Sars-Cov-2 Infection in People with Type 1 Diabetes and Hospital Admission: An Analysis of Risk Factors for England.

INTRODUCTION: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus (coronavirus disease 2019 [COVID-19]) pandemic revealed the vulnerability of specific population groups in relation to susceptibility to acute deterioration in their health, including hospital admission and mortality. There is less data on outcomes for people with type 1 diabetes (T1D) following SARS-CoV-2 infection than for those with type 2 diabetes (T2D). In this study we set out to determine the relative likelihood of hospital admission following SARS-CoV-2 infection in people with T1D when compared to those without T1D. METHODS: This study was conducted as a retrospective cohort study and utilised an all-England dataset. Electronic health record data relating to people in a national England database (NHS England's Secure Data Environment, accessed via the BHF Data Science Centre's CVD-COVID-UK/COVID-IMPACT consortium) were analysed. The cohort consisted of patients with a confirmed SARS-CoV-2 infection, and the exposure was whether or not an individual had T1D prior to infection (77,392 patients with T1D). The patients without T1D were matched for sex, age and approximate date of the positive COVID-19 test, with three SARS-CoV-2-infected people living without diabetes (n = 223,995). Potential factors influencing the relative likelihood of the outcome of hospital admission within 28 days were ascertained using univariable and multivariable logistic regression. RESULTS: Median age of the people living with T1D was 37 (interquartile range 25-52) years, 47.4% were female and 89.6% were of white ethnicity. Mean body mass index was 27 (standard error [SE] 0.022) kg/m2, and mean glycated haemoglobin (HbA1c) was 67.3 (SE 0.069) mmol/mol (8.3%). A significantly higher proportion of people with T1D (10.7%) versus matched non-diabetes individuals (3.9%) were admitted to hospital. In combined analysis including individuals with T1D and matched controls, multiple regression modelling indicated that the factors independently relating to a higher likelihood of hospital admission were: T1D (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.62-1.80]), age (OR 1.02, 95% CI 1.02-1.03), social deprivation (higher Townsend deprivation score: OR 1.07, 95% CI 1.06-1.08), lower estimated glomerular filtration rate (eGFR) value (OR 0.975, 95% CI 0.974-0.976), non-white ethnicity (OR black 1.19, 95% CI 1.06-1.33/OR Asian 1.21, 95% CI 1.05-1.39) and having asthma (OR 1.27, 95% CI 1.19-1.35]), chronic obstructive pulmonary disease (OR 2.10, 95% CI 1.89-2.32), severe mental illness (OR 1.83, 95% CI 1.57-2.12) or hypertension (OR 1.44, 95% CI 1.37-1.52). CONCLUSION: In this all-England study, we describe that, following confirmed infection with SARS-CoV-2, the risk factors for hospital admission for people living with T1D are similar to people without diabetes following confirmed SARS-CoV-2 infection, although the former were more likely to be admitted to hospital. The younger age of individuals with T1D in relation to risk stratification must be taken into account in any ongoing risk reduction strategies regarding COVID-19/future viral pandemics.

Pre-Meal Whey Protein Alters Postprandial Insulinemia by Enhancing ß-Cell Function and Reducing Insulin Clearance in T2D.

CONTEXT: Treatments that reduce postprandial glycemia (PPG) independent of stimulating insulin secretion are appealing for the management of type 2 diabetes (T2D). Consuming pre-meal whey protein (WP) reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on ß-cell function and insulin kinetics remains unclear. OBJECTIVE: To examine the PPG-regulatory effects of pre-meal WP by modeling insulin secretion rates (ISR), insulin clearance, and ß-cell function. METHODS: This was a single-blind, randomized, placebo-controlled, crossover design study in 18 adults with T2D (HbA1c, 56.7 ± 8.8 mmol/mol) who underwent 2 240-minute mixed-meal tolerance tests. Participants consumed WP (15 g protein) or placebo (0 g protein) 10 minutes before a mixed-macronutrient breakfast meal. PPG, pancreatic islet, and incretin hormones were measured throughout. ISR was calculated by C-peptide deconvolution. Estimates of insulin clearance and ß-cell function were modeled from glucose, insulin, and ISR. Changes in PPG incremental area under the curve (iAUC; prespecified) and insulin clearance (post hoc) were measured. RESULTS: ß-cell function was 40% greater after WP (P = .001) and was accompanied with a -22% reduction in postprandial insulin clearance vs placebo (P < .0001). Both the peak change and PPG iAUC were reduced by WP (-1.5 mmol/L and -16%, respectively; both P < .05). Pre-meal WP augmented a 5.9-fold increase in glucagon and glucagon-like peptide 1 iAUC (both P < .0001), and a 1.5-fold increase in insulin iAUC (P < .001). Although the plasma insulin response was greater following WP, ISR was unaffected (P = .133). CONCLUSION: In adults with T2D, pre-meal WP reduced PPG by coordinating an enhancement in ß-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further ß-cell stimulation.Trial registry ISRCTN ID: ISRCTN17563146 Website link: www.isrctn.com/ISRCTN17563146.

Thrice daily consumption of a novel, premeal shot containing a low dose of whey protein increases time in euglycemia during 7 days of free-living in individuals with type 2 diabetes.

INTRODUCTION: During acute feeding trials, consuming a large dose of whey protein (WP) before meals improves postprandial glucose regulation in people with type 2 diabetes. It is unclear if the reported benefits of premeal WP supplementation are translatable to everyday care or are associated with clinically meaningful, real-world glycemic outcomes. This study examined the application of a novel, premeal shot containing a low dose of WP on parameters of free-living glycemic control in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, placebo-controlled, single-blind crossover design, 18 insulin naive individuals with type 2 diabetes ((mean±SD) age, 50±6 years; HbA1c (glycated hemoglobin), 7.4%±0.8%; duration of diabetes, 6±5 years) consumed a ready-to-drink WP shot (15 g of protein) or a nutrient-depleted placebo beverage 10 min before breakfast, lunch, and dinner over a 7-day free-living period. Free-living glucose control was measured by blinded continuous glucose monitoring and determined by the percentage of time spent above range (>10 mmol/L), in euglycemic range (3.9-10.0 mmol/L), below range (<3.9 mmol/L) and mean glucose concentrations. RESULTS: Mealtime WP supplementation reduced the prevalence of daily hyperglycemia by 8%±19% (30%±25% vs 38%±28%, p<0.05), thereby enabling a 9%±19% (~2 hours/day) increase in the time spent in euglycemia (p<0.05). Mean 24-hour blood glucose concentrations were 0.6±1.2 mmol/L lower during WP compared with placebo (p<0.05). Similar improvements in glycemic control were observed during the waken period with premeal WP supplementation (p<0.05), whereas nocturnal glycemic control was unaffected (p>0.05). Supplemental compliance/acceptance was high (>98%), and no adverse events were reported. CONCLUSIONS: Consuming a novel premeal WP shot containing 15 g of protein before each main meal reduces the prevalence of daily hyperglycemia, thereby enabling a greater amount of time spent in euglycemic range per day over 7 days of free-living in people with type 2 diabetes. TRIAL REGISTRATION NUMBER: ISRCTN17563146; www.isrctn.com/ISRCTN17563146.

Mortality in People with Type 2 Diabetes Following SARS-CoV-2 Infection: A Population Level Analysis of Potential Risk Factors.

INTRODUCTION: Research is ongoing to increase our understanding of how much a previous diagnosis of type 2 diabetes mellitus (T2DM) affects someone's risk of becoming seriously unwell following a COVID-19 infection. In this study we set out to determine the relative likelihood of death following COVID-19 infection in people with T2DM when compared to those without T2DM. This was conducted as an urban population study and based in the UK. METHODS: Analysis of electronic health record data was performed relating to people living in the Greater Manchester conurbation (population 2.82 million) who had a recorded diagnosis of T2DM and subsequent COVID-19 confirmed infection. Each individual with T2DM (n = 13,807) was matched with three COVID-19-infected non-diabetes controls (n = 39,583). Data were extracted from the Greater Manchester Care Record (GMCR) database for the period 1 January 2020 to 30 June 2021. Social disadvantage was assessed through Townsend scores. Death rates were compared in people with T2DM to their respective non-diabetes controls; potential predictive factors influencing the relative likelihood of admission were ascertained using univariable and multivariable logistic regression. RESULTS: For individuals with T2DM, their mortality rate after a COVID-19 positive test was 7.7% vs 6.0% in matched controls; the relative risk (RR) of death was 1.28. From univariate analysis performed within the group of individuals with T2DM, the likelihood of death following a COVID-19 recorded infection was lower in people taking metformin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 (GLP-1) agonist. Estimated glomerular filtration rate (eGFR) and hypertension were associated with increased mortality and had odds ratios of 0.96 (95% confidence interval 0.96-0.97) and 1.92 (95% confidence interval 1.68-2.20), respectively. Likelihood of death following a COVID-19 infection was also higher in those people with a diagnosis of chronic obstructive pulmonary disease (COPD) or severe enduring mental illness but not with asthma, and in people taking aspirin/clopidogrel/insulin. Smoking in people with T2DM significantly increased mortality rate (odds ratio of 1.46; 95% confidence interval 1.29-1.65). In a combined analysis of patients with T2DM and controls, multiple regression modelling indicated that the factors independently relating to a higher likelihood of death (accounting for 26% of variance) were T2DM, age, male gender and social deprivation (higher Townsend score). CONCLUSION: Following confirmed infection with COVID-19 a number of factors are associated with mortality in individuals with T2DM. Prescription of metformin, SGLT2is or GLP-1 agonists and non-smoking status appeared to be associated with a reduced the risk of death for people with T2DM. Age, male sex and social disadvantage are associated with an increased risk of death.

The Risk Factors Potentially Influencing Hospital Admission in People with Diabetes, Following SARS-CoV-2 Infection: A Population-Level Analysis.

INTRODUCTION: Since early 2020 the whole world has been challenged by the SARS-CoV-2 virus and the associated global pandemic (Covid-19). People with diabetes are particularly at high risk of becoming seriously unwell after contracting this virus. METHODS: This population-based study included people living in the Greater Manchester conurbation who had a recorded diagnosis of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and subsequent Covid-19 infection. Each individual with T1DM (n = 862) or T2DM (n = 13,225) was matched with three Covid-19-infected non-diabetes controls. RESULTS: For individuals with T1DM, hospital admission rate in the first 28 days after a positive Covid-19 test was 10% vs 4.7% in age/gender-matched controls [relative risk (RR) 2.1]. For individuals with T2DM, hospital admission rate after a positive Covid-19 test was 16.3% vs 11.6% in age/gender-matched controls (RR 1.4). The average Townsend score was higher in T2DM (1.8) vs matched controls (0.4), with a higher proportion of people with T2DM observed in the top two quintiles of greatest disadvantage (p < 0.001). For Covid-19-infected individuals with T1DM, factors influencing admission likelihood included age, body mass index (BMI), hypertension, HbA1c, low HDL-cholesterol, lower estimated glomerular filtration rate (eGFR), chronic obstructive pulmonary disease (COPD) and being of African/mixed ethnicity. In Covid-19-infected individuals with T2DM, factors related to a higher admission rate included age, Townsend index, comorbidity with COPD/asthma and severe mental illness (SMI), lower eGFR. Metformin prescription lowered the likelihood. For multivariate analysis in combined individuals with T2DM/controls, factors relating to higher likelihood of admission were having T2DM/age/male gender/diagnosed COPD/diagnosed hypertension/social deprivation (higher Townsend index) and non-white ethnicity (all groups). CONCLUSION: In a UK population we have confirmed a significantly higher likelihood of admission in people with diabetes following Covid-19 infection. A number of factors mediate that increased likelihood of hospital admission. For T2DM, the majority of factors related to increased admission rate are common to the general population but more prevalent in T2DM. There was a protective effect of metformin in people with T2DM.

The Postprandial Glycaemic and Hormonal Responses Following the Ingestion of a Novel, Ready-to-Drink Shot Containing a Low Dose of Whey Protein in Centrally Obese and Lean Adult Males: A Randomised Controlled Trial.

Purpose: Elevated postprandial glycaemia [PPG] increases the risk of cardiometabolic complications in insulin-resistant, centrally obese individuals. Therefore, strategies that improve PPG are of importance for this population. Consuming large doses of whey protein [WP] before meals reduces PPG by delaying gastric emptying and stimulating the secretion of the incretin peptides, glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]. It is unclear if these effects are observed after smaller amounts of WP and what impact central adiposity has on these gastrointestinal processes. Methods: In a randomised-crossover design, 12 lean and 12 centrally obese adult males performed two 240 min mixed-meal tests, ~5-10 d apart. After an overnight fast, participants consumed a novel, ready-to-drink WP shot (15 g) or volume-matched water (100 ml; PLA) 10 min before a mixed-nutrient meal. Gastric emptying was estimated by oral acetaminophen absorbance. Interval blood samples were collected to measure glucose, insulin, GIP, GLP-1, and acetaminophen. Results: WP reduced PPG area under the curve [AUC0-60] by 13 and 18.2% in the centrally obese and lean cohorts, respectively (both p <0.001). In both groups, the reduction in PPG was accompanied by a two-three-fold increase in GLP-1 and delayed gastric emptying. Despite similar GLP-1 responses during PLA, GLP-1 secretion during the WP trial was ~27% lower in centrally obese individuals compared to lean (p = 0.001). In lean participants, WP increased the GLP-1ACTIVE/TOTAL ratio comparative to PLA (p = 0.004), indicative of reduced GLP-1 degradation. Conversely, no treatment effects for GLP-1ACTIVE/TOTAL were seen in obese subjects. Conclusion: Pre-meal ingestion of a novel, ready-to-drink WP shot containing just 15 g of dietary protein reduced PPG in lean and centrally obese males. However, an attenuated GLP-1 response to mealtime WP and increased incretin degradation might impact the efficacy of nutritional strategies utilising the actions of GLP-1 to regulate PPG in centrally obese populations. Whether these defects are caused by an individual's insulin resistance, their obese state, or other obesity-related ailments needs further investigation. Clinical Trial Registration: ISRCTN.com, identifier [ISRCTN95281775]. https://www.isrctn.com/.

Short-Term Physical Inactivity Induces Endothelial Dysfunction.

OBJECTIVE: This study examined the effects of a short-term reduction in physical activity, and subsequent resumption, on metabolic profiles, body composition and cardiovascular (endothelial) function. DESIGN: Twenty-eight habitually active (≥10,000 steps/day) participants (18 female, 10 male; age 32 ± 11 years; BMI 24.3 ± 2.5 kg/m2) were assessed at baseline, following 14 days of step-reduction and 14 days after resuming habitual activity. METHODS: Physical activity was monitored throughout (SenseWear Armband). Endothelial function (flow mediated dilation; FMD), cardiorespiratory fitness ( V . ⁢ O 2 peak) and body composition including liver fat (dual-energy x-ray absorptiometry and magnetic resonance spectroscopy) were determined at each assessment. Statistical analysis was performed using one-way within subject's ANOVA; data presented as mean (95% CI). RESULTS: Participants decreased their step count from baseline by 10,111 steps/day (8949, 11,274; P < 0.001), increasing sedentary time by 103 min/day (29, 177; P < 0.001). Following 14 days of step-reduction, endothelial function was reduced by a 1.8% (0.4, 3.3; P = 0.01) decrease in FMD. Following resumption of habitual activity, FMD increased by 1.4%, comparable to the baseline level 0.4% (-1.8, 2.6; P = 1.00). Total body fat, waist circumference, liver fat, whole body insulin sensitivity and cardiorespiratory fitness were all adversely affected by 14 days step-reduction (P < 0.05) but returned to baseline levels following resumption of activity. CONCLUSION: This data shows for the first time that whilst a decline in endothelial function is observed following short-term physical inactivity, this is reversed on resumption of habitual activity. The findings highlight the need for public health interventions that focus on minimizing time spent in sedentary behavior.

The Clinical Application of Mealtime Whey Protein for the Treatment of Postprandial Hyperglycaemia for People With Type 2 Diabetes: A Long Whey to Go.

Mitigating postprandial hyperglycaemic excursions may be effective in not only enhancing glycaemic control for people with type 2 diabetes but also reducing the onset of diabetes-related complications. However, there are growing concerns over the long-term efficacy of anti-hyperglycaemic pharmacotherapies, which coupled with their rising financial costs, underlines the need for further non-pharmaceutical treatments to regulate postprandial glycaemic excursions. One promising strategy that acutely improves postprandial glycaemia for people with type 2 diabetes is through the provision of mealtime whey protein, owing to the slowing of gastric emptying and increased secretion of insulin and the incretin peptides. The magnitude of this effect appears greater when whey protein is consumed before, rather than with, a meal. Herein, this dietary tool may offer a simple and inexpensive strategy in the management of postprandial hyperglycaemia for people with type 2 diabetes. However, there are insufficient long-term studies that have investigated the use of mealtime whey protein as a treatment option for individuals with type 2 diabetes. The methodological approaches applied in acute studies and outcomes reported may also not portray what is achievable long-term in practice. Therefore, studies are needed to refine the application of this mealtime strategy to maximize its clinical potential to treat hyperglycaemia and to apply these long-term to address key components of successful diabetes care. This review discusses evidence surrounding the provision of mealtime whey protein to treat postprandial hyperglycaemia in individuals with type 2 diabetes and highlights areas to help facilitate its clinical application.

Diurnal Differences in Human Muscle Isometric Force In Vivo Are Associated with Differential Phosphorylation of Sarcomeric M-Band Proteins.

We investigated whether diurnal differences in muscle force output are associated with the post-translational state of muscle proteins. Ten physically active men (mean ± SD; age 26.7 ± 3.7 y) performed experimental sessions in the morning (08:00 h) and evening (17:00 h), which were counterbalanced in order of administration and separated by at least 72 h. Knee extensor maximal voluntary isometric contraction (MVIC) force and peak rate of force development (RFD) were measured, and samples of vastus lateralis were collected immediately after exercise. MVIC force was greater in the evening (mean difference of 67 N, 10.2%; p < 0.05). Two-dimensional (2D) gel analysis encompassed 122 proteoforms and discovered 6 significant (p < 0.05; false discovery rate [FDR] = 10%) diurnal differences. Phosphopeptide analysis identified 1693 phosphopeptides and detected 140 phosphopeptides from 104 proteins that were more (p < 0.05, FDR = 22%) phosphorylated in the morning. Myomesin 2, muscle creatine kinase, and the C-terminus of titin exhibited the most robust (FDR < 10%) diurnal differences. Exercise in the morning, compared to the evening, coincided with a greater phosphorylation of M-band-associated proteins in human muscle. These protein modifications may alter the M-band structure and disrupt force transmission, thus potentially explaining the lower force output in the morning.

The Effects of a High-Protein Diet on Markers of Muscle Damage Following Exercise in Active Older Adults: A Randomized, Controlled Trial.

PURPOSE: This study examined whether a higher protein diet following strenuous exercise can alter markers of muscle damage and inflammation in older adults. METHODS: Using a double-blind, independent group design, 10 males and eight females (age 57 ± 4 years; mass 72.3 ± 5.6 kg; height 1.7 ± 6.5 m) were supplied with a higher protein (2.50 g·kg-1·day-1) or moderate protein (1.25 g·kg-1·day-1) diet for 48 hr after 140 squats with 25% of their body mass. Maximal isometric voluntary contractions, muscle soreness, creatine kinase, Brief Assessment of Mood Adapted, and inflammatory markers were measured preexercise, and 24 hr and 48 hr postexercise. RESULTS: The maximal isometric voluntary contractions decreased postexercise (p = .001, ηp2=.421), but did not differ between groups (p = .822, ηp2=.012). Muscle soreness peaked at 24 hr post in moderate protein (44 ± 30 mm) and 48 hr post in higher protein (70 ± 46 mm; p = .005; ηp2=.282); however, no group differences were found (p = .585; ηp2=.083). Monocytes and lymphocytes significantly decreased postexercise, and eosinophils increased 24 hr postexercise (p < 0.05), but neutrophils, creatine kinase, interleukin-6, C-reactive protein, monocyte chemotactic protein-1, and Brief Assessment of Mood Adapted were unchanged by exercise or the intervention (p > .05). CONCLUSION: In conclusion, 2.50 g·kg-1·day-1 of protein is not more effective than 1.25 g·kg-1·day-1 for attenuating indirect markers of muscle damage and inflammation following strenuous exercise in older adults.

Zinc-alpha2-glycoprotein, dysglycaemia and insulin resistance: a systematic review and meta-analysis.

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.m2). 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; I2 = 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; I2 = 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.

Metabolic syndrome is associated with reduced flow mediated dilation independent of obesity status.

BACKGROUND: Data suggest that metabolic health status, incorporating components of metabolic syndrome (MetS), predicts cardiovascular disease (CVD) risk better than BMI. This study explored the association of MetS and obesity with endothelial function, a prognostic risk factor for incident CVD. METHODS: Forty-four participants were phenotyped according to BMI as non-obese vs obese (<30 or >30 kg/m2) and according to the International Diabetes Federation criteria of MetS: ≤2 criteria MetS (MetS-) vs ≥3 criteria MetS (MetS+); (1.)non-obese MetS- vs (2.) non-obese MetS+ and (3.) obese MetS- vs (4.) obese MetS+. Flow-mediated dilation (FMD), body composition including liver fat (MRI and spectroscopy), dietary intake, intensities of habitual physical activity and cardio-respiratory fitness were determined. Variables were analysed using a one-factor between-groups ANOVA and linear regression; mean (95% CI) are presented. RESULTS: Individuals with MetS+ displayed lower FMD than those with MetS-. For non-obese individuals mean difference between MetS+ and MetS- was 4.1% ((1.0, 7.3); P = 0.004) and obese individuals had a mean difference between MetS+ and MetS- of 6.2% ((3.1, 9.2); P < 0.001). Although there was no association between BMI and FMD (P = 0.27), an increased number of MetS components was associated with a lower FMD (P = 0.005), and after adjustment for age and sex, 19.7% of the variance of FMD was explained by MetS, whereas only 1.1% was explained by BMI. CONCLUSIONS: In this study cohort, components of MetS, rather than obesity per se, contribute to reduced FMD, which suggests a reduced bioavailability of nitric oxide and thus increased risk of CVD.

Reduced physical activity in young and older adults: metabolic and musculoskeletal implications.

BACKGROUND: Although the health benefits of regular physical activity and exercise are well established and have been incorporated into national public health recommendations, there is a relative lack of understanding pertaining to the harmful effects of physical inactivity. Experimental paradigms including complete immobilization and bed rest are not physiologically representative of sedentary living. A useful 'real-world' approach to contextualize the physiology of societal downward shifts in physical activity patterns is that of short-term daily step reduction. RESULTS: Step-reduction studies have largely focused on musculoskeletal and metabolic health parameters, providing relevant disease models for metabolic syndrome, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), sarcopenia and osteopenia/osteoporosis. In untrained individuals, even a short-term reduction in physical activity has a significant impact on skeletal muscle protein and carbohydrate metabolism, causing anabolic resistance and peripheral insulin resistance, respectively. From a metabolic perspective, short-term inactivity-induced peripheral insulin resistance in skeletal muscle and adipose tissue, with consequent liver triglyceride accumulation, leads to hepatic insulin resistance and a characteristic dyslipidaemia. Concomitantly, various inactivity-related factors contribute to a decline in function; a reduction in cardiorespiratory fitness, muscle mass and muscle strength. CONCLUSIONS: Physical inactivity maybe particularly deleterious in certain patient populations, such as those at high risk of T2D or in the elderly, considering concomitant sarcopenia or osteoporosis. The effects of short-term physical inactivity (with step reduction) are reversible on resumption of habitual physical activity in younger people, but less so in older adults. Nutritional interventions and resistance training offer potential strategies to prevent these deleterious metabolic and musculoskeletal effects. IMPACT: Individuals at high risk of/with cardiometabolic disease and older adults may be more prone to these acute periods of inactivity due to acute illness or hospitalization. Understanding the risks is paramount to implementing countermeasures.

Physical Activity and Sedentary Time: Association with Metabolic Health and Liver Fat.

INTRODUCTION/PURPOSE: To investigate whether (a) lower levels of daily physical activity (PA) and greater sedentary time accounted for contrasting metabolic phenotypes (higher liver fat/presence of metabolic syndrome [METS+] vs lower liver fat/absence of metabolic syndrome [METS-]) in individuals of similar body mass index and (b) the association of sedentary time on metabolic health and liver fat. METHODS: Ninety-eight habitually active participants (53 female, 45 male; age, 39 ± 13 yr; body mass index 26.9 ± 5.1 kg·m), underwent assessments of PA (SenseWear armband; wear time ~98%), cardiorespiratory fitness (V˙O2 peak), body composition (magnetic resonance imaging and magnetic resonance spectroscopy) and multiorgan insulin sensitivity (oral glucose tolerance test). We undertook a) cross-sectional analysis comparing four groups: nonobese or obese, with and without metabolic syndrome (METS+ vs METS-) and b) univariate and multivariate regression for sedentary time and other levels of PA in relation to liver fat. RESULTS: Light, moderate, and vigorous PA did not account for differences in metabolic health between individuals, whether nonobese or obese, although METS+ individuals were more sedentary, with a higher number, and prolonged bouts (~1-2 h). Overall, sedentary time, average daily METS and V˙O2 peak were each independently associated with liver fat percentage. Each additional hour of daily sedentary time was associated with a 1.15% (95% confidence interval, 1.14%-1.50%) higher liver fat content. CONCLUSIONS: Greater sedentary time, independent of other levels of PA, is associated with being metabolically unhealthy; even in habitually active people, lesser sedentary time, and higher cardiorespiratory fitness and average daily METS is associated with lower liver fat.

Short-term decreased physical activity with increased sedentary behaviour causes metabolic derangements and altered body composition: effects in individuals with and without a first-degree relative with type 2 diabetes.

AIMS/HYPOTHESIS: Low physical activity levels and sedentary behaviour are associated with obesity, insulin resistance and type 2 diabetes. We investigated the effects of a short-term reduction in physical activity with increased sedentary behaviour on metabolic profiles and body composition, comparing the effects in individuals with first-degree relatives with type 2 diabetes (FDR+ve) vs those without (FDR-ve). METHODS: Forty-five habitually active participants (16 FDR+ve [10 female, 6 male] and 29 FDR-ve [18 female, 11 male]; age 36 ± 14 years) were assessed at baseline, after 14 days of step reduction and 14 days after resuming normal activity. We determined physical activity (using a SenseWear armband), cardiorespiratory fitness ([Formula: see text]), body composition (dual-energy x-ray absorptiometry/magnetic resonance spectroscopy) and multi-organ insulin sensitivity (OGTT) at each time point. Statistical analysis was performed using a two-factor between-groups ANCOVA, with data presented as mean ± SD or (95% CI). RESULTS: There were no significant between-group differences in physical activity either at baseline or following step reduction. During the step-reduction phase, average daily step count decreased by 10,285 steps (95% CI 9389, 11,182; p < 0.001), a reduction of 81 ± 8%, increasing sedentary time by 223 min/day (151, 295; p < 0.001). Pooling data from both groups, following step reduction there was a significant decrease in whole-body insulin sensitivity (Matsuda index) (p < 0.001), muscle insulin sensitivity index (p < 0.001), cardiorespiratory fitness (p = 0.002) and lower limb lean mass (p = 0.004). Further, there was a significant increase in total body fat (p < 0.001), liver fat (p = 0.001) and LDL-cholesterol (p = 0.013), with a borderline significant increase in NEFA AUC during the OGTT (p = 0.050). Four significant between-group differences were apparent: following step reduction, FDR+ve participants accumulated 1.5% more android fat (0.4, 2.6; p = 0.008) and increased triacylglycerol by 0.3 mmol/l (0.1, 0.6; p = 0.044). After resuming normal activity, FDR+ve participants engaged in lower amounts of vigorous activity (p = 0.006) and had lower muscle insulin sensitivity (p = 0.023). All other changes were reversed with no significant between-group differences. CONCLUSIONS/INTERPRETATION: A short-term reduction in physical activity with increased sedentary behaviour leads to a reversible reduction in multi-organ insulin sensitivity and cardiorespiratory fitness, with concomitant increases in central and liver fat and dyslipidaemia. The effects are broadly similar in FDR+ve and FDR-ve individuals. Public health recommendations promoting physical activity should incorporate advice to avoid periods of sedentary behaviour.