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The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation.

To examine changes in racial and ethnic disparities in glucose-lowering drugs (GLD) use and glycated haemoglobin A1c in US adults with diabetes from 2005 to 2018.We conducted pooled cross-sectional analysis using data from the 2005-2018 Medical Expenditure Panel Surveys, and the 2005-2018 National Health and Nutrition Examination Survey. Individuals ≥18 years with diabetes were included. Racial and ethnic disparities were measured in (a) newer non-insulin GLD use; (b) insulin analogue use; (c) non-insulin GLDs adherence; (d) insulin adherence; and (e) glucose management, along with (f) the proportion of the disparities explained by potential contributing factors.From 2005 to 2018, racial and ethnic disparities persisted in newer GLD use, non-insulin GLDs adherence, insulin analogue use and glucose management. In 2018, compared with non-Hispanic white adults, non-Hispanic black, Hispanic and other race/ethnicity groups had lower rates of using newer GLDs (adjusted risk ratio: 0.44, 0.52, 0.64, respectively; p .05 for all) and insulin analogues (adjusted risk ratio: 0.93, 0.89, 0.95, respectively; p .05 for all except other groups), lower non-insulin GLD adherence (proportion of days covered: -4.5%, -5.6%, -4.3%, respectively; p .05 for all), higher glycated haemoglobin A1c (0.29%, 0.32%, 0.02%, respectively; p .05 for all except other group), and similar insulin adherences. Socioeconomic and health status were the main contributors to these disparities.Our findings provide evidence of racial and ethnic disparities in newer GLD use and quality of care in glucose management. Our study results can inform decision-makers of the status of racial and ethnic disparities and identify ways to reduce these disparities.

A quarter of the world’s population is estimated to meet the criteria for metabolic syndrome, a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type II diabetes, leading to increased risk of premature death and significant health costs. In this study we investigate whether the genetics associated with metabolic syndrome components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations between fasting glucose, high-density lipoprotein cholesterol, systolic blood pressure, triglycerides, and waist circumference was used; which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on metabolic syndrome to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more metabolic syndrome components, indicating that metabolic syndrome is a complex, heterogeneous disorder. Associated loci harbour genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the metabolic syndrome factor GWAS predicts 5.9% of the variance in metabolic syndrome. These results provide mechanistic insights in the genetics of metabolic syndrome and suggestions for drug targets, especially fenofibrate, which has the promise of tackling multiple metabolic syndrome components.

This study investigated the mechanism underlying the beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with resistant hypertension and diabetic nephropathy by examining post-translational modification of the MR by O-linked-N-acetylglucosamine (O-GlcNAc), which is strongly associated with type 2 diabetes. Coimmunoprecipitation assays in HEK293T cells showed that MR is a target of O-GlcNAc modification (O-GlcNAcylation). The expression levels and transcriptional activities of the receptor increased in parallel with its O-GlcNAcylation under high-glucose conditions. Liquid chromatography-tandem mass spectrometry revealed O-GlcNAcylation of the MR at amino acids 295-307. Point mutations in those residues decreased O-GlcNAcylation, and both the protein levels and transcriptional activities of MR. In db/db mouse kidneys, MR protein levels increased in parallel with overall O-GlcNAc levels of the tissue, accompanied by increased SGK1 mRNA levels. The administration of 6-diazo-5-oxo-L-norleucin, an inhibitor of O-GlcNAcylation, reduced tissue O-GlcNAc levels and MR protein levels in db/db mice. Thus, our study showed that O-GlcNAcylation of the MR directly increases protein levels and transcriptional activities of the receptor under high-glucose conditions in vitro and in vivo. These findings provide a novel mechanism of MR as a target for prevention of complications associated with diabetes mellitus.

BACKGROUND: Metabolic disease risk in youth is influenced by sedentary behaviors. Acute in-lab studies show that, during a single day, interrupting a sedentary period with short bouts of physical activity improves glucometabolic outcomes. OBJECTIVE: To determine if acutely improved glucose metabolism persists after multi-day interruptions of sitting with walking brief bouts. We hypothesized that children who underwent interrupting sitting on multiple days would demonstrate lower insulin area under the curve during an oral glucose tolerance test compared to uninterrupted sitting. METHODS: Healthy, normoglycemic children (N=109) ages 7-11 years were randomized to one of two conditions: Control (3h of daily Uninterrupted Sitting) or Interrupted Sitting (3-min of moderate-intensity walking every 30min for 3h daily); with dietary intake controlled through provision of foodstuffs for the entire experiment. Participants attended six consecutive daily visits at a research ambulatory unit. The primary outcome was insulin area under the curve during the oral glucose tolerance test on day 6 during interrupted or uninterrupted sitting; secondary outcomes included glucose and c-peptide area under the curve, energy intake at a buffet meal on day 6, and free-living activity. RESULTS: Among 93 children (42 uninterrupted sitting, 51 interrupted sitting), daily interrupted sitting resulted in 21% lower insulin (β=0.102 CI:0.032–0.172, p=.005) and a 10% lower C-peptide (β=0.043, CI:0.001-0.084, p=0.045) area under the curve. Matsuda and Glucose Effectiveness Indices were also improved (p’s

Progression of diabetic kidney disease has slowed over the past 40 years by as much as 70-75%, thanks to a diversity of drug classes that have less effect on glucose and more on reducing cardiorenal risk.With the advent of sodium-glucose co-transporter 2 (SGLT2) inhibitors and the novel nonsteroidal mineralocorticoid antagonist, finerenone, we now have three 'pillars of therapy' considering the renin-angiotensin system (RAS) inhibitors as already established treatment to slow diabetic kidney disease. Both renal and cardiovascular outcomes trials have provided solid evidence of the benefit by these agents to slow kidney disease progression and reduce heart failure hospitalizations. Using these agents together reduces the risk of hyperkalemia by finerenone and further reduces albuminuria in animal models. Trials are underway to also see if the glucagon-like peptide 1 receptor agonist, semaglutide, will also protect against diabetic kidney disease progression as seen in post hoc analyses of positive cardiovascular outcome trials. If positive, this would be the fourth pillar to support cardiorenal protection without fear of hypoglycemia.Nephrologists now have three different agents neither of which has a major effect on blood pressure but both add to further reduce progression of diabetic nephropathy and hospitalization from heart failure.

Fluid and insulin treatments are the cornerstones of DKA management and indications on dosages are available. However, according to possible confounding factors, relevant data are still required to explain the different insulin dosages adopted at diabetes onset, particularly based upon insulin sensitivity.We aimed to explore whether DKA severity is related to different insulin sensitivity states, thus resulting in different insulin requirement at diabetes onset.Retrospective data from hospital records of 62 newly diagnosed children with type 1 diabetes with DKA were analyzed. The population was divided into three groups: severe, moderate, and mild DKA. Anthropometric, laboratory test, insulin, and glucose administration data were analyzed. The Glucose Infusion Rate (GIR), Insulin Infusion Rate (IIR), and GIR/IIR were calculated and used as indexes of insulin sensitivity. The area under the curve (AUC) for insulin and glucose infusion was calculated.Moving among the three groups, IIR decreased while GIR and GIR/IIR increased from severe to mild DKA group (all p 0.01). A similar trend was documented for AUC-insulin and AUC-glucose as well as AUC-glucose/AUC-insulin ratio. The Spearman correlation showed a negative correlation between pH and both IIR and AUC-Insulin as well as a positive correlation between pH and both GIR/IIR and AUC-glucose/AUC-insulin ratio.Subjects with severe DKA have a higher insulin requirement compared to those with less severe DKA. Significant differences in terms of insulin sensitivity might be documented according to the severity of DKA, which might result in tailored insulin pH requirement in children with new onset type 1 diabetes.

Obesity and insulin resistance are significant contributors to hypertension. There is a high prevalence of obesity among Uyghurs in the rural areas of Xinjiang, China. Therefore, this study aimed to explore the association between insulin resistance indices and hypertension according to different body weights in rural Uyghur residents of Xinjiang, China. A total of 12 813 local Uyghur residents were recruited for the study. Excluding those with incomplete data and those using antihypertensive, lipid-lowering, or glycemic drugs, 9577 permanent residents were eligible for the study. Three insulin resistance indicators were calculated: triglyceride to high-density lipoprotein cholesterol ratio, product of fasting triglyceride and glucose (TYG), and metabolic score for insulin resistance. Multivariate logistic regression analysis was performed to estimate the association between the three non-insulin-based insulin resistance indices and the risk of hypertension for different body weights. TYG was significantly associated with hypertension in the normal-weight group, particularly in women. In the obese group that was obese, all three indicators were associated with hypertension. Since TYG was associated with hypertension in the groups with normal weight and obesity, it may be useful as a reference indicator for insulin resistance. This indicator may provide a basis for the identification and management of hypertension risk among adults in the Uyghur population.

We examined the safety and efficacy of del Nido cardioplegic solution compared with histidine-tryptophan-ketoglutarate cardioplegic solution in minimally invasive cardiac surgery.Patients who underwent minimally invasive cardiac surgery using del Nido or histidine-tryptophan-ketoglutarate from 2015 to 2019 were enrolled. Various clinical outcomes were compared between the groups. Postoperative laboratory findings including the levels of electrolytes, cardiac enzymes (creatine kinase-MB and troponin I), and serial blood lactate were also measured and compared. Based on 28 baseline covariates, propensity score matching was performed to reduce selection bias.Among 766 patients, del Nido and histidine-tryptophan-ketoglutarate were used in 330 patients (43.1%) and 436 patients (56.9%), respectively. There were no significant intergroup differences in postoperative clinical outcomes and early adverse outcomes among 228 pairs of propensity score-matched patients. Immediate postoperative sodium levels were within the normal range in both groups without a significant difference (P = .50). However, peak creatine kinase-MB (median, 31.9 vs 37.7 ng/mL, P = .026) and troponin I (6.9 vs 9.1 ng/mL, P = .014) levels were significantly lower in the del Nido group. Linear regression analysis revealed a significant association between the peak cardiac enzyme levels and the cardiac ischemic time depending on the cardioplegia type, with lower cardiac isoenzymes for del Nido over histidine-tryptophan-ketoglutarate (P .001) until the crossover point at the cardiac ischemic time over 100 minutes.In comparison with histidine-tryptophan-ketoglutarate solution, del Nido solution seems to have acceptable safety and efficacy with good myocardial protection in minimally invasive cardiac surgery. Further studies focusing on complex surgeries requiring longer cardiac ischemic time are needed.

Aims/hypothesis Time-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6–8 h TRE regimens in healthy, overweight adults under controlled conditions. However, the effects of TRE on glucose homeostasis in individuals with type 2 diabetes are unclear. Here, we extensively investigated the effects of TRE on hepatic glycogen levels and insulin sensitivity in individuals with type 2 diabetes. Methods Fourteen adults with type 2 diabetes (BMI 30.5±4.2 kg/m2, HbA1c 46.1±7.2 mmol/mol [6.4±0.7%]) participated in a 3 week TRE (daily food intake within 10 h) vs control (spreading food intake over ≥14 h) regimen in a randomised, crossover trial design. The study was performed at Maastricht University, the Netherlands. Eligibility criteria included diagnosis of type 2 diabetes, intermediate chronotype and absence of medical conditions that could interfere with the study execution and/or outcome. Randomisation was performed by a study-independent investigator, ensuring that an equal amount of participants started with TRE and CON. Due to the nature of the study, neither volunteers nor investigators were blinded to the study interventions. The quality of the data was checked without knowledge on intervention allocation. Hepatic glycogen levels were assessed with 13C-MRS and insulin sensitivity was assessed using a hyperinsulinaemic–euglycaemic two-step clamp. Furthermore, glucose homeostasis was assessed with 24 h continuous glucose monitoring devices. Secondary outcomes included 24 h energy expenditure and substrate oxidation, hepatic lipid content and skeletal muscle mitochondrial capacity. Results Results are depicted as mean ± SEM. Hepatic glycogen content was similar between TRE and control condition (0.15±0.01 vs 0.15±0.01 AU, p=0.88). M value was not significantly affected by TRE (19.6±1.8 vs 17.7±1.8 μmol kg−1 min−1 in TRE vs control, respectively, p=0.10). Hepatic and peripheral insulin sensitivity also remained unaffected by TRE (p=0.67 and p=0.25, respectively). Yet, insulin-induced non-oxidative glucose disposal was increased with TRE (non-oxidative glucose disposal 4.3±1.1 vs 1.5±1.7 μmol kg−1 min−1, p=0.04). TRE increased the time spent in the normoglycaemic range (15.1±0.8 vs 12.2±1.1 h per day, p=0.01), and decreased fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l, p=0.03) and 24 h glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l, pp=0.04). No adverse events were reported that were related to the interventions. Conclusions/interpretation We show that a 10 h TRE regimen is a feasible, safe and effective means to improve 24 h glucose homeostasis in free-living adults with type 2 diabetes. However, these changes were not accompanied by changes in insulin sensitivity or hepatic glycogen. Trial registration ClinicalTrials.gov NCT03992248 Funding ZonMW, 459001013 Graphical abstract

OBJECTIVE In patients with moderate to severe albuminuric kidney disease, sodium–glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to RESULTS Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38–0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

Heterogeneity within specific cell types is common and increasingly apparent with the advent of single cell transcriptomics. Transcriptional and functional cellular specialization has been described for insulin-secreting β cells of the endocrine pancreas, including so-called extreme β cells exhibiting >2-fold higher insulin gene activity. However, it is not yet clear whether β cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in β cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of β cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single β cells over time. Autocorrelation analysis indicated that cells displaying fluctuations in Ins2 gene activity most commonly exhibited a frequency of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing determined that Ins2(GFP)HIGH β cells were enriched for markers of β cell maturity and had reduced expression of anti-oxidant genes. Ins2(GFP)HIGH β cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β cells, can be accounted for by dynamic states of insulin gene activity. Our observations define a previously uncharacterized form of β cell plasticity. Understanding the dynamics of insulin production has relevance for understanding the pathobiology of diabetes and for regenerative therapy research.

AIM: To investigate the impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the risk of incident heart failure and adverse cardiovascular outcomes.METHODS: All patients with diabetes who were registered between January 2018 and December 2019 were identified from a federated electronic medical record database (TriNetX) and followed up for 2 years. A 1:1 propensity-score matching (PSM) analysis was performed to balance the SGLT2 inhibitor and non-SGLT2 inhibitor cohorts. The primary outcome was incident heart failure. Secondary outcomes included all-cause mortality, cardiac arrest, ventricular tachycardia/ventricular fibrillation (VT/VF), incident atrial fibrillation (AF), ischaemic stroke/transient ischaemic attack (TIA), composite of arterial and venous thrombotic events, and composite of incident VT/VF and cardiac arrest.RESULTS: A total of 131 189 and 2 692 985 patients were treated with and without SGLT2 inhibitors, respectively. After PSM, 131 188 patients remained in each group. The risk of incident heart failure was significantly lower in the SGLT2 inhibitor cohort compared to the non-SGLT2 inhibitor cohort (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.68-0.73). SGLT2 inhibitor use was also associated with a significantly lower risk of all-cause mortality (HR 0.61, 95% CI 0.58-0.64), cardiac arrest (HR 0.70, 95% CI 0.63-0.78), incident AF (HR 0.81, 95% CI 0.76-0.84), ischaemic stroke/TIA (HR 0.90, 95% CI 0.88-0.93), composite of arterial and venous thrombotic events (HR 0.90, 95% CI 0.88-0.92), and composite of incident VT/VF and cardiac arrest (HR 0.76, 95% CI 0.71-0.81). There were no significant differences for VT/VF (HR 0.94, 95% CI 0.88-1.00).CONCLUSION: Use of SGLT2 inhibitors was associated with a significant reduction in the risk of incident heart failure and adverse cardiovascular outcomes but not ventricular arrhythmias.

Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.

OBJECTIVE To evaluate associations between a broad range of approaches to classifying diet and incident type 2 diabetes in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. RESEARCH DESIGN AND METHODS This study included 8,750 Black and White adults without diabetes at baseline. Diabetes was defined according to fasting glucose ≥70 mmol/L, random glucose ≥111 mmol/L, or use of diabetes medications. The exposures were diet scores for Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), dietary inflammatory index (DII), dietary inflammation score (DIS), and empirical dietary patterns (plant-based and Southern) determined using data collected with use of the Block98 food-frequency questionnaire. Modified Poisson regression was used to assess association of dietary measures with risk of incident type 2 diabetes, with models adjusted for total energy intake, demographics, lifestyle factors, and waist circumference. RESULTS There were 1,026 cases of incident type 2 diabetes during follow-up (11.7%). Adherence to the Southern dietary pattern was most strongly associated with risk of incident type 2 diabetes after adjustment for demographics and lifestyle (quintile [Q]5 vs. lowest Q1: risk ratio [RR] 1.95; 95% CI 1.57, 2.41). Of the diet scores, DIS (Q5 vs. Q1 RR 1.41) and MIND (Q1 vs. Q5 RR 1.33), demonstrated anti-inflammatory diets, had strongest associations with lower diabetes incidence. CONCLUSIONS We found associations of several dietary approaches with incident type 2 diabetes. Investigation into mechanisms driving the association with the Southern dietary pattern is warranted. Further research into use of DIS, DII, and MIND diet score should be considered for dietary recommendations for diabetes prevention.

South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25–40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.

Cardiovascular disease is of paramount importance, yet there are few relevant rat models to investigate its pathology and explore potential therapeutics. Housing at thermoneutral temperature (30 °C) is being employed to humanize metabolic derangements in rodents. We hypothesized that housing rats in thermoneutral conditions would potentiate a high-fat diet, resulting in diabetes and dysmetabolism, and deleteriously impact vascular function, in comparison to traditional room temperature housing (22 °C).Male Wistar rats were housed at either room temperature or thermoneutral temperatures for 16 weeks on either a low or high-fat diet. Glucose and insulin tolerance tests were conducted at the beginning and end of the study. At the study's conclusion, vasoreactivity and mitochondrial respiration of aorta and carotid were conducted.We observed diminished vasodilation in vessels from thermoneutral rats ( P 0.05), whereas high-fat diet had no effect. This effect was also observed in endothelium-denuded aorta in thermoneutral rats ( P 0.05). Vasoconstriction was significantly elevated in aorta of thermoneutral rats ( P 0.05). Diminished nitric oxide synthase activity and nitrotyrosine, and elevated glutathione activity were observed in aorta from rats housed under thermoneutral conditions, indicating a climate of lower nitric oxide and excess reactive oxygen species in aorta. Thermoneutral rat aorta also demonstrated less mitochondrial respiration with lipid substrates compared with the controls ( P 0.05).Our data support that thermoneutrality causes dysfunctional vasoreactivity, decreased lipid mitochondrial metabolism, and modified cellular signaling. These are critical observations as thermoneutrality is becoming prevalent for translational research models. This new model of vascular dysfunction may be useful for dissection of targetable aspects of cardiovascular disease and is a novel and necessary model of disease.

Background: Continuous glucose monitoring (CGM) is approved for insulin dosing decisions in the ambulatory setting, but not currently for inpatients. CGM has the capacity to reduce patient-provider contact in inpatients with coronavirus disease 2019 (COVID-19), thus potentially reducing in hospital virus transmission. However, there are sparse data on the accuracy and efficacy of CGM to titrate insulin doses in inpatients. Methods: Under an emergency use protocol, CGM (Dexcom G6) was used alongside standard point-of-care (POC) glucose measurements in patients critically ill from complications of COVID-19 requiring intravenous (IV) insulin. Glycemic control during IV insulin therapy was retrospectively assessed comparing periods with and without adjunctive CGM use. Accuracy metrics were computed and Clarke Error Grid analysis performed comparing CGM glucose values with POC measurements. Results: Twenty-four critically ill patients who met criteria for emergency use of CGM resulted in 47 333 CGM and 5677 POC glucose values. During IV insulin therapy, individuals’ glycemic control improved when CGM was used (mean difference –30.7 mg/dL). Among 2194 matched CGM: POC glucose pairs, a high degree of concordance was observed with a mean absolute relative difference of 14.8% and 99.5% of CGM: POC pairs falling in Zones A and B of the Clarke Error Grid. Conclusions: Continuous glucose monitoring use in critically ill COVID-19 patients improved glycemic control during IV insulin therapy. Continuous glucose monitoring glucose data were highly concordant with POC glucose during IV insulin therapy in critically ill patients suggesting that CGM could substitute for POC measurements in inpatients thus reducing patient-provider contact and mitigating infection transmission.

Objective: Pediatric obesity predisposes children and adolescents to early onset insulin resistance and dysglycemia. In the last 20 years this has led to a rise in the prevalence of prediabetes, diabetes and fatty liver in youngsters, due to the high degree of insulin resistance experienced by these patients and the consequent high availability of glucose. As glucose accesses the liver, it is partly metabolized through glycolysis, whose main product is pyruvate that is then converted into Acetyl CoA and lactate. Therefore, lactate production rate (LPR) represents the best proxy for the assessment of glycolysis. Since to date there are not methods to estimate postprandial LPR, here we proposed a novel oral glucose-lactate model to estimate LPR during an oral glucose tolerance test and tested it in 24 youth with and without obesity. Methods: The model is based on the oral glucose minimal model and assumes that LPR is a fraction (fr) of glucose disposal rate, proportional to glucose concentration and controlled by insulin action. Results: The model well fitted the glucose and lactate data, and provided both precise parameter estimates (e.g. fr=22.5 [12.6-54.1]%, median [IQR]), CV=18 [13-25]%) and LPR time course. Conclusions: The proposed model is a valid tool to assess LPR, and thus glycolysis, during OGTT in nondiabetic subjects. Significance: The proposed methodology will allow to assess postprandial LPR in simple and cost-effective way.

OBJECTIVE We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN & METHODS Uncorrelated genetic variants associated with type 2 diabetes (n=231), fasting insulin (n=38), fasting glucose (n=71), and hemoglobin A1c (n=75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies, and other large consortia. RESULTS Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per one-unit increase in log-transformed odds ratio of type 2 diabetes, the odds ratio was 1.06 (95% confidence interval (CI) 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI 1.07-1.17) for gastric ulcer, 1.11 (95% CI 1.03-1.20) for acute gastritis, 1.07 (95% CI 1.01-1.13) for chronic gastritis, 1.08 (95% CI 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI 1.01-1.07) for diverticular disease, 1.08 (95% CI 1.02-1.14) for acute pancreatitis, 1.09 (95% CI 1.05-1.12) for cholelithiasis, 1.09 (95% CI 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI 1.17-1.43) for non-alcoholic fatty liver disease, 1.12 (95% CI 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with 6 and 1 GDs, respectively. CONCLUSIONS This study found associations between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in type 2 diabetes patients.

Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy.Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents. Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism.

OBJECTIVE To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial–Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis. RESULTS Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years prediagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years prediagnosis, AUC C-peptide increased from baseline until 1.5 years prediagnosis (DPT-1, P = 0.004; TNPTP, P = 0.012) and then decreased from 1.5 to 0.5 years prediagnosis (DPT-1, P = 0.017; TNPTP, P = 0.093). This change was mostly attributable to change in the late AUC C-peptide response (i.e., 60- to 120-min AUC C-peptide). Median Index60 values of DPT-1 (1.44) and TNPTP (1.05) progressors to T1D 1.5 years prediagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for T1D in the full cohort at baseline (5-year risk of 0.75–0.88 for those above thresholds). CONCLUSIONS A transition from an increase to a decrease in AUC C-peptide ∼1.5 years prediagnosis was validated in two independent cohorts. The median Index60 value at that time point can be used as a pathophysiologic-based threshold for identifying individuals at high risk for T1D.

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.

OBJECTIVE The efficacy and safety of continuous glucose monitoring (CGM) in adjusting inpatient insulin therapy have not been evaluated. RESEARCH DESIGN AND METHODS This randomized trial included 185 general medicine and surgery patients with type 1 and type 2 diabetes treated with a basal-bolus insulin regimen. All subjects underwent point-of-care (POC) capillary glucose testing before meals and bedtime. Patients in the standard of care (POC group) wore a blinded Dexcom G6 CGM with insulin dose adjusted based on POC results, while in the CGM group, insulin adjustment was based on daily CGM profile. Primary end points were differences in time in range (TIR; 70–180 mg/dL) and hypoglycemia ( RESULTS There were no significant differences in TIR (54.51% ± 27.72 vs. 48.64% ± 24.25; P = 0.14), mean daily glucose (183.2 ± 40 vs. 186.8 ± 39 mg/dL; P = 0.36), or percent of patients with CGM values CONCLUSIONS The inpatient use of real-time Dexcom G6 CGM is safe and effective in guiding insulin therapy, resulting in a similar improvement in glycemic control and a significant reduction of recurrent hypoglycemic events compared with POC-guided insulin adjustment.

We investigated the association of adipose tissue insulin resistance with blood pressure and hypertension incidence, comparing it with hepatic and skeletal muscle insulin resistance. The cross-sectional analysis included 6892 general health checkup examinees (mean age: 69.3 years; 51.3% women and 48.7% men) who had no cardiovascular disease. Of those, 3948 normotensive participants (mean age: 68.4 years; 54.8% women and 45.2% men) were enrolled in the retrospective cohort analysis. The adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and free fatty acid levels. A high adipo-IR, high homeostasis model assessment of insulin resistance (HOMA-IR), and low Matsuda index were indicated based on the optimal cutoff values in a receiver operating characteristic curve analysis. Adipo-IR (β = 0.096, P 0.001), HOMA-IR (β = 0.052, P 0.001), and Matsuda index (β = -0.055, P 0.001) were associated with systolic blood pressure in the cross-sectional analysis. Over a mean 5.3-year follow-up period, 1310 participants developed hypertension. A high adipo-IR (adjusted OR, 1.29; 95% CI, 1.11-1.51), but not HOMA-IR or Matsuda index, was significantly associated with the incidence of hypertension. Moreover, the combination of high adipo-IR with high HOMA-IR or low Matsuda index showed no higher odds of hypertension than a high adipo-IR alone. These results suggest that insulin resistance is associated with blood pressure control regardless of the tissue in which it occurs; however, the risk of hypertension is determined by insulin resistance in adipose tissue rather than in liver or muscle tissue.