk and quartiles of FPG or insulin in either sex. Compared to women with NGT, those with pre-diabetes had a reduced risk of fracture [OR (95% CI) for all fractures, 0.70 (0.52–0.95); for low trauma fractures, 0.75 (0.53–1.05)].

Conclusion : Elevated 2-h PG levels and pre-diabetes were inversely associated with low trauma and/or all fractures in non-diabetic women, independent of BMI and fasting insulin levels.

Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy

ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome or to a newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence microscopy indicated a shift in steady-state equilibrium of ATP7AT994I and ATP7AP1386S, with exaggerated PM localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with the Venus fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7AT994I and p97/VCP, an ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and fronto-temporal dementia. Small-interfering RNA (SiRNA) knockdown of p97/VCP corrected ATP7AT994I mislocalization. Flow cytometry documented that non-permeabilized ATP7AP1386S fibroblasts bound a carboxyl-terminal ATP7A antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface and partially destabilized insertion of the eighth transmembrane helix. Our findings illuminate the mechanisms underlying ATP7A-related DMN and establish a link between p97/VCP and genetically distinct forms of motor neuron degeneration.

Investigational agents that protect pancreatic islet β-cells from failure

Type 2 diabetes is associated with insulin resistance and reduced insulin secretion, which results in hyperglycaemia. This can then lead to diabetic complications such as retinopathy, neuropathy, nephropathy and cardiovascular disease. Although insulin resistance may be present earlier in the progression of the disease, it is now generally accepted that it is the deterioration in insulin-secretory function that leads to hyperglycaemia. This reduction in insulin secretion in Type 2 diabetes is due to both islet β-cell dysfunction and death. Therefore, interventions that maintain the normal function and protect the pancreatic islet β-cells from death are crucial in the treatment of Type 2 diabetes so that plasma glucose levels may be maintained within the normal range. Recently, a number of compounds have been shown to protect β-cells from failure. This review examines the evidence that the existing therapies for Type 2 diabetes that were developed to lower plasma glucose (metformin) or improve insulin sensitivity (thiazolidinediones) may also have islet-protective function. Newer emerging therapeutic agents that are designed to increase the levels of glucagon-like peptide-1 not only stimulate insulin secretion but also appear to increase islet β-cell mass. Evidence will also be presented that the future of drug therapy designed to prevent β-cell failure should target the formation of advanced glycation end products and alleviate oxidative and endoplasmic reticulum stress.

Electroretinography in streptozotocin diabetic rats following acute intraocular pressure elevation

Background
We consider whether pre-existing streptozotocin induced hyperglycemia in rats affects the ability of the eye to cope with a single episode of acute intraocular pressure (IOP) elevation.
Methods
Electroretinogram (ERG) responses were measured (−6.08 to 1.92 log cd.s.m−2) in anaesthetized (60:5 mg/kg ketamine:xylazine) dark-adapted (>12 h) adult Sprague–Dawley rats 1 week after a single acute IOP elevation to 70 mmHg for 60 min. This was undertaken in rats treated 11 weeks earlier with streptozotocin (STZ, n = 12, 50 mg/kg at 6 weeks of age) or citrate buffer (n = 12). ERG responses were analyzed to derive an index of photoreceptor (a-wave), ON-bipolar (b-wave), amacrine (oscillatory potentials) and inner retinal (positive scotopic threshold response, pSTR) function.
Results
One week following acute IOP elevation there was a significant reduction of the ganglion cell pSTR (−35 ± 11 %, P = 0.0161) in STZ-injected animals. In contrast the pSTR in citrate-injected animals was not significant changed (+16 ± 14 %). The negative component of the STR was unaffected by IOP elevation in either citrate or STZ-treated groups. Photoreceptoral (a-wave, citrate-control +4 ± 3 %, STZ +4 ± 5 %) and ON-bipolar cell (b-wave, control +4 ± 3 %, STZ +4 ± 5 %) mediated responses were not significantly affected by IOP elevation in either citrate- or STZ-injected rats. Finally, oscillatory potentials (citrate-control +8 ± 23 %, STZ +1 ± 17 %) were not reduced 1 week after IOP challenge.
Conclusions
The ganglion cell dominated pSTR was reduced following a single episode of IOP elevation in STZ diabetic, but not control rats. These data indicate that hyperglycemia renders the inner retina more susceptible to IOP elevation.

Empirical investigation of multi-tier ensembles for the detection of cardiac autonomic neuropathy using subsets of the Ewing Features

This article is devoted to an empirical investigation of per- formance of several new large multi-tier ensembles for the detection of cardiac autonomic neuropathy (CAN) in diabetes patients using subsets of the Ewing features. We used new data collected by the diabetes screening research initiative (DiScRi) project, which is more than ten times larger than the data set originally used by Ewing in the investigation of CAN. The results show that new multi-tier ensembles achieved better performance compared with the outcomes published in the literature previously. The best accuracy 97.74% of the detection of CAN has been achieved by the novel multi-tier combination of AdaBoost and Bagging, where AdaBoost is used at the top tier and Bagging is used at the middle tier, for the set consisting of the following four Ewing features: the deep breathing heart rate change, the Valsalva manoeuvre heart rate change, the hand grip blood pressure change and the lying to standing blood pressure change.

Improving classifications for cardiac autonomic neuropathy using multi-level ensemble classifiers and feature selection based on random forest

This paper is devoted to empirical investigation of novel multi-level ensemble meta classifiers for the detection and monitoring of progression of cardiac autonomic neuropathy, CAN, in diabetes patients. Our experiments relied on an extensive database and concentrated on ensembles of ensembles, or multi-level meta classifiers, for the classification of cardiac autonomic neuropathy progression. First, we carried out a thorough investigation comparing the performance of various base classifiers for several known sets of the most essential features in this database and determined that Random Forest significantly and consistently outperforms all other base classifiers in this new application. Second, we used feature selection and ranking implemented in Random Forest. It was able to identify a new set of features, which has turned out better than all other sets considered for this large and well-known database previously. Random Forest remained the very best classier for the new set of features too. Third, we investigated meta classifiers and new multi-level meta classifiers based on Random Forest, which have improved its performance. The results obtained show that novel multi-level meta classifiers achieved further improvement and obtained new outcomes that are significantly better compared with the outcomes published in the literature previously for cardiac autonomic neuropathy.

Prevention of diabetes in rural India with a telemedicine intervention

Background : Diabetes care is not presently available, accessible, or affordable to people living in rural areas in developing countries, such as India. The Chunampet Rural Diabetes Prevention Project (CRDPP) was conceived with the aim of implementing comprehensive diabetes screening, prevention, and treatment using a combination of telemedicine and personalized care in rural India.

Methods : This project was undertaken in a cluster of 42 villages in and around the Chunampet village in the state of Tamil Nadu in southern India. A telemedicine van was used to screen for diabetes and its complications using retinal photography, Doppler imaging, biothesiometry, and electrocardiography using standardized techniques. A rural diabetes center was set up to provide basic diabetes care.

Results : Of the total 27,014 adult population living in 42 villages, 23,380 (86.5%) were screened for diabetes, of which 1138 (4.9%) had diabetes and 3410 (14.6%) had prediabetes. A total of 1001 diabetes subjects were screened for complications (response rate of 88.0%). Diabetic retinopathy was detected in 18.2%, neuropathy in 30.9%, microalbuminuria in 24.3%, peripheral vascular disease in 7.3%, and coronary artery disease in 10.8%. The mean hemoglobin A1c levels among the diabetes subjects in the whole community decreased from9.3 ± 2.6% to 8.5 ± 2.4% within 1 year. Less than 5% of patients needed referral for further management to the tertiary diabetes hospital in Chennai.