The association of smoking status with glycemic control, metabolic profile and diabetic complications:Results of the Australian National Diabetes Audit (ANDA).

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 72.2% with type 2 diabetes. Current smokers comprised 13.5% of the study population. Current and past smokers had a median HbA1c 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

Monotreme glucagon-like peptide-1 in venom and gut: one gene – two very different functions

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/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

Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin’s ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Cα-Cα distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues

Age-related differences in glycaemic control, cardiovascular disease risk factors and treatment in patients with type 2 diabetes:A cross-sectional study from the Australian National Diabetes Audit

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 (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

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

Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity

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

Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

AIM To determine if manipulation of dietary advanced glycation end product (AGE), intake affects nonalcoholic 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

Probing the correlation between insulin activity and structural stability through introduction of the rigid A6–A11 bond

This research was originally published in the Journal of Biological Chemistry. Ong, S. C., Belgi, A., van Lierop, B., Delaine, C., Andrikopoulos, S., MacRaild, C. A., … Forbes, B. E. Probing the correlation between insulin activity and structural stability through introduction of the rigid A6–A11 bond. J. Biol. Chem. 2018; V293, 11928-11943. © the Author(s). which has been published in final form at https://doi.org/10.1074/jbc.RA118.002486The development of fast-acting and highly stable insulin analogues is challenging. Insulin undergoes structural transitions essential for binding and activation of the insulin receptor (IR), but these conformational changes can also affect insulin stability. Previously, we substituted the insulin A6–A11 cystine with a rigid, non-reducible C=C linkage (“dicarba” linkage). A cis-alkene permitted the conformational flexibility of the A-chain N-terminal helix necessary for high-affinity IR binding, resulting in surprisingly rapid activity in vivo. Here, we show that, unlike the rapidly acting LysB28ProB29 insulin analogue (KP insulin), cis-dicarba insulin is not inherently monomeric. We also show that cis-dicarba KP insulin lowers blood glucose levels even more rapidly than KP insulin, suggesting that an inability to oligomerize is not responsible for the observed rapid activity onset of cis-dicarba analogues. Although rapid-acting, neither dicarba species is stable, as assessed by fibrillation and thermodynamics assays. MALDI analyses and molecular dynamics simulations of cis-dicarba insulin revealed a previously unidentified role of the A6–A11 linkage in insulin conformational dynamics. By controlling the conformational flexibility of the insulin B-chain helix, this linkage affects overall insulin structural stability. This effect is independent of its regulation of the A-chain N-terminal helix flexibility necessary for IR engagement. We conclude that high-affinity IR binding, rapid in vivo activity, and insulin stability can be regulated by the specific conformational arrangement of the A6–A11 linkage. This detailed understanding of insulin's structural dynamics may aid in the future design of rapid-acting insulin analogues with improved stability.SCO and BVL acknowledge the financial support from the Australian postgraduate scholarships. RSN acknowledges fellowship support from the Australian National Health and Medical Research Council. AJR and BEF acknowledge funding from the National Health and Medical Research Council (Project Grant APP1069328) and Australian Research Council (LP12020200792)