Tau suppresses microtubule-regulated pancreatic insulin secretion.

Tau protein is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies, but its physiological function is in debate. Mostly explored in the brain, tau is also expressed in the pancreas. We further explored the mechanism of tau's involvement in the regulation of glucose-stimulated insulin secretion (GSIS) in islet ß-cells, and established a potential relationship between type 2 diabetes mellitus (T2DM) and AD. We demonstrate that pancreatic tau is crucial for insulin secretion regulation and glucose homeostasis. Tau levels were found to be elevated in ß-islet cells of patients with T2DM, and loss of tau enhanced insulin secretion in cell lines, drosophila, and mice. Pharmacological or genetic suppression of tau in the db/db diabetic mouse model normalized glucose levels by promoting insulin secretion and was recapitulated by pharmacological inhibition of microtubule assembly. Clinical studies further showed that serum tau protein was positively correlated with blood glucose levels in healthy controls, which was lost in AD. These findings present tau as a common therapeutic target between AD and T2DM.

Stimulation parameters for directional vagus nerve stimulation.

BACKGROUND: Autonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic. METHODS: Male rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude. RESULTS: During application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range). CONCLUSIONS: This study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

ANDA-Evaluating Facilitated Feedback Enhancement - a Cluster randomised Trial (ANDA-EFFECT): protocol for a cluster randomised trial of audit feedback augmented with education and support, compared to feedback alone, on acceptability, utility and health outcomes in diabetes centres in Australia.

BACKGROUND: People living with diabetes must manage a range of factors for optimal control of glycaemia and to minimise the risk of diabetes-related complications. Diabetes practitioners are expected to follow guidelines for the key process of care and clinical outcomes, to help people living with diabetes achieve clinical targets. In Australia, the performance of diabetes centres against guidelines is evaluated by the Australian National Diabetes Audit, an annual clinical audit and feedback activity. Previous work has identified areas for improvement in the feedback provided to participating diabetes centres and suggested additional educational and support resources to assist in using audit feedback for the development of quality improvement activities. This cluster randomised trial will test the acceptability, utility and impact on selected clinical outcomes of the developed study intervention (audit feedback and a tailored educational and peer support cointervention). METHODS: Two-armed cluster randomised trial with Australian Diabetes Centres that participated in the Australian National Diabetes Audit in 2021 as the clusters, stratified by location and type of centre. We aim to recruit 35 diabetes centres in each arm. Both the intervention and control arms will receive an augmented feedback report, accompanied by a partially pre-populated slide deck. In addition, the intervention arm will receive a tailored theory-based intervention designed to address identified, modifiable barriers to utilising and implementing the recommendations from diabetes audit feedback. The co-primary outcomes are (1) HbA1c at the patient level, measured at 6 months after delivery of the intervention, and (2) the acceptability and utility of the augmented feedback and cointerventions at the practitioner level, measured at 3 months after delivery of the intervention. DISCUSSION: This trial aims to test the effects of systematic development and implementation of theory and evidence-informed changes to the audit feedback delivered to diabetes centres participating in an established national clinical diabetes audit. Potential benefits of improved audit feedback include more optimal engagement with the feedback by end clinical users which, ultimately, may lead to improvements in care for people living with diabetes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12621000765820. Prospectively registered on June 21, 2021.

The Australian Obesity Management Algorithm: A simple tool to guide the management of obesity in primary care.

Obesity is a complex and multifactorial chronic disease with genetic, environmental, physiological and behavioural determinants that requires long-term care. Obesity is associated with a broad range of complications including type 2 diabetes, cardiovascular disease, dyslipidaemia, metabolic associated fatty liver disease, reproductive hormonal abnormalities, sleep apnoea, depression, osteoarthritis and certain cancers. An algorithm has been developed (with PubMed and Medline searched for all relevant articles from 1 Jan 2000-1 Oct 2021) to (i) assist primary care physicians in treatment decisions for non-pregnant adults with obesity, and (ii) provide a practical clinical tool to guide the implementation of existing guidelines (summarised in Appendix 1) for the treatment of obesity in the Australian primary care setting. MAIN RECOMMENDATIONS AND CHANGES IN MANAGEMENT: Treatment pathways should be determined by a person's anthropometry (body mass index (BMI) and waist circumference (WC)) and the presence and severity of obesity-related complications. A target of 10-15% weight loss is recommended for people with BMI 30-40 kg/m2 or abdominal obesity (WC > 88 cm in females, WC > 102 cm in males) without complications. The treatment focus should be supervised lifestyle interventions that may include a reduced or low energy diet, very low energy diet (VLED) or pharmacotherapy. For people with BMI 30-40 kg/m2 or abdominal obesity and complications, or those with BMI > 40 kg/m2 a weight loss target of 10-15% body weight is recommended, and management should include intensive interventions such as VLED, pharmacotherapy or bariatric surgery, which may be required in combination. A weight loss target of > 15% is recommended for those with BMI > 40 kg/m2 and complications and they should be referred to specialist care. Their treatment should include a VLED with or without pharmacotherapy and bariatric surgery.

Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond.

The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6-A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.

Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model.

Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high-fat diet and low doses of streptozotocin. Stimulation of the abdominal vagus nerve was achieved by pairing 15 Hz pulses on a distal pair of electrodes with high-frequency blocking stimulation (26 kHz, 4 mA) on a proximal pair of electrodes to preferentially produce efferent conducting activity (eVNS). Stimulation was well tolerated in awake, freely moving rats. During 1 h of eVNS, glycemia decreased in 90% of subjects (-1.25 ± 1.25 mM h, p = 0.017), and 2 dB above neural threshold was established as the most effective "dose" of eVNS (p = 0.009). Following 5 weeks of implantation, eVNS was still effective, resulting in significantly decreased glycemia (-1.7 ± 0.6 mM h, p = 0.003) during 1 h of eVNS. There were no overt changes in fascicle area or signs of histopathological damage observed in implanted vagal nerve tissue following chronic implantation and stimulation. Demonstration of the biocompatibility and safety of eVNS in awake, metabolically compromised animals is a critical first step to establishing this therapy for clinical use. With further development, eVNS could be a promising novel therapy for treating type 2 diabetes.

Exploring HbA1c variation between Australian diabetes centres: The impact of centre-level and patient-level factors.

BACKGROUND: Increasing global diabetes incidence has profound implications for health systems and for people living with diabetes. Guidelines have established clinical targets but there may be variation in clinical outcomes including HbA1c, based on location and practice size. Investigating this variation may help identify factors amenable to systemic improvement interventions. The aims of this study were to identify centre-specific and patient-specific factors associated with variation in HbA1c levels and to determine how these associations contribute to variation in performance across diabetes centres. METHODS: This cross-sectional study analysed data for 5,872 people with type 1 (n = 1,729) or type 2 (n = 4,143) diabetes mellitus collected through the Australian National Diabetes Audit (ANDA). A linear mixed-effects model examined centre-level and patient-level factors associated with variation in HbA1c levels. RESULTS: Mean age was: 43±17 years (type 1), 64±13 (type 2); median disease duration: 18 years (10,29) (type 1), 12 years (6,20) (type 2); female: 52% (type 1), 45% (type 2). For people with type 1 diabetes, volume of patients was associated with increases in HbA1c (p = 0.019). For people with type 2 diabetes, type of centre was associated with reduction in HbA1c (p <0.001), but location and patient volume were not. Associated patient-level factors associated with increases in HbA1c included past hyperglycaemic emergencies (type 1 and type 2, p<0.001) and Aboriginal and Torres Strait Islander status (type 2, p<0.001). Being a non-smoker was associated with reductions in HbA1c (type 1 and type 2, p<0.001). CONCLUSIONS: Centre-level and patient-level factors were associated with variation in HbA1c, but patient-level factors had greater impact. Interventions targeting patient-level factors conducted at a centre level including sick-day management, smoking cessation programs and culturally appropriate diabetes education for and Aboriginal and Torres Strait Islander peoples may be more important for improving glycaemic control than targeting factors related to the Centre itself.

Making the most of audit and feedback to improve diabetes care: a qualitative study of the perspectives of Australian Diabetes Centres.

BACKGROUND: Diabetes has high burden on the health system and the individual, and many people living with diabetes struggle to optimally manage their condition. In Australia, people living with diabetes attend a mixture of primary, secondary and tertiary care centres. Many of these Diabetes Centres participate in the Australian National Diabetes Audit (ANDA), a quality improvement (QI) activity that collects clinical information (audit) and feeds back collated information to participating sites (feedback). Despite receiving this feedback, many process and care outcomes for Diabetes Centres continue to show room for improvement. The purpose of this qualitative study was to inform improvement of the ANDA feedback, identify the needs of those receiving feedback and elicit the barriers to and enablers of optimal feedback use. METHODS: Semi-structured interviews were conducted with representatives of Australian Diabetes Centres, underpinned by the Consolidated Framework for Implementation Research (CFIR). De-identified transcripts were analysed thematically, underpinned by the domains and constructs of the CFIR. RESULTS: Representatives from 14 Diabetes centres participated in this study, including a diverse range of staff typical of the Diabetes Centres who take part in ANDA. In general, participants wanted a shorter report with a more engaging, simplified data visualisation style. Identified barriers to use of feedback were time or resource constraints, as well as access to knowledge about how to use the data provided to inform the development of QI activities. Enablers included leadership engagement, peer mentoring and support, and external policy and incentives. Potential cointerventions to support use include exemplars from clinical change champions and peer leaders, and educational resources to help facilitate change. CONCLUSIONS: This qualitative study supported our contention that the format of ANDA feedback presentation can be improved. Healthcare professionals suggested actionable changes to current feedback to optimise engagement and potential implementation of QI activities. These results will inform redesign of the ANDA feedback to consider the needs and preferences of end users and to provide feedback and other supportive cointerventions to improve care, and so health outcomes for people with diabetes. A subsequent cluster randomised trial will enable us to evaluate the impact of these changes.

Role of the adaptive immune system in diabetic kidney disease.

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end-stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro-inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor-α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Women's distinct diabetes self-management behaviours demand gender-specific diabetes research: improving chronic disease management and addressing clinical governance issues.

Management of diabetes mellitus continues to pose challenges for primary health-care professionals, with estimates of as many as 2 million Australians requiring ongoing care. Although most cases are men, women living with diabetes have presenting concerns and self-management characteristics distinct from men. A threat to women's optimal diabetes management is being at greater risk of developing mental health conditions, especially for women with insulin-dependent type 2 diabetes. In addition, complementary medicine use is highly prevalent among women and is associated with significant direct and indirect risks, which raises clinical governance issues. To date, limited gender-specific diabetes research exists that has explored women's diabetes self-management behaviours and risk profiles. We argue that this is essential to inform the design of targeted care approaches that address clinical governance issues and help health-care professionals to better support women living with diabetes.

Targeting the insulin granule for modulation of insulin exocytosis.

The pancreatic ß-cells control insulin secretion in the body to regulate glucose homeostasis, and ß-cell stress and dysfunction is characteristic of Type 2 Diabetes. Pharmacological targeting of the ß-cell to increase insulin secretion is typically utilised, however, extended use of common drugs such as sulfonylureas are known to result in secondary failure. Moreover, there is evidence they may induce ß-cell failure in the long term. Within ß-cells, insulin secretory granules (ISG) serve as compartments to store, process and traffic insulin for exocytosis. There is now growing evidence that ISG exist in multiple populations, distinct in their protein composition, motility, age, and capacity for secretion. In this review, we discuss the implications of a heterogenous ISG population in ß-cells and highlight the need for more understanding into how unique ISG populations may be targeted in anti-diabetic therapies.

Utilisation, access and recommendations regarding technologies for people living with type 1 diabetes: consensus statement of the ADS/ADEA/APEG/ADIPS Working Group.

INTRODUCTION: Type 1 diabetes presents significant challenges for optimal management. Despite intensive glycaemic control being the standard of care for several decades, glycaemic targets are infrequently achieved and the burden of complications remains high. Therefore, the advancement of diabetes management technologies has a major role in reducing the clinical and economic impact of the disease on people living with type 1 diabetes and on health care systems. However, a national framework is needed to ensure equitable and sustainable implementation of these technologies as part of holistic care. MAIN RECOMMENDATIONS: This consensus statement considers technologies for insulin delivery, glucose sensing and insulin dose advice that are commercially available in Australia. While international position statements have provided recommendations for technology implementation, the ADS/ADEA/APEG/ADIPS Working Group believes that focus needs to shift from strict trial-based glycaemic criteria towards engagement and individualised management goals that consider the broad spectrum of benefits offered by technologies. CHANGES IN MANAGEMENT AS RESULT OF THIS STATEMENT: This Australian consensus statement from peak national bodies for the management of diabetes across the lifespan outlines a national framework for the optimal implementation of technologies for people with type 1 diabetes. The Working Group highlights issues regarding equity of access to technologies and services, scope of clinical practice, credentialling and accreditation requirements, regulatory issues with "do-it-yourself" technology, national benchmarking, safety reporting, and ongoing patient advocacy.

What Gets Measured Gets Improved-Setting Standards and Accreditation for Quality Improvement for Diabetes Services in Australia.

The purpose of this article is to illustrate that setting standards of care is the cornerstone for excellence in diabetes management. This is underpinned by 3 activities: a standards and accreditation process, an audit and benchmarking program and a linked quality improvement plan. While there are many examples of local auditing and quality improvement programs, there are very few that are at a national level. The National Association of Diabetes Centres (NADC) was formed by the Australian Diabetes Society and the Australian Diabetes Educators Association to set standards of diabetes care in Australia. A rigorous accreditation process was put in place to recognize primary, secondary, and tertiary level diabetes centers that meet these standards. The NADC accreditation process is underpinned by a quality improvement plan, which must be submitted for accreditation to be granted and is informed by the Australian National Diabetes Audit (ANDA). ANDA is conducted annually to gather information about treatments, complications, self-care practices and quality of life outcomes and provides a national as well as an individual report to the participating center that is used to benchmark against other like centers. The ANDA reports are important to inform national policy and advocacy for diabetes care and to also provide information for quality improvement purposes for the individual participating center. We believe that the NADC Standards and Accreditation can be an exemplar for other countries to adapt and adopt to standardize diabetes care at the highest level.

Glycaemia and utilisation of technology across the lifespan of adults with type 1 diabetes: Results of the Australian National Diabetes Audit (ANDA).

AIMS: To evaluate the utilisation of technologies and associated glycaemia among adults with type 1 diabetes. METHODS: De-identified data from adults with type 1 diabetes (≥18 years old) in the Australian National Diabetes Audit (ANDA)-2019 were analysed. Proportions using insulin pumps or injections with continuous glucose monitoring (CGM) or capillary-glucose testing were compared. Technology use among adults was compared to young people (<21 years old) with subsidised CGM. Glycaemia and complication-burden were assessed across management strategies. RESULTS: 1,693 adults were analysed. Mean(±SD) age, diabetes duration, and HbA1c were 43.3 ± 17.0 years, 20.3 ± 14.3 years and 8.4% ± 1.7 [68 ± 19 mmol/mol], respectively. Among adults, 40% used at least one device, 27% used insulin pumps, and 23% used CGM. CGM was used by 62% of young people with subsidised access. Mean HbA1c was consistently lower among adults using CGM, insulin pumps, or combined insulin pump and CGM compared to standard care (8.3% ± 1.6 [67 ± 18 mmol/mol], 8.2% ± 1.4 [66 ± 15 mmol/mol], and 7.8% ± 1.4 [62 ± 15 mmol/mol] respectively compared to 8.6% ± 1.8 [70 ± 20 mmol/mol], p < 0.001). Technology use was not associated with diabetic ketoacidosis but CGM was associated with more hypoglycaemia. CONCLUSIONS: Government subsidy is an important consideration for utilisation of technologies among adults with type 1 diabetes. Technology use across the adult lifespan was associated with lower HbA1c than insulin injections and capillary-glucose testing.

Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution.

Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

E2f8 and Dlg2 genes have independent effects on impaired insulin secretion associated with hyperglycaemia.

AIMS/HYPOTHESIS: Reduced insulin secretion results in hyperglycaemia and diabetes involving a complex aetiology that is yet to be fully elucidated. Genetic susceptibility is a key factor in beta cell dysfunction and hyperglycaemia but the responsible genes have not been defined. The Collaborative Cross (CC) is a recombinant inbred mouse panel with diverse genetic backgrounds allowing the identification of complex trait genes that are relevant to human diseases. The aim of this study was to identify and characterise genes associated with hyperglycaemia. METHODS: Using an unbiased genome-wide association study, we examined random blood glucose and insulin sensitivity in 53 genetically unique mouse strains from the CC population. The influences of hyperglycaemia susceptibility quantitative trait loci (QTLs) were investigated by examining glucose tolerance, insulin secretion, pancreatic histology and gene expression in the susceptible mice. Expression of candidate genes and their association with insulin secretion were examined in human islets. Mechanisms underlying reduced insulin secretion were studied in MIN6 cells using RNA interference. RESULTS: Wide variations in blood glucose levels and the related metabolic traits (insulin sensitivity and body weight) were observed in the CC population. We showed that elevated blood glucose in the CC strains was not due to insulin resistance nor obesity but resulted from reduced insulin secretion. This insulin secretory defect was demonstrated to be independent of abnormalities in islet morphology, beta cell mass and pancreatic insulin content. Gene mapping identified the E2f8 (p = 2.19 × 10-15) and Dlg2 loci (p = 3.83 × 10-8) on chromosome 7 to be significantly associated with hyperglycaemia susceptibility. Fine mapping the implicated regions using congenic mice demonstrated that these two loci have independent effects on insulin secretion in vivo. Significantly, our results revealed that increased E2F8 and DLG2 gene expression are correlated with enhanced insulin secretory function in human islets. Furthermore, loss-of-function studies in MIN6 cells demonstrated that E2f8 is involved in insulin secretion through an ATP-sensitive K+ channel-dependent pathway, which leads to a 30% reduction in Abcc8 expression. Similarly, knockdown of Dlg2 gene expression resulted in impaired insulin secretion in response to glucose and non-glucose stimuli. CONCLUSIONS/INTERPRETATION: Collectively, these findings suggest that E2F transcription factor 8 (E2F8) and discs large homologue 2 (DLG2) regulate insulin secretion. The CC resource enables the identification of E2f8 and Dlg2 as novel genes associated with hyperglycaemia due to reduced insulin secretion in pancreatic beta cells. Taken together, our results provide better understanding of the molecular control of insulin secretion and further support the use of the CC resource to identify novel genes relevant to human diseases.

Impaired exercise performance is independent of inflammation and cellular stress following genetic reduction or deletion of selenoprotein S.

Selenoprotein S (Seps1) can be protective against oxidative, endoplasmic reticulum (ER), and inflammatory stress. Seps1 global knockout mice are less active, possess compromised fast muscle ex vivo strength, and, depending on context, heightened inflammation. Oxidative, ER, and inflammatory stress modulates contractile function; hence, our aim was to investigate the effects of Seps1 gene dose on exercise performance. Seps1-/- knockout, Seps1-/+ heterozygous, and wild-type mice were randomized to 3 days of incremental, high-intensity treadmill running or a sedentary control group. On day 4, the in situ contractile function of fast tibialis anterior (TA) muscles was determined. Seps1 reduction or deletion compromised exercise capacity, decreasing distance run. TA strength was also reduced. In sedentary Seps1-/- knockout mice, TA fatigability was greater than wild-type mice, and this was ameliorated with exercise. Whereas, in Seps1+/- heterozygous mice, exercise compromised TA endurance. These impairments in exercise capacity and TA contractile function were not associated with increased inflammation or a dysregulated redox state. Seps1 is highly expressed in muscle fibers and blood vessels. Interestingly, Nos1 and Vegfa mRNA transcripts were decreased in TA muscles from Seps1-/- knockout and Seps1-/+ heterozygous mice. Impaired exercise performance with Seps1 reduction or deletion cannot be attributed to heightened cellular stress, but it may potentially be mediated, in part, by the effects of Seps1 on the microvasculature.

Metformin: time to review its role and safety in chronic kidney disease.

■Metformin is recommended as first-line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) - a condition that commonly coexists with diabetes - due to concerns over drug accumulation and metformin-associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all-cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin-associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present-day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73m2 ). However, prescribing metformin in people with severe renal impairment (eGFR < 30 mL/min/1.73m2 ) remains a controversial issue. Due to observed increased risk of lactic acidosis and all-cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration.