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Abstract Background Many human infections are transmitted through contact with animals (zoonoses), including household pets. Although pet ownership is common in most countries and non-pet owners may have frequent contact with pets, there is limited knowledge of the public’s pet contact practices and awareness of zoonotic disease risks from pets. The objective of this study was to characterize the general public’s knowledge, attitudes and risks related to pet ownership and animal contact in southern Ontario, Canada. Methods A self-administered questionnaire was distributed to individuals at two multi-physician clinics in Waterloo, Ontario, Canada during 2010. A single adult from each household was invited to participate in the study. Results Seventy five percent (641/853) of individuals approached completed the questionnaire. Pet ownership and contact were common; 64% of participants had a pet in their household and 37% of non-pet owning households had a member with at least weekly animal contact outside the home. Pet ownership was high (55%) for households with individuals at higher risk for infections (i.e., < 5 yrs, ≥ 65 yrs, immunocompromised). Most respondents (64%) indicated that they had never received information regarding pet-associated disease risks. When given a list of 11 infectious pathogens, respondents were only able to correctly classify just over half on their potential to be transmitted from pets to people (mean 6.4); independently, pet owners and those who recalled receiving information in the past about this topic were able to make significantly more correct identifications. Pet (36%) and non-pet owning households (10%) reported dog or cat bites or scratches during the preceding year. Households with individuals at higher risk for an infection did not differ from the remaining households regarding their perceived disease risk of pets, zoonotic disease knowledge, recall of being asked by their medical provider if they owned any pets, or recall of having received information regarding pet-associated disease risks and preventive measures. Conclusions These results suggest that there is a need for accessible zoonotic disease information for both pet and non-owning households, with additional efforts made by veterinary, human and public health personnel. Immediate educational efforts directed toward households with individuals at higher risk to infections are especially needed.

Abstract Background In Ontario, local public health inspectors play an important frontline role in protecting the public from foodborne illness. This study was an in-depth exploration of public health inspectors' perceptions of the key food safety issues in public health, and their opinions and needs with regards to food safety information resources. Methods Four focus group discussions were conducted with public health inspectors from the Central West region of Ontario, Canada during June and July, 2008. A questioning route was used to standardize qualitative data collection. Audio recordings of sessions were transcribed verbatim and data-driven content analysis was performed. Results A total of 23 public health inspectors participated in four focus group discussions. Five themes emerged as key food safety issues: time-temperature abuse, inadequate handwashing, cross-contamination, the lack of food safety knowledge by food handlers and food premise operators, and the lack of food safety information and knowledge about specialty foods (i.e., foods from different cultures). In general, participants reported confidence with their current knowledge of food safety issues and foodborne pathogens. Participants highlighted the need for a central source for food safety information, access to up-to-date food safety information, resources in different languages, and additional food safety information on specialty foods. Conclusions The information gathered from these focus groups can provide a basis for the development of resources that will meet the specific needs of public health inspectors involved in protecting and promoting food safety.

Abstract Background The demographics and lifestyles of Canadians are changing, thereby influencing food choices and food preparation in the home. Although different dietary practices are associated with increased risk of foodborne illness, our ability to evaluate food consumption trends and assess risks associated with foodborne illness is limited by lack of data on current eating habits and consumer food safety practices. The objective of this study was to describe, for the first time, the food consumption patterns in a Canadian-based population from a food safety perspective, in order to establish baseline data on actual food intake of individuals. Method A cross-sectional telephone survey of 2,332 randomly selected residents of Waterloo Region, Ontario, Canada (C-EnterNet pilot site) was conducted between November 2005 and March 2006. Food intake was assessed using a 7-day dietary recall method. Results Certain food items were consumed more than others among the same food groups, and consumption of many food items varied by gender and age. Specific foods considered high-risk for the transmission of certain enteric pathogens were significantly more likely to be consumed by males (i.e. unpasteurized juice, bean sprouts, and undercooked meat) and elderly individuals (i.e. undercooked eggs). The majority of households prepared and consumed most meals at home, allocating an average of 44 minutes to prepare a meal. Conclusion Baseline data on actual food intake is useful to public health professionals and food safety risk assessors for developing communication messages to consumers and in foodborne outbreak investigations.

Aims: Do associations between age at diagnosis of type 2 diabetes and vascular risk factors vary by ethnicity and deprivation?, Methods: Utilising the Clinical Practice Research Datalink, we matched 16-50-year-old individuals with newly diagnosed type 2 diabetes to ∼10 individuals without using sex, age and primary care practice. Differences in BMI, obesity, LDL-cholesterol, HbA1c, and hypertension between individuals with vs without type 2 diabetes across sex, age, ethnicity and deprivation quintiles were explored using generalised linear models., Results: We included 108,061 individuals (45.6% women) with newly diagnosed type 2 diabetes and 829,946 controls. BMI, obesity, LDL-cholesterol, and hypertension were higher in individuals with vs without type 2 diabetes. Across both sexes, all ethnic groups and deprivation quintiles, these differences were larger with an earlier age, particularly for BMI and obesity. Association between age and HbA1c were variable across subgroups. Differences in BMI, obesity, and hypertension (individuals with vs without diabetes) were largest in White individuals and with less deprivation., Conclusions: The increased vascular risk phenotype associated with an earlier age of diagnosis of type 2 diabetes was consistent across ethnic and deprivation groups. Population-based strategies are needed to address the risk associated with early-onset type 2 diabetes, especially weight-management-based strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Weight loss without adequate anabolic stimuli can lead to reductions in lean, as well as adipose, tissue. Health benefits typically associated with weight loss are therefore attenuated, as body composition potentially shifts from an obese to sarcopenic/frail phenotype. In contrast to the traditional connotation of frailty, this might occur in younger adults and is characterized by reduced performance in functional tasks of daily living. Nutritional supplements as an adjunct to weight loss intervention could support the maintenance of lean mass, particularly if structured exercise is contraindicated. This systematic review aims to quantify the effect of nutritional supplements, without concurrent exercise, on lean mass in individuals undergoing pharmacological and nonpharmacological-induced weight loss., Methods: This protocol describes a prospective systematic review and meta-analysis of randomized controlled trials investigating the effect of nutritional supplements on lean mass during weight loss. Comparison arms will not use nutritional supplements. Literature searches will be conducted using the following online databases: Embase, MEDLINE, Web of Science, Google Scholar, and OpenGrey. Outcome measures related to body composition, lean mass, skeletal muscle mass/size, or physical function will be extracted. Risk of bias will be assessed using the United States National Heart Lung and Blood Institute quality assessment tool for controlled intervention studies. A meta-analysis will be conducted to synthesize comparable outcomes., Results: The results of this review will be reported in adherence to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) standards, and published in a peer-reviewed journal., Conclusion: This study will be the first to systematically review nutritional interventions for the preservation or accretion of lean mass during weight loss. This review will identify gaps in the literature and inform the development of optimized weight loss strategies, for use in research and practice., Trial Registration: International Prospective Register of Systematic Reviews: PROSPERO CRD42024521540., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Aims: To design a regional clinical service for people with early-onset type 2 diabetes (EOT2D) in Leicester, Leicestershire and Rutland (England)., Methods: A literature search was undertaken to identify important considerations. A working group of key stakeholders was formed to design a triage system and service pathway. Electronic medical records (EMRs) were searched (15th November 2023) to assess feasibility of the pathway and adapt accordingly., Results: A literature search identified important considerations: High risk of complications; large proportion from minority ethnic and socioeconomically deprived backgrounds; significant psychological burden; stigma and other social challenges; and misclassification and miscoding. Novel clinical risk criteria were developed, implementable in EMRs, to match intervention-intensity to clinical need. Specialist clinics were planned, one for people at the highest-clinical risk, another for women with adverse perinatal risk factors. A healthcare professional training package was developed to increase awareness of the unmet clinical needs of people with EOT2D and to upskill in provision of holistic care. Subsequent EMR searches supported the need for our service. Due to the large numbers with HbA1c ≥86mmol/mol (10.0%; n=299; 10.8% of total), these people were prioritised for clinic access. We opted for specialist nurse/educator support to practices with clustering of patients and to financially incentivise referrals from primary care into services., Conclusions: We showcase a service specifically for people with EOT2D based on the literature, a broad range of stakeholder involvement and utilising a locally-sourced data-driven approach. We further discuss areas for development and recommendations based on the challenges we encountered., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with weight loss, diverse cardiorenal benefits and improved glycaemic control. However, the effects of SGLT2i on physical function and fitness are uncertain. The Dapagliflozin, Exercise Training and physicAl function trial investigates whether the SGLT2i dapagliflozin, alone or in combination with structured exercise training, improves physical function compared with diet-induced weight loss in adults with type 2 diabetes mellitus (T2DM), overweight/obesity and impaired physical function., Methods and Analysis: This single-centre randomised controlled trial will assign 1:1:1, 135 adults with T2DM and low physical function to receive one of three treatments: (1) dapagliflozin (10 mg once-daily) alone, (2) dapagliflozin (10 mg once-daily) plus structured exercise training or (3) diet control (where participants are supported to achieve 3% weight loss, equivalent to estimated weight loss with dapagliflozin treatment). Primary and secondary outcomes will be assessed at baseline, 12 and 24 weeks. The primary outcome is the difference in physical function, assessed using the modified Physical Performance Test, between the treatment groups and diet control at 24 weeks. Secondary outcomes include MRI-measured cardiac structure and function, maximal aerobic capacity, resting metabolic rate, device-measured physical activity and sleep, body composition, haemoglobin A1c and cardiovascular risk markers., Ethics and Dissemination: The Heath Research Authority (HRA) and the Medicines and Healthcare Products Regulatory Authority (MHRA) Research Ethics Committee have approved the study. The findings of the study will be published in peer-reviewed journals., Trial Registration Number: ISRCTN11459997., Eudract Number: 2019-004586-41., Competing Interests: Competing interests: JAS has received funding from Astra Zeneca UK in relation to an investigator-initiated trial. EA has received fellowship funding from Astra Zeneca. KK has acted as a consultant, speaker or received grants for investigator-initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche and Applied Therapeutics. GPM has received grant funding from NIHR, BHF and research support from Circle CVi, Resonance Health. TY was a named investigator on the funding application for this trial and has received research funding from Abbott. MJD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi, an advisory board member Lexicon, Pfizer, ShouTi Pharma Inc, Astra Zeneca, Zealand Pharma and Medtronic and as a speaker for Astra Zeneca, Napp Pharmaceuticals, Novartis and Amgen. She has received grants from Astra Zeneca, Novo Nordisk, Boehringer Ingelheim, Janssen and Sanofi-Aventis and Eli Lilly. LB, JMB, NAC, GG, EJ, JK, ER, AR, EW and JW have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To explore the 5-year incidence and relative rates of sleep disorders in younger (16-≤40 years) and middle-older (=>40 years) age adults with and without newly diagnosed type 2 diabetes., Methods: This retrospective, observational cohort study utilised data from the US Collaborative Network within the TriNetX database. We compared 5-year cumulative incidence of sleep disorders in younger (n = 110,088) and middle-older populations (n = 1,185,961)., Results: The absolute risk of developing any type of sleep disorder was greater in individuals with type 2 diabetes vs. those without. Over the 5-year follow-up period, 14.2 % of younger adults and 18.5 % of middle-older age adults with newly diagnosed type 2 diabetes developed any form of sleep disorder, compared to 4.5 % and 7.9 % propensity matched individuals without diabetes. We observed a more pronounced relative rate across the observed sleep disorders in younger adults., Conclusions: The 5-year risk of sleep disorders is higher in those with newly diagnosed type 2 diabetes vs. those without. A higher absolute risk was seen in middle-older adults, but relative rates were consistently higher in younger adults with type 2 diabetes. Sleep should be regularly discussed as part of a holistic approach to diabetes care, particularly in those aged ≤40., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [TY has received research funding from AstraZeneca and Abbott. KK has served as a consultant, speaker or received research grants/support from AstraZeneca, Boehringer Ingelheim, Lilly, and Novo Nordisk. MJD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc and as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. The other authors have no conflicts of interest to declare]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: To investigate the relationship between age at diagnosis of type 2 diabetes and the risk of macrovascular disease, heart failure, and microvascular disease., Methods: In August 2022, PubMed/EMBASE were searched for articles reporting (i) coronary artery disease, cerebrovascular disease, peripheral vascular disease, amputation; (ii) heart failure; and (iii) retinopathy, neuropathy, nephropathy (albuminuria, chronic kidney disease [CKD], end-stage renal disease) by age at diagnosis of type 2 diabetes. Random effects, non-linear dose-response meta-analysis was undertaken for each outcome to assess the association with age at diagnosis (40 years = reference), using both crude and maximally adjusted odds ratios separately, with and without adjustment for current age (age at sampling)., Results: We identified 42 articles (230,003 to 3,465,590 participants; 1035 to 391,140 events). Age at diagnosis was positively associated with the risk of macrovascular diseases, heart failure, and CKD, independent of current age, and negatively associated with retinopathy. For other microvascular outcomes, when adjusting for current age, a "reverse U" relationship was observed (peak risk = 55-60 years)., Discussion: Retinopathy was negatively associated with age at diagnosis, highlighting the importance of retinopathy screening in early-onset type 2 diabetes. The implications of other associations were unclear due to the heterogeneity in methodologies and findings., Competing Interests: Declaration of competing interest KK has acted as a consultant, speaker or received grants for investigator-initiated studies for AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim and Bayer. MJD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc. and as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. JAS received a grant for an investigator-initiated study for AstraZeneca. The other authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To examine the impact of impaired glycaemic regulation (IGR) and exercise training on hepatic lipid composition in men with metabolic dysfunction-associated steatotic liver disease (MASLD)., Materials and Methods: In Part A (cross-sectional design), 40 men with MASLD (liver proton density fat fraction [PDFF] ≥5.56%) were recruited to one of two groups: (1) normal glycaemic regulation (NGR) group (glycated haemoglobin [HbA1c] < 42 mmol∙mol -1 [<6.0%]; n = 14) or (2) IGR group (HbA1c ≥ 42 mmol∙mol -1 [≥6.0%]; n = 26). In Part B (randomized controlled trial design), participants in the IGR group were randomized to one of two 6-week interventions: (1) exercise training (EX; 70%-75% maximum heart rate; four sessions/week; n = 13) or (2) non-exercise control (CON; n = 13). Saturated (SI; primary outcome), unsaturated (UI) and polyunsaturated (PUI) hepatic lipid indices were determined using proton magnetic resonance spectroscopy. Additional secondary outcomes included liver PDFF, HbA1c, fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA-IR), peak oxygen uptake (VO 2 peak), and plasma cytokeratin-18 (CK18) M65, among others., Results: In Part A, hepatic SI was higher and hepatic UI was lower in the IGR versus the NGR group (p = 0.038), and this hepatic lipid profile was associated with higher HbA1c levels, FPG levels, HOMA-IR and plasma CK18 M65 levels (r s  ≥0.320). In Part B, hepatic lipid composition and liver PDFF were unchanged after EX versus CON (p ≥ 0.257), while FPG was reduced and VO 2 peak was increased (p ≤ 0.030). ΔVO 2 peak was inversely associated with Δhepatic SI (r = -0.433) and positively associated with Δhepatic UI and Δhepatic PUI (r ≥ 0.433)., Conclusions: Impaired glycaemic regulation in MASLD is characterized by greater hepatic lipid saturation; however, this composition is not altered by 6 weeks of moderate-intensity exercise training., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The updated European Working Group on Sarcopenia in Older People (EWGSOP2) recommends handgrip strength (HGS) and the chair stand test (CST) to assess muscle strength, with the CST being a convenient proxy for lower limb strength. However, adiposity may differentially influence these strength criteria and produce discrepant sarcopenia prevalence., Objective: To determine the prevalence of sarcopenia using HGS or the CST, and to investigate the associations between these strength criteria and adiposity in adults with type 2 diabetes mellitus., Methods: The EWGSOP2 definition was used to assess the prevalence of probable (low muscle strength), confirmed (plus low muscle mass) and severe (plus poor physical performance) sarcopenia. Linear regression models were used to study the association between different measures of muscle strength and adiposity., Results: We used data from 732 adults with type 2 diabetes mellitus (35.7% female, aged 64 ± 8 years, body mass index 30.7 ± 5.0 kg/m2). Using the CST compared with HGS produced a higher prevalence of probable (31.7% vs. 7.1%), confirmed (5.6% vs. 1.6%) and severe (1.0% vs. 0.3%) sarcopenia, with poor agreement between strength criteria to identify probable sarcopenia. CST performance, but not HGS, was significantly associated with all measures of adiposity in unadjusted and adjusted models., Conclusions: Higher levels of adiposity may impact CST performance, but not HGS, resulting in a higher prevalence of sarcopenia in adults with type 2 diabetes mellitus. Consideration should be paid to the most appropriate measure of muscle function in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objective: To examine the associations between age at type 2 diabetes diagnosis and the relative and absolute risk of all-cause and cause-specific mortality in England., Research Design and Methods: In this cohort study using primary care data from the Clinical Practice Research Datalink, we identified 108,061 individuals with newly diagnosed type 2 diabetes (16-50 years of age), matched to 829,946 individuals without type 2 diabetes. We estimated all-cause and cause-specific mortality (cancer, cardiorenal, other [noncancer or cardiorenal]) by age at diagnosis, using competing-risk survival analyses adjusted for key confounders., Results: Comparing individuals with versus without type 2 diabetes, the relative risk of death decreased with an older age at diagnosis: the hazard ratio for all-cause mortality was 4.32 (95% CI 3.35-5.58) in individuals diagnosed at ages 16-27 years compared with 1.53 (95% CI 1.46-1.60) at ages 48-50 years. Smaller relative risks by increasing age at diagnosis were also observed for cancer, cardiorenal, and noncancer or cardiorenal death. Irrespective of age at diagnosis, the 10-year absolute risk of all-cause and cause-specific mortality were higher in individuals with type 2 diabetes; yet, the absolute differences were small., Conclusions: Although the relative risk of death in individuals with versus without type 2 was higher at younger ages, the 10-year absolute risk of all investigated causes of death was small and similar in the two groups. Further multidecade studies could help estimate the long-term risk of complications and death in individuals with early-onset type 2 diabetes., (© 2023 by the American Diabetes Association.)

Background/objectives: Inadequate movement, excess adiposity, and insulin resistance augment cardiometabolic risk. This study examined the associations of objectively measured moderate-to-vigorous intensity physical activity (MVPA), sedentary time and cardiorespiratory fitness (CRF), with adipose tissue insulin resistance and ectopic fat., Methods: Data were combined from two previous experimental studies with community volunteers (n = 141, male = 60%, median (interquartile range) age = 37 (19) years, body mass index (BMI) = 26.1 (6.3) kg·m -2 ). Adipose tissue insulin resistance was assessed using the adipose tissue insulin resistance index (Adipo-IR); whilst magnetic resonance imaging (MRI) was used to measure liver, visceral (VAT) and subcutaneous abdominal adipose tissue (ScAT). Sedentary time and MVPA were measured via an ActiGraph GT3X+ accelerometer. Generalized linear models examined the association of CRF, MVPA, and sedentary time with Adipo-IR and fat depots. Interaction terms explored the moderating influence of age, sex, BMI and CRF., Results: After controlling for BMI and cardiometabolic variables, sedentary time was positively associated with Adipo-IR (β = 0.68 AU [95%CI = 0.27 to 1.10], P < 0.001). The association between sedentary time and Adipo-IR was moderated by age, CRF and BMI; such that it was stronger in individuals who were older, had lower CRF and had a higher BMI. Sedentary time was also positively associated with VAT (β = 0.05 L [95%CI = 0.01 to 0.08], P = 0.005) with the relationship being stronger in females than males. CRF was inversely associated with VAT (β = -0.02 L [95%CI = -0.04 to -0.01], P = 0.003) and ScAT (β = -0.10 L [95%CI = -0.13 to -0.06], P < 0.001); with sex and BMI moderating the strength of associations with VAT and ScAT, respectively., Conclusions: Sedentary time is positively associated with adipose tissue insulin resistance which regulates lipogenesis and lipolysis. CRF is independently related to central fat storage which is a key risk factor for cardiometabolic disease., (© 2023. The Author(s).)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases., (© 2023. The Author(s).)

Introduction: This cross-sectional study examined associations of device-measured sedentary time and moderate-to-vigorous physical activity (MVPA) with adipose tissue insulin resistance in people with or at high risk of type 2 diabetes (T2DM)., Method: Data were combined from six previous experimental studies (within our group) involving patients with T2DM or primary risk factors (median (interquartile range) age, 66.2 (66.0-70.8) yr; body mass index (BMI), 31.1 (28.0-34.4) kg·m -2 ; 62% male; n = 179). Adipose tissue insulin resistance was calculated as the product of fasted circulating insulin and nonesterified fatty acids (ADIPO-IR), whereas sedentary time and MVPA were determined from wrist-worn accelerometery. Generalized linear models examined associations of sedentary time and MVPA with ADIPO-IR with interaction terms added to explore the moderating influence of ethnicity (White European vs South Asian), BMI, age, and sex., Results: In finally adjusted models, sedentary time was positively associated with ADIPO-IR, with every 30 min of sedentary time associated with a 1.80-unit (95% confidence interval, 0.51-3.06; P = 0.006) higher ADIPO-IR. This relationship strengthened as BMI increased ( β = 3.48 (95% confidence interval, 1.50-5.46), P = 0.005 in the upper BMI tertile (≥33.2 kg·m -2 )). MVPA was unrelated to ADIPO-IR. These results were consistent in sensitivity analyses that excluded participants taking statins and/or metformin ( n = 126) and when separated into the participants with T2DM ( n = 32) and those at high risk ( n = 147)., Conclusions: Sedentary time is positively related to adipose tissue insulin sensitivity in people with or at high risk of T2DM. This relationship strengthens as BMI increases and may help explain established relationships between greater sedentary time, ectopic lipid, and hyperglycemia., (Copyright © 2023 by the American College of Sports Medicine.)

Aims: We investigated evidence from randomised, placebo-controlled trials of novel glucose-lowering therapies; sodium-glucose co-transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), on physical function in people with type 2 diabetes (T2D)., Methods: PubMed, Medline, Embase and Cochrane library were searched from 1 April 2005 to 20 January 2022. The primary outcome was change in physical function in groups receiving a novel glucose-lowering therapy versus placebo at the trial end-point., Results: Eleven studies met our criteria including nine for GLP-1RA and one each for SGLT2i and DPP4i. Eight studies included a self-reported measure of physical function, seven with GLP-1RA. Pooled meta-analysis showed an improvement of 0.12 (0.07, 017) points in favour of novel glucose-lowering therapies, mainly GLP-1RA. These findings were consistent when assessed individually for commonly used subjective assessments of physical function; namely the Short-Form 36 item-questionnaire (SF-36; all investigating GLP-1RA) and the Impact of Weight on Quality of Life-Lite (IWQOL-LITE; all, except one, exploring GLP-1RA) with estimated treatment differences (ETDs) of 0.86 (0.28, 1.45) and 3.72 (2.30, 5.15) respectively in favour of novel GLTs. For objective measures of physical function (VO 2max and 6-minute walk test (6MWT)) no significant between-group differences between the intervention and the placebo were found., Conclusions: GLP-1RAs showed improvements in self-reported outcomes of physical function. However, there is limited evidence to draw definitive conclusions especially because of lack of studies exploring the impact of SGLT2i and DPP4i on physical function. There is a need for dedicated trials to establish the association between novel agents and physical function., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Leukocyte cell-derived chemotaxin-2 (LECT2) and fibroblast growth factor 21 (FGF21) are hepatokines that are regulated by energy balance and mediate insulin sensitivity and glycaemic control. This cross-sectional study examined the independent associations of cardiorespiratory fitness (CRF), moderate-to-vigorous intensity physical activity (MVPA), and sedentary time with circulating LECT2 and FGF21. Data were combined from two previous experimental studies in healthy volunteers ( n  = 141, male = 60%, mean ± SD age = 37 ± 19 years, body mass index (BMI) = 26.1 ± 6.3 kg·m -2 ). Sedentary time and MVPA were measured via an ActiGraph GT3X + accelerometer, while magnetic resonance imaging quantified liver fat. CRF was assessed using incremental treadmill tests. Generalized-linear models examined the association of CRF, sedentary time, and MVPA with LECT2 and FGF21 while controlling for key demographic and anthropometric variables. Interaction terms explored the moderating influence of age, sex, BMI, and CRF. In the fully adjusted models, each SD increase in CRF was independently associated with a 24% (95% CI: -37% to -9%, P  = 0.003) lower plasma LECT2 concentration and 53% lower FGF21 concentration (95% CI: -73% to -22%, P  = 0.004). Each SD increase in MVPA was independently associated with 55% higher FGF21 (95% CI: 12% to 114%, P  = 0.006), and this relationship was stronger in those with lower BMI and higher levels of CRF. These findings demonstrate that CRF and wider activity behaviours may independently modulate the circulating concentrations of hepatokines and thereby influence inter-organ cross-talk., Competing Interests: The authors declare there are no competing interests.

Exercise is recommended for those with, or at risk of nonalcoholic fatty liver disease (NAFLD), owing to beneficial effects on hepatic steatosis and cardiometabolic risk. Whilst exercise training reduces total intrahepatic lipid in people with NAFLD, accumulating evidence indicates that exercise may also modulate hepatic lipid composition. This metabolic influence is important as the profile of saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) dramatically affect the metabolic consequences of hepatic lipid accumulation; with SFA being especially lipotoxic. Relatedly, obesity and NAFLD are associated with hepatic PUFA depletion and elevated SFA. This review summarizes the acute (single bout) and chronic (exercise training) effects of exercise on hepatic lipid composition in rodents (acute studies: n = 3, chronic studies: n = 13) and humans (acute studies: n = 1, chronic studies: n = 3). An increased proportion of hepatic PUFA after acute and chronic exercise is the most consistent finding of this review. Mechanistically, this may relate to an enhanced uptake of adipose-derived PUFA (reflecting habitual diet), particularly in rodents. A relative decrease in the proportion of hepatic MUFA after chronic exercise is also documented repeatedly, particularly in rodent models with elevated hepatic MUFA. This outcome is related to decreased hepatic stearoyl-CoA desaturase-1 activity in some studies. Findings regarding hepatic SFA are less consistent and limited by the absence of metabolic challenge in rodent models. These findings require confirmation in well-controlled interventions in people with NAFLD. These studies will be facilitated by recently validated magnetic resonance spectroscopy techniques, able to precisely quantify hepatic lipid composition in vivo., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Weight-lowering pharmacotherapies provide an option for weight management; however, their effects on physical activity, function, and cardiorespiratory fitness are not fully understood. We conducted a systematic review and meta-analysis of randomized controlled trials to investigate the effect of licensed weight loss pharmacotherapies on physical activity, physical function, and cardiorespiratory fitness in individuals with obesity. Fourteen trials met our prespecified inclusion criteria: Five investigated liraglutide, four semaglutide, three naltrexone/bupropion, and two phentermine/topiramate. All 14 trials included a self-reported measure of physical function, with the pooled findings suggesting an improvement favoring the pharmacotherapy intervention groups (SMD: 0.27; 95% CI: 0.22 to 0.32) and effects generally consistent across different therapies. Results were also consistent when stratified by the two most commonly used measures: The Short-Form 36-Item Questionnaire (SF-36) (0.24; 0.17 to 0.32) and the Impact of Weight on Quality Of Life-Lite (IWQOL-Lite) (0.29; 0.23 to 0.35). Meta-regression confirmed a significant association between pharmacotherapy induced weight loss and improved physical function for IWQOL-Lite (p = 0.003). None of the studies reported a physical activity outcome, and only one study reported objectively measured cardiorespiratory fitness. Improvements in self-reported physical function were observed with weight loss therapy, but the effect on physical activity or objectively measured physical function and fitness could not be determined., (© 2023 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

Background: A step cadence of 100 steps/minute is widely used to define moderate-intensity walking. However, the generalizability of this threshold to different populations needs further research. We investigate moderate-intensity step cadence values during treadmill walking and daily living in older adults., Methods: Older adults (≥ 60 years) were recruited from urban community venues. Data collection included 7 days of physical activity measured by an activPAL3™ thigh worn device, followed by a laboratory visit involving a 60-min assessment of resting metabolic rate, then a treadmill assessment with expired gas measured using a breath-by-breath analyser and steps measured by an activPAL3™. Treadmill stages were undertaken in a random order and lasted 5 min each at speeds of 1, 2, 3, 4 and 5 km/h. Metabolic equivalent values were determined for each stage as standardised values (METS standard ) and as multiples of resting metabolic rate (METS relative ). A value of 3 METS standard defined moderate-intensity stepping. Segmented generalised estimating equations modelled the association between step cadence and MET values., Results: The study included 53 participants (median age = 75, years, BMI = 28.0 kg/m 2 , 45.3% women). At 2 km/h, the median METS standard and METS relative values were above 3 with a median cadence of 81.00 (IQR 72.00, 88.67) steps/minute. The predicted cadence at 3 METS standard was 70.3 (95% CI 61.4, 75.8) steps/minute. During free-living, participants undertook median (IQR) of 6988 (5933, 9211) steps/day, of which 2554 (1297, 4456) steps/day were undertaken in continuous stepping bouts lasting ≥ 1 min. For bouted daily steps, 96.4% (90.7%, 98.9%) were undertaken at ≥ 70 steps/minute., Conclusion: A threshold as low as 70 steps/minute may be reflective of moderate-intensity stepping in older adults, with the vast majority of all bouted free-living stepping occurring above this threshold., (© 2023. The Author(s).)

Objective: To investigate the association between age at diagnosis of type 2 diabetes and depressive symptoms, diabetes-specific distress, and self-compassion among adults with type 2 diabetes., Research Design and Methods: This analysis used data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycemic Control (CODEC) cross-sectional study. Information was collected on depressive symptoms, diabetes-specific distress, and self-compassion, measured using validated self-report questionnaires, in addition to sociodemographic and clinical data. Multivariable regression models, adjusted for diabetes duration, sex, ethnicity, deprivation status, prescription of antidepressants (selective serotonin reuptake inhibitors), and BMI were used to investigate the association between age at diagnosis of type 2 diabetes and each of the three psychological outcomes., Results: A total of 706 participants were included; 64 (9.1%) were diagnosed with type 2 diabetes at <40 years, 422 (59.8%) between 40 and 59 years, and 220 (31.2%) at ≥60 years of age. After adjustment for key confounders, including diabetes duration, younger age at diagnosis was significantly associated with higher levels of depressive symptoms (βadj: -0.18 [95% CI -0.25 to -0.10]; P < 0.01) and diabetes-specific distress (βadj: -0.03 [95% CI -0.04 to -0.02]; P < 0.01) and lower levels of self-compassion (βadj: 0.01 [95% CI 0.00 to 0.02]; P < 0.01)., Conclusions: Diagnosis of type 2 diabetes at a younger age is associated with lower psychological well-being, suggesting the need for clinical vigilance and the availability of age-appropriate psychosocial support., (© 2023 by the American Diabetes Association.)

Background & Aims: Physical activity (PA) is recommended in the management of non-alcoholic fatty liver disease (NAFLD) given its beneficial effects on liver fat and cardiometabolic risk. Using data from the UK Biobank population-cohort, this study examined associations between habitual PA and hepatic fibro-inflammation., Methods: A total of 840 men and women aged 55-70 years were included in this cross-sectional study. Hepatic fibro-inflammation (iron-corrected T1 [cT1]) and liver fat were measured using MRI, whilst body fat was measured using dual-energy X-ray absorptiometry. PA was measured using accelerometry. Generalised linear models examined associations between PA (light [LPA], moderate [MPA], vigorous [VPA], moderate-to-vigorous [MVPA] and mean acceleration) and hepatic cT1. Models were fitted for the whole sample and separately for upper and lower median groups for body and liver fat. Models were adjusted for sociodemographic and lifestyle variables., Results: In the full sample, LPA (-0.08 ms [-0.12 to -0.03]), MPA, (-0.13 ms [-0.21 to -0.05]), VPA (-1.16 ms [-1.81 to -0.51]), MVPA (-0.14 ms [-0.21 to -0.06]) and mean acceleration (-0.67 ms [-1.05 to-0.28]) were inversely associated with hepatic cT1. With the sample split by median liver or body fat, only VPA was inversely associated with hepatic cT1 in the upper median groups for body (-2.68 ms [-4.24 to -1.13]) and liver fat (-2.33 [-3.73 to -0.93]). PA was unrelated to hepatic cT1 in the lower median groups., Conclusions: Within a population-based cohort, device-measured PA is inversely associated with hepatic fibro-inflammation. This relationship is strongest with VPA and is greater in people with higher levels of body and liver fat., Lay Summary: This study has shown that people who regularly perform greater amounts of physical activity have a reduced level of inflammation and fibrosis in their liver. This beneficial relationship is particularly strong when more intense physical activity is undertaken ( i . e ., vigorous-intensity), and is most visible in individuals with higher levels of liver fat and body fat., Competing Interests: None of the authors have any conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce body weight and improve cardiometabolic health, but their effect on physical activity is unknown., Research Design and Methods: We pooled data (n = 148) from three randomized trials to investigate the effect of empagliflozin (SGLT2i) and liraglutide (GLP-1RA), in comparison with sitagliptin (dipeptidyl peptidase 4 inhibitor) and dietary therapies, on accelerometer-assessed physical activity., Results: Liraglutide (mean -1,144 steps/day; 95% CI -2,069 to -220), empagliflozin (-1,132 steps/day; -1,739, -524), and sitagliptin (-852 steps/day; -1,625, -78) resulted in reduced total daily physical activity after 6 months (P < 0.01 vs. control). Moderate- to vigorous-intensity physical activity was also reduced. Dietary interventions led to no change or an increase in physical activity., Conclusions: The initiation of all glucose-lowering therapies was associated with reduced physical activity, warranting further investigation., (© 2022 by the American Diabetes Association.)

Aim: To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity., Materials and Methods: In a double-blind, placebo-controlled trial, 68 adults (aged 30-75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%-10.0% [42-86 mmol/mol]) and body mass index of 25 kg/m 2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide-YY (PYY) during a 3-hour mixed-meal tolerance test from baseline to 24 weeks. Postprandial total glucagon-like peptide-1 (GLP-1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance., Results: The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: -8.6 [-28.6 to 11.4], 13.4 [-6.1 to 33.0] and 1.0 [-18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions., Conclusions: In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy., Clinical Trials Registration: NCT02798744, www., Clinicaltrials: gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms., Methods: One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators., Results: Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes., Conclusions: Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant., (© 2022. The Author(s).)

This systematic review and meta-analysis determined the impact of exercise training on adipose tissue insulin sensitivity in adults. Its scope extended to studies measuring whole-body and localized subcutaneous adipose tissue insulin sensitivity using validated techniques. Consensus from four studies demonstrates that exercise training improved whole-body adipose tissue insulin sensitivity when measured via stable-isotope lipid tracers (rate of appearance suppression in response to hyperinsulinemia). Meta-analysis of 20 studies (26 intervention arms) employing the adipose tissue insulin resistance index (ADIPO-IR) supported these findings (-10.63 [-14.12 to -7.15] pmol·L -1  × mmol·L -1 ). With ADIPO-IR, this response was greater in studies documenting weight loss and shorter sampling time (≤48 h) post-training. Overall, exercise training did not affect whole-body adipose tissue insulin sensitivity in seven studies (11 intervention arms) measuring the suppression of circulating non-esterified fatty acids in response to insulin infusion (1.51 [-0.12 to 3.14]%); however, subgroup analysis identified an enhanced suppression post-training in trials reporting weight loss. From four microdialysis studies, consensus indicates no effect of exercise training on localized (abdominal/femoral) adipose tissue insulin sensitivity, potentially suggesting that enhanced whole-body responses are related to improvements in central adipose depots. However, heterogeneity within microdialysis protocols dictates that findings must be viewed with caution., (© 2022 World Obesity Federation.)

Background: The diagnosis of type 2 diabetes (T2D) in younger adults, an increasingly common public health issue, is associated with a higher risk of cardiovascular complications and mortality, which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age., Aim: To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D., Methods: A pooled dataset was used, comprised of data from five previous studies of adults with T2D, including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years. Anthropometric and blood biomarker measurements included body weight, body mass index (BMI), waist circumference, body fat percentage, glycaemic control (HbA1c), lipid profile and blood pressure. Univariable and multivariable linear regression models, adjusted for diabetes duration, sex, ethnicity and smoking status, were used to investigate the association between age at diagnosis and each cardiovascular risk factor., Results: A higher proportion of participants diagnosed with T2D under the age of 40 were female, current smokers and treated with glucose-lowering medications, compared to participants diagnosed later in life. Participants diagnosed with T2D under the age of 40 also had higher body weight, BMI, waist circumference and body fat percentage, in addition to a more adverse lipid profile, compared to participants diagnosed at an older age. Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight [95% confidence interval (CI): 0.52-0.82 kg], 0.18 kg/m 2 higher BMI (95%CI: 0.10-0.25) and 0.32 cm higher waist circumference (95%CI: 0.14-0.49), after adjustment for duration of diabetes and other confounders. Younger age at diagnosis was also significantly associated with higher HbA1c, total cholesterol, low-density lipoprotein cholesterol and triglycerides., Conclusion: The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile, compared to those diagnosed later in life., Competing Interests: Conflict-of-interest statement: Barker MM, Zaccardi F, Brady EM, Gulsin GS, Hall AP, Henson J, Htike ZZ, McCann GP, Redman EL, Webb DR and Yeo J report no conflicts of interest. Khunti K has acted as consultant, advisory board member and speaker for Abbott, Amgen, Astrazeneca, Bayer, NAPP, Lilly, Merck Sharp and Dohme, Novartis, Novo Nordisk, Roche, Berlin-Chemie AG/Menarini Group, Sanofi-Aventis, Servier, Boehringer Ingelheim, EACME grants from Boehringer Ingelheim, AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme. Yates T and Sargeant JA are supported by the NIHR Leicester BRC and have received project funding in the form an investigator-initiated grant from AstraZeneca. EGW has received personal fees from Abbott Diabetes Care, Dexcom, Eli lilly, Insulet, Medtronic, Novo Nordisk, Sanofi Aventis. Davies MJ has acted as consultant, advisory board member and speaker for Novo Nordisk, Sanofi, Lilly and Boehringer Ingelheim, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Servier and Gilead Sciences Ltd and as a speaker for Napp Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m 2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further., (© 2021 John Wiley & Sons Ltd.)

Aim: To quantify how differences in metrics characterizing physical activity and sedentary behaviour in type 2 diabetes are associated with physical function., Methods: This analysis included participants' data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) cross-sectional study. Data were stratified into two groups according to their short physical performance battery (SPPB) score (impaired physical function = SPPB < 10 and normal physical function = SPPB ≥ 10). Hand-grip strength, sit-to-stand 60 (STS-60) and the Duke Activity Status Index (DASI) score were used to assess functional capacity, while physical activity metrics were measured with a wrist-worn accelerometer. The associations between physical activity metrics and measures of functional capacity were analysed using generalized linear modelling., Results: Some 635 adults (median age 66 years, 34% female) were included in this analysis. Overall, 29% of the cohort scored < 10 in the SPPB test indicating impaired physical function. This group spent more time in prolonged sedentary behaviour (600.7 vs. 572.5 min) and undertook less-intense physical activity. Each sd increase in physical activity volume and intensity gradients for those with impaired physical function was associated with 17% more repetitions for STS-60 with similar associations seen for DASI score. Each sd in sedentary time was associated with 15% fewer repetitions in STS-60 and 16% lower DASI score in those with impaired physical function, whereas in normal physical function group it was 2% and 1%, respectively., Conclusions: The strength of the associations for physical activity measures and functional capacity were modified by physical function status, with the strongest association seen in those with impaired physical function., (© 2020 Diabetes UK.)

Objective: To examine whether circulating metabolic responses to low-volume high-intensity interval exercise (LV-HIIE) or continuous moderate-intensity aerobic exercise (CME) differ between white Europeans and South Asians with nondiabetic hyperglycemia (NDH)., Research Design and Methods: Thirteen white Europeans and 10 South Asians (combined median [interquartile range] age 67 [60-68] years, HbA 1c 5.9% [5.8-6.1%] [41.0 (39.9-43.2) mmol ⋅ mol -1 ]) completed three 6-h conditions (sedentary control [CON], LV-HIIE, and CME) in a randomized order. Exercise conditions contained a single bout of LV-HIIE and CME, respectively (each ending at 2 h), with meals provided at 0 and 3 h. Circulating glucose (primary outcome), insulin, insulin resistance index (IRI), triglycerides, and nonesterified fatty acids were measured at 0, 0.5, 1, 2, 3, 3.5, 4, 5, and 6 h. Data were analyzed as postexercise time-averaged area under the curve (AUC) adjusted for age, sex, and preexercise AUC., Results: Glucose was similar in each condition and with ethnicity, with no condition-by-ethnicity interaction ( P ≥ 0.28). However, insulin was lower in LV-HIIE (mean [95% CI] -44.4 [-23.7, -65.1] mU ⋅ L -1 ) and CME (-33.8 [-13.7, -53.9] mU ⋅ L -1 ) compared with CON. Insulin responses were greater in South Asians (interaction P = 0.03) such that values were similar in each ethnicity during exercise conditions, despite being 33% higher in South Asians during CON. IRI followed a similar pattern to insulin. Lipids were unaffected by exercise., Conclusions: Reductions in insulin and insulin resistance after acute LV-HIIE and CME are greater in South Asians than in white Europeans with NDH. Further trials are required to examine the longer-term impact of LV-HIIE and CME on cardiometabolic health., Competing Interests: J.A.S. and C.J. are joint first authors., (© 2020 by the American Diabetes Association.)

Objective: To evaluate the temporal patterns of cardiometabolic multimorbidity (CM) and depression in White Caucasians (WCs) and African Americans (AAs) with early-onset type 2 diabetes and their impact on long-term atherosclerotic cardiovascular disease (ASCVD)., Research Design and Methods: From U.S. electronic medical records, 101,104 AA and 505,336 WC subjects with type 2 diabetes diagnosed between 2000 and 2017 were identified (mean follow-up 5.3 years). Among those without ASCVD at diagnosis, risk of ASCVD and three-point major adverse cardiovascular events (MACE-3) (heart failure, myocardial infarction, or stroke) was evaluated between ethnicities by age-groups., Results: The proportion of patients diagnosed at <50 years of age increased during 2012-2017 (AA 34-38%, WC 26-29%). Depression prevalence increased during 2000-2017 (AA 15-23%, WC 20-34%), with an increasing trend for CM at diagnosis in both groups. Compared with WC, the adjusted MACE-3 risk was significantly higher in AA across all age-groups, more pronounced in the 18-39-year age-group (hazard ratio 95% CI 1.42, 1.88), and in patients with and without depression. AAs had a 17% (1.05, 1.31) significantly higher adjusted ASCVD risk in the 18-39-year age-group only. Depression was independently associated with ASCVD and MACE-3 risk in both ethnic groups across all age-groups. Other comorbidities were independently associated with ASCVD and MACE-3 risk only among WCs., Conclusions: AAs have higher cardiovascular risk compared with WCs, particularly in early-onset type 2 diabetes. CM and depression at diabetes diagnosis have been increasing over the past two decades in both ethnic groups. Strategies for screening and optimal management of CM and depression, particularly in early-onset type 2 diabetes, may result in a lower cardiovascular risk., (© 2020 by the American Diabetes Association.)

To systematically review the current literature investigating associations between zinc-alpha2-glycoprotein (ZAG) and dysglycaemia (including type 2 diabetes (T2DM), poly-cystic-ovary syndrome (PCOS), pre-diabetes or insulin resistance). This included relationships between ZAG and continuous measures of insulin and glucose. Additionally, we performed a meta-analysis to estimate the extent that ZAG differs between individuals with or without dysglycaemia; whilst examining the potential influence of adiposity. A systematic search was performed on four databases for studies on circulating ZAG concentrations in adult human populations, comparing healthy controls to individuals with dysglycaemia. Key characteristics, including the mean ZAG concentrations (mg∙L -1 ), and any correlational statistics between ZAG and continuous measures of glucose, glycated haemoglobin (HbA1c) or insulin were extracted. Meta-analyses were performed to compare metabolically healthy controls to cases, and on studies that compared controls and cases considered overweight or obese (body mass index (BMI) ≥25 kg . m 2 ). 1575 papers were identified and 14 studies (16 cohorts) were considered eligible for inclusion. Circulating ZAG was lower in individuals with dysglycaemia compared to metabolically healthy controls (-4.14 [-8.17, -0.11] mg . L -1 ; I 2  = 98.5%; p < 0.001). When using data from only studies with overweight or obese groups with or without dysglycaemia (three studies (four cohorts); pooled n = 332), the difference in circulating ZAG was no longer significant (-0.30 [-3.67, 3.07] mg . L -1 ; I 2  = 28.0%; p = 0.225). These data suggest that ZAG may be implicated in dysglycaemia, although there was significant heterogeneity across different studies and the mediating effect of adiposity cannot be excluded. Therefore, more research is needed before robust conclusions can be drawn.

Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin's position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin's status as a first-line agent and finally answer key questions when considering metformin's role in the modern-day management of T2D.

Single bouts of land-based exercise (for example, walking, running, cycling) do not typically alter post-exercise energy intake on the day of exercise. However, anecdotal and preliminary empirical evidence suggests that swimming may increase appetite and energy intake. This study compared the acute effects of swimming on appetite, energy intake, and food preference and reward, versus exertion-matched cycling and a resting control. Thirty-two men (n = 17; mean ± SD age 24 ± 2 years, body mass index [BMI] 25.0 ± 2.6 kg/m 2 ) and women (n = 15; age 22 ± 3 years, BMI 22.8 ± 2.3 kg/m 2 ) completed three experimental trials (swimming, cycling, control) in a randomised, crossover design. The exercise trials involved 60-min of 'hard' exercise (self-selected rating of perceived exertion: 15) performed 90-min after a standardised breakfast. Food preference and reward were assessed via the Leeds Food Preference Questionnaire 15-min after exercise, whilst ad libitum energy intake was determined 30-min after exercise. The control trial involved identical procedures except no exercise was performed. Compared with control (3259 ± 1265 kJ), swimming increased ad libitum energy intake (3857 ± 1611 kJ; ES = 0.47, 95% CI of the mean difference between trials 185, 1010 kJ, P = 0.005); the magnitude of increase was smaller after cycling (3652 ± 1619 kJ; ES = 0.31, 95% CI -21, 805 kJ, P = 0.062). Ad libitum energy intake was similar between swimming and cycling (ES = 0.16, 95% CI -207, 618 kJ, P = 0.324). This effect was consistent across sexes and unrelated to food preference and reward which were similar after swimming and cycling compared with control. This study has identified an orexigenic effect of swimming. Further research is needed to identify the responsible mechanism(s), including the relevance of water immersion and water temperature per se., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To assess the relationship between subclinical cardiac dysfunction and aerobic exercise capacity (peak VO 2 ) in adults with type 2 diabetes (T2D), a group at high risk of developing heart failure., Research Design and Methods: Cross-sectional study. We prospectively enrolled a multiethnic cohort of asymptomatic adults with T2D and no history, signs, or symptoms of cardiovascular disease. Age-, sex-, and ethnicity-matched control subjects were recruited for comparison. Participants underwent bioanthropometric profiling, cardiopulmonary exercise testing, and cardiovascular magnetic resonance with adenosine stress perfusion imaging. Multivariable linear regression analysis was undertaken to identify independent associations between measures of cardiovascular structure and function and peak VO 2 ., Results: A total of 247 adults with T2D (aged 51.8 ± 11.9 years, 55% males, 37% black or south Asian ethnicity, HbA 1c 7.4 ± 1.1% [57 ± 12 mmol/mol], and duration of diabetes 61 [32-120] months) and 78 control subjects were included. Subjects with T2D had increased concentric left ventricular remodeling, reduced myocardial perfusion reserve (MPR), and markedly lower aerobic exercise capacity (peak VO 2 18.0 ± 6.6 vs. 27.8 ± 9.0 mL/kg/min; P < 0.001) compared with control subjects. In a multivariable linear regression model containing age, sex, ethnicity, smoking status, and systolic blood pressure, only MPR (β = 0.822; P = 0.006) and left ventricular diastolic filling pressure (E/e') (β = -0.388; P = 0.001) were independently associated with peak VO 2 in subjects with T2D., Conclusions: In a multiethnic cohort of asymptomatic people with T2D, MPR and diastolic function are key determinants of aerobic exercise capacity, independent of age, sex, ethnicity, smoking status, or blood pressure., (© 2020 by the American Diabetes Association.)

Short-term overfeeding may provoke compensatory appetite responses to correct the energy surplus. However, the initial time-course of appetite, appetite-related hormone, and reward-related responses to hyperenergetic, high-fat diets (HE-HFD) are poorly characterised. Twelve young healthy men consumed a HE-HFD (+50% energy, 65% fat) or control diet (36% fat) for seven days in a randomised crossover design. Mean appetite perceptions were determined during an oral glucose tolerance test (OGTT) before and after each diet. Fasted appetite perceptions, appetite-related hormones, and reward parameters were measured pre-diet and after 1-, 3- and 7-days of each diet. The HE-HFD induced a pre-to-post diet suppression in mean appetite during the OGTT (all ratings p ≤ 0.058, effect size ( d ) ≥ 0.31), and reduced the preference for high-fat vs. low-fat foods (main effect diet p = 0.036, d = 0.32). Fasted leptin was higher in the HE-HFD than control diet (main effect diet p < 0.001, d = 0.30), whilst a diet-by-time interaction ( p = 0.036) revealed fasted acylated ghrelin was reduced after 1-, 3- and 7-days of the HE-HFD (all p ≤ 0.040, d ≥ 0.50 vs. pre-diet). Appetite perceptions and total peptide YY in the fasted state exhibited similar temporal patterns between the diets (diet-by-time interaction p ≥ 0.077). Seven days of high-fat overfeeding provokes modest compensatory changes in subjective, hormonal, and reward-related appetite parameters.

Aims/hypothesis: Early-onset adult type 2 diabetes (diagnosed between ages 18 and 39 years) is increasingly prevalent and associated with poor long-term outcomes. We hypothesised that individuals with early-onset adult type 2 diabetes were underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines., Methods: We reviewed the mean age of the study populations recruited to 90 prominent trials in type 2 diabetes, including 37 cardio-renal outcomes trials across a range of pharmacological, non-pharmacological and multifactorial interventions, 28 trials from the phase III programmes of three representative glucose-lowering therapies used routinely in clinical practice (empagliflozin, liraglutide and sitagliptin) and 25 prominent trials of diabetes self-management education and support or intensive lifestyle interventions (diet or supervised exercise training). We then estimated the number of individuals within these trials who were aged between 18 and 39 years., Results: Across all 90 trials, the mean age of 268,978 participants was 63 years (range 51-69 years in individual trials). In 73 trials (81%), <5% of participants were estimated to be aged 18-39 years, despite this age group representing ~15-20% of the adult type 2 diabetes population. Twenty-nine of these trials (32%; total 164,953 participants) excluded individuals below 40 years of age altogether., Conclusions/interpretation: Guidelines for early-onset adult type 2 diabetes are extrapolated predominantly from evidence in older individuals. Strategies to support the participation of individuals with early-onset adult type 2 diabetes in future research are imperative to ensure guidelines for these high-risk individuals are evidence-based.

Aim: To compare the effects of a glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor on magnetic resonance imaging-derived measures of cardiovascular function., Materials and Methods: In a prospective, randomized, open-label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non-insulin treated young (aged 18-50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight., Results: Seventy-six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m -2 ), of whom 65% had ≥1 cardiovascular risk factor. Sixty-one participants had primary outcome data available. There were no statistically significant between-group differences (intention-to-treat; mean [95% confidence interval]) in PEDSR change (-0.01 [-0.07, +0.06] s -1 ), left ventricular ejection fraction (-1.98 [-4.90, +0.94]%), left ventricular mass (+1.14 [-5.23, +7.50] g) or aortic distensibility (-0.35 [-0.98, +0.28] mmHg -1  × 10 -3 ) after 26 weeks. Reductions in HbA1c (-4.57 [-9.10, -0.37] mmol mol -1 ) and body weight (-3.88 [-5.74, -2.01] kg) were greater with liraglutide., Conclusion: There were no differences in cardiovascular structure or function after short-term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin-based therapies., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)