This review is to systematically explore the relationship between muscle dysfunction and diabetes in adults, and to examine the impact of glycemic variability on muscle health and the development of diabetes-related complications. The review was conducted using three databases: MEDLINE, Scopus, and EMBASE, targeting peer-reviewed journal articles written in English and published from January 2014 to September 2024. The methodological quality assessment of the eligible studies was conducted using Joanna Briggs Institute Critical Appraisal Checklists. A total of 17 studies were included. Most studies were undertaken in Asian countries (n = 11) and focused on adults with type 2 diabetes (n = 12). There were 8,392 adults with diabetes, and their mean age ranged from 52 to 75 years old. The measurements for muscle function and glycemic variability varied across studies. The research findings regarding the relationship between muscle dysfunction and glycemic variability metrics among adults with diabetes, both with and without complications were inconsistent. For adults with diabetes and sarcopenic obesity, poor glycemic control was identified as an independent risk factor for sarcopenic obesity. Additionally, all included studies were rated as moderate or high quality in relation to their methodology. In conclusion, this review underscores the complex and inconsistent relationship between glycemic variability and muscle dysfunction in older adults with diabetes. Poor glycemic management is a significant risk factor for sarcopenic obesity, highlighting the need for tailored interventions to improve glycemic control and muscle health in this population.

Abstract Background Management of type 1 diabetes (T1D) requires the use of insulin, which can cause hypoglycaemia (low blood glucose levels). While most hypoglycaemic episodes can be self-treated, all episodes can be sudden, inconvenient, challenging to prevent or manage, unpleasant and/or cause unwanted attention or embarrassment. Severe hypoglycaemic episodes, requiring assistance from others for recovery, are rare but potentially dangerous. Repeated exposure to hypoglycaemia can reduce classic warning symptoms (‘awareness’), thereby increasing risk of severe episodes. Thus, fear of hypoglycaemia is common among adults with T1D and can have a negative impact on how they manage their diabetes, as well as on daily functioning, well-being and quality of life. While advances in glycaemic technologies and group-based psycho-educational programmes can reduce fear, frequency and impact of hypoglycaemia, they are not universally or freely available, nor do they fully resolve problematic hypoglycaemia or associated worries. This study aims to determine the effectiveness of a fully online, self-directed, scalable, psycho-educational intervention for reducing fear of hypoglycaemia: the Hypoglycaemia Prevention, Awareness of Symptoms, and Treatment (HypoPAST) programme. Methods A 24-week, two-arm, parallel-group, hybrid type 1 randomised controlled trial, conducted remotely (online and telephone). Australian adults (≥ 18 years) with self-reported T1D and fear of hypoglycaemia will be recruited, and allocated at random (1:1) to HypoPAST or control (usual care). The primary outcome is the between-group difference in fear of hypoglycaemia (assessed using HFS-II Worry score) at 24 weeks. A sample size of N = 196 is required to detect a 9-point difference, with 90% power and allowing for 30% attrition. Multiple secondary outcomes include self-reported psychological, behavioural, biomedical, health economic, and process evaluation data. Data will be collected at baseline, 12 and 24 weeks using online surveys, 2-week ecological momentary assessments, website analytics and semi-structured interviews. Discussion This study will provide evidence regarding the effectiveness, cost-effectiveness and acceptability of a novel, online psycho-educational programme: HypoPAST. Due to the fully online format, HypoPAST is expected to provide an inexpensive, convenient, accessible and scalable solution for reducing fear of hypoglycaemia among adults with T1D. Trial registration Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000894695 (21 August 2023).

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (WT, global-AR knockouts (KOs)) were fed a chow or high-caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT and Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity, however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, the action of testosterone via the AR in BM-PCs to negatively regulate fat mass and improve metabolism confers resistance from short-term diet-induced weight gain and partial protection from long-term diet-induced obesity in male mice.

To investigate temporal changes in glycaemic control and the use of antihyperglycaemic therapies in females and males with type 2 diabetes from 2013 to 2019.

The COVID-19 pandemic has had a significant impact on the economy and health system of most countries in the world and this is also true of Australia. Australia has not seen the huge surge of COVID-19 positive cases and subsequent hospitalisations and deaths experienced in other parts of the world. However there have been important social and health strategies to "flatten" the curve, to reduce infections and to manage those infected. These have included closure of international and interstate borders, local lockdown measures, physical distancing, shift to work from home, closure of non-essential businesses and full or partial closure of all schools and tertiary education facilities. From the diabetes care perspective, there was a significant and concerted diversion of hospital resources and staff to COVID-19 specific activities. Reduced access to primary care, diagnostic and hospital services for diabetes, combined with fear of exposure to the virus in these settings, led to a significant drop in access to usual diabetes care. Provision of outpatient and private sector diabetes services via telehealth was encouraged and supported by expanded and new government subsidies. Importantly, for the first time, there was government funded subsidy for care delivered via the telephone and inclusion of credentialled diabetes educators in funded telephone/telehealth support. The Australian health professional and consumer organisations worked cooperatively producing guidelines, position statements and other educational resources specific for the COVID-19 setting. Once the COVID-19 pandemic is over, review of all the changes will be important, determining which should be permanently implemented. The learnings from COVID-19 should help prepare Australia for future pandemics or other major health crises.

Background: Tobacco smoking and diabetes mellitus contribute significantly to the overall health burden and mortality of Australians. We aimed to assess the relationship of smoking with glycemic control, metabolic profile and complications in Australian patients living with diabetes. Methods: We analysed the 2011-2017 biennial Australian National Diabetes Audit cross-sectional data. Patients were classified as current, past or never smokers. Linear (or quantile) and logistic regression models were used to assess for associations. Results: Data from 15,352 patients were analysed, including 722% with type 2 diabetes. Current smokers comprised 13.5% of the study population. Current and past smokers had a median HbA(1c) that was 0.49% and 0.14% higher than never smokers, respectively, as well as higher triglyceride and lower HDL levels (all p values < .0001). Compared to never smokers, current smokers had higher odds of severe hypoglycemia and current and past smokers had higher odds of myocardial infarction, stroke, peripheral vascular disease, lower limb amputation, erectile dysfunction and peripheral neuropathy (all p values <=.001), with no significant change over time. Conclusion: When compared to never smokers, current and past smokers had poorer glycemic and lipid control and higher odds of macrovascular and microvascular complications. Despite this, current smoking remains prevalent among Australians with diabetes. (C) 2020 Elsevier Inc. All rights reserved.

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and is the leading cause of ESKD. The role of T lymphocytes in DKD remains unclear. We aimed to determine the distribution of T lymphocytes in renal biopsies in people with T2DM with varying degrees of kidney function and albuminuria. Fresh renal biopsy samples were provided by the Victorian Cancer Biobank at the time of surgery from individuals undergoing partial/complete nephrectomy or from people with diabetes who had a renal biopsy for clinical indications at Austin Health. Participants were divided into the following groups: Diabetic kidney disease group (DKD was diagnosed by clinical and histologic characteristics), nondiabetic and intact renal function (Control) (eGFR > 60ml/min/m2, no albuminuria) and nondiabetic kidney disease (NDKD) (eGFR < 60ml/min/m2, no history of diabetes). DKD group was further stratified into normo-, micro-, or macroalbuminuria groups. Sections were immunostained with CD3 antibody. Results showed higher level of creatinine, systolic blood pressure, and reduced level of eGFR, poor glycemic control in people with DKD and macroalbuminuria as compared with people without diabetes. T lymphocytes numbers were significantly increased in the interstitial compartment of people with T2DM and macroalbuminuria compared to those without diabetes, suggesting the immunopathologic role of T lymphocytes in the development of DKD. Disclosure L. Kong: None. S. Andrikopoulos: None. R. MacIsaac: None. N. Torkamani: None. M. Coughlan: None. D. Power: None. E.C. Marin: None. L.K. Mackay: None. E.I. Ekinci: None.

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr-391-/-) as for GHR-null (GHR-/-) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)-1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.-Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

Objective To compare the glycaemic control and cardiovascular risk factor profiles of younger and older patients with type 2 diabetes. Cross-sectional analysis of data from the 2015 Australian National Diabetes Audit was undertaken. Methods Data were obtained from adults with type 2 diabetes presenting to Australian secondary/tertiary diabetes centres. Logistic regression examined associations with glycated haemoglobin A1c (HbA1c) >7% (53 mmol/mol) and cardiovascular risk factors. Results Data from 3492 patients were analysed. Mean (±SD) age was 62.9±12.5 years, mean diabetes duration 13.5±9.4 years and mean HbA1c 8.2%±1.8%. Mean HbA1c was 8.6%±2.1% and 8.0%±1.6% for the younger (<60 years) and older subgroups (≥60 years), respectively (p<0.001). The adjusted OR (aOR) of HbA1c above >7.0% was 1.5 times higher (95% CI 1.22 to 1.84) for younger patients compared with older patients after adjustment for gender, smoking, diabetes duration, renal function and body mass index. Younger patients were also more likely to have dyslipidaemia (aOR 2.02, 95% CI 1.53 to 2.68; p<0.001), be obese (aOR 1.25, 95% CI 1.05 to 1.49; p<0.001) and be current smokers (aOR 2.13 95% CI 1.64 to 2.77; p<0.001) than older patients. Conclusions Younger age was associated with poorer glycaemic control and adverse cardiovascular risk factor profiles. It is imperative to optimise and monitor treatment in order to improve long-term outcomes.

Chronic metabolic stress leads to cellular dysfunction, characterized by excessive reactive oxygen species, endoplasmic reticulum (ER) stress and inflammation, which has been implicated in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. The ER is gaining recognition as a key organelle in integrating cellular stress responses. ER homeostasis is tightly regulated by a complex antioxidant system, which includes the seven ER-resident selenoproteins - 15 kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins S, N, K, M and T. Here, the findings from biochemical, cell-based and mouse studies investigating the function of ER-resident selenoproteins are reviewed. Human experimental and genetic studies are drawn upon to highlight the relevance of these selenoproteins to the pathogenesis of metabolic disease. ER-resident selenoproteins have discrete roles in the regulation of oxidative, ER and inflammatory stress responses, as well as intracellular calcium homeostasis. To date, only two of these ER-resident selenoproteins, selenoproteins S and N have been implicated in human disease. Nonetheless, the potential of all seven ER-resident selenoproteins to ameliorate metabolic dysfunction warrants further investigation.

Introduction: Type 2 diabetes is increasingly diagnosed among younger people. Patient engagement with self-care practices is crucial for the optimal management of type 2 diabetes. This study examines the self-care practices of younger and older patients with type 2 diabetes. Methods: Data were analysed from the Australian National Diabetes Audit (ANDA) that included 2552 adult patients with type 2 diabetes from 56 participating Diabetes Centres. Pre-specified demographic and clinical variables were obtained. Self-care variables (physical activity, following dietary recommendations, medication adherence and monitoring blood glucose levels) were compared in patients ≤64 years and >64 years of age. Results: Mean age (±SD) of participants was 63±13 years overall, 53±9 years for the younger group and 73±6 years for the older group. Mean diabetes duration was 9±8 years and 15±10 years for younger and older patients, respectively (p<0.01). A greater proportion of younger patients had HbA1c levels above 7.0% compared with older patients (76% vs. 68%, p<0.001). A greater proportion of younger compared to older patients reported difficulty following dietary recommendations (50% vs. 32%) and forgetting medications (37% vs. 22%) (all p values <0.001). A smaller proportion of younger compared with older patients reported monitoring their blood glucose levels as often as recommended (60%vs. 70%, p<0.001). Younger age was associated with a 2-fold increase in the odds of not following the recommended self-care practices after adjustment for gender, smoking, insulin therapy, depression and allied health attendance (all p values <0.001). Conclusion: Despite shorter diabetes duration, younger age was associated with worse glycaemic control and poorer diabetes self-care practices among patients with type 2 diabetes. Targeted strategies are urgently required to optimise diabetes self-care practices and thereby improve glycaemic control. Disclosure N. Nanayakkara: None. A.J. Pease: None. S. Ranasinha: None. N. Wischer: None. B. de Courten: None. S. Zoungas: Advisory Panel; Self; AstraZeneca.

The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication.

AIM:To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE.METHODS:Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined.RESULTS:Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury.CONCLUSION:In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.

BACKGROUND/OBJECTIVES:Dietary guidelines for the past 20 years have recommended that dietary fat should be minimized. In contrast, recent studies have suggested that there could be some potential benefits for reducing carbohydrate intake in favor of increased fat. It has also been suggested that low-carbohydrate diets be recommended for people with type 2 diabetes. However, whether such diets can improve glycemic control will likely depend on their ability to improve β-cell function, which has not been studied. The objective of the study was to assess whether a low-carbohydrate and therefore high-fat diet (LCHFD) is beneficial for improving the endogenous insulin secretory response to glucose in prediabetic New Zealand Obese (NZO) mice.METHODS:NZO mice were maintained on either standard rodent chow or an LCHFD from 6 to 15 weeks of age. Body weight, food intake and blood glucose were assessed weekly. Blood glucose and insulin levels were also assessed after fasting and re-feeding and during an oral glucose tolerance test. The capacity of pancreatic β-cells to secrete insulin was assessed in vivo with an intravenous glucose tolerance test. β-Cell mass was assessed in histological sections of pancreata collected at the end of the study.RESULTS:In NZO mice, an LCHFD reduced plasma triglycerides (P=0.001) but increased weight gain (P<0.0001), adipose tissue mass (P=0.0015), high-density lipoprotein cholesterol (P=0.044) and exacerbated glucose intolerance (P=0.013). Although fasting insulin levels tended to be higher (P=0.08), insulin secretory function in LCHFD-fed mice was not improved (P=0.93) nor was β-cell mass (P=0.75).CONCLUSIONS:An LCHFD is unlikely to be of benefit for preventing the decline in β-cell function associated with the progression of hyperglycemia in type 2 diabetes.