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An increase in visceral fat is associated with an increase in insulin resistance, so reducing body fat mass through exercise may help alleviate type 2 diabetes mellitus (T2DM). The current meta-analysis evaluated the effect of changes in body fat via an intervention of regular exercise on hemoglobin A1c (HbA1c) in patients with T2DM. The inclusion criteria were randomized controlled trials involving adults with T2DM, intervention involving exercise alone, an overall duration of intervention ≥12 weeks, and reporting HbA1c and body fat mass. The mean differences (MDs) were defined as the MD between the exercise group and the control group, and the MDs in HbA1c (in percentage) and body fat mass (in kilograms) were calculated. All MDs in HbA1c were pooled as overall effects. A meta-regression analysis was performed to evaluate the relationship between the MD in the body fat mass (in kilograms) and the MD in HbA1c. Twenty studies (1,134 subjects) were analyzed. The pooled MD in HbA1c (in percentage) decreased significantly (−0.4; 95% confidence interval [−0.5, −0.3]) but contained significant heterogeneity (Q = 52.7, p <.01; I2 = 41.6%). A meta-regression analysis showed that a decrease in the MD in body fat mass was significantly associated with a decrease in the MD in HbA1c (R2 = 80.0%) and heterogeneity decreased (Q = 27.3, p =.61; I2 = 11.9%), and a reduction in body fat mass of 1 kg was estimated to decrease the HbA1c (%) by approximately 0.2. The current study suggested that a decrease in HbA1c due to regular exercise depends on a reduction in body fat mass in patients with T2DM. [ABSTRACT FROM AUTHOR]

Summary: Background: There are limited data on the prevalence and treatment of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. Aim: To estimate the prevalence of at‐risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. Methods: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction‐associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. Results: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co‐existing T2DM and obesity, the prevalence of MASLD, at‐risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). Conclusion: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at‐risk MASH and cirrhosis is high, posing a significant risk for liver‐related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH‐related fibrosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585). Experimental Approach: The cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose. Key Results: Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose. Conclusion and Implications: The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds. [ABSTRACT FROM AUTHOR]

Metformin (MET) and sitagliptin (STG) are widely used as the first-line and long-term oral hypoglycemic agents for managing type 2 diabetes mellitus (T2DM). However, the current lack of convenient and rapid measurement methods poses a challenge for individualized management. This study developed a point-of-care (POC) assay method utilizing a miniature mass spectrometer, enabling rapid and accurate quantification of MET and STG concentrations in human blood and urine. By combining the miniature mass spectrometer with paper spray ionization, this method simplifies the process into three to four steps, requires minimal amounts of bodily fluids (50 μL of blood and 2 μL of urine), and is able to obtain quantification results within approximately 2 min. Stable isotope-labeled internal standards were employed to enhance the accuracy and stability of measurement. The MS/MS responses exhibited good linear relationship with concentration, with relative standard deviations (RSDs) below 25%. It has the potential to provide immediate treatment feedback and decision support for patients and healthcare professionals in clinical practice. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions To assess the differential association of risk factors with severe and non‐severe hypoglycaemia.The Hypoglycaemia Assessment Tool study evaluated the risk of hypoglycaemia over a 4‐week period in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) on insulin in 24 countries. Negative binomial regressions were applied to examine the associations of several risk factors with severe and non‐severe hypoglycaemia.The median age was 41 years in 5949 patients with T1D and 62 years in 12 914 patients with T2D. The 4‐week rates of non‐severe hypoglycaemic were 5.57 and 1.40 episodes per person in T1D and T2D, respectively; the corresponding rates for severe hypoglycaemia were 0.94 and 0.30. The excess risk was 42% higher for severe than non‐severe hypoglycaemia in females versus males with T2D; 27% higher in patients with T2D with versus without a continuous glucose monitoring (CGM); and 47% lower in patients with T1D with versus without an insulin pump. The excess risk also differed across geographical areas and was marginally lower for severe than non‐severe hypoglycaemia for higher values of HbA1c in patients with T2D. Associations with severity of hypoglycaemia were not different for age, diabetes and insulin therapy duration, previous hypoglycaemic episodes and insulin regimen.The risk of severe versus non‐severe hypoglycaemia differs in patients with T1D and T2D; sex, the use of a CGM and insulin pump, and geographical areas were differently associated with one type of hypoglycaemia than the other. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions To explore biomarkers that can predict the response of type 2 diabetes (T2D) patients to metformin at an early stage to provide better treatment for T2D.T2D patients with (responders) or without response (non‐responders) to metformin were recruited, and their serum samples were used for metabolomic analysis to identify candidate biomarkers. Moreover, the efficacy of metformin was verified by insulin‐resistant mice, and the candidate biomarkers were verified to determine the biomarkers. Five different machine learning methods were used to construct the integrated biomarker profiling (IBP) with the biomarkers to predict the response of T2D patients to metformin.A total of 73 responders and 63 non‐responders were recruited, and 88 differential metabolites were identified in the serum samples. After being verified in mice, 19 of the 88 were considered as candidate biomarkers. Next, after metformin regulation, nine candidate biomarkers were confirmed as the biomarkers. After comparing five machine learning models, the nine biomarkers were constructed into the IBP for predicting the response of T2D patients to metformin based on the Naïve Bayes classifier, which was verified with an accuracy of 89.70%.The IBP composed of nine biomarkers can be used to predict the response of T2D patients to metformin, enabling clinicians to start a combined medication strategy as soon as possible if T2D patients do not respond to metformin. [ABSTRACT FROM AUTHOR]

Epidemiological evidence showed that patients suffering from obesity and T2DM are significantly at higher risk for chronic low-grade inflammation, oxidative stress, nonalcoholic fatty liver (NAFLD) and intestinal flora imbalance. Increasing evidence of pathological characteristics illustrates that some common signaling pathways participate in the occurrence, progression, treatment, and prevention of obesity and T2DM. These signaling pathways contain the pivotal players in glucose and lipid metabolism, e.g., AMPK, PI3K/AKT, FGF21, Hedgehog, Notch, and WNT; the inflammation response, for instance, Nrf2, MAPK, NF- kB, and JAK/STAT. Bioactive compounds from plants have emerged as key food components related to healthy status and disease prevention. They can act as signaling molecules to initiate or mediate signaling transduction that regulates cell function and homeostasis to repair and re-functionalize the damaged tissues and organs. Therefore, it is crucial to continuously investigate bioactive compounds as sources of new pharmaceuticals for obesity and T2DM. This review provides comprehensive information of the commonly shared signaling pathways between obesity and T2DM, and we also summarize the therapeutic bioactive compounds that may serve as anti-obesity and/or anti-diabetes therapeutics by regulating these associated pathways, which contribute to improving glucose and lipid metabolism, attenuating inflammation. [ABSTRACT FROM AUTHOR]

Background: Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). Methods: A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96 years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Results: Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44–0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. Conclusions: A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a common co-morbidity in patients who receive esophagectomy and has unfavorable effects on glucose and lipid metabolism in patients. This study examines how weight and glycolipid metabolism change in patients with T2DM following esophagectomy. Methods: This retrospective, one-center, observational analysis with a propensity score matching analysis (PSM) included 114 patients who underwent esophageal surgery in the Department of Cardiothoracic Surgery, the 900th Hospital of Joint Logistic Support Force from 2017 to 2020, which were separated into T2DM group and Non-T2DM group. Weight, body mass index (BMI), fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured and analyzed before and after the operation. Results: Two groups showed similar reductions in weight and BMI after surgery. In the T2DM group, weight decreased from 63.10(10.31) before surgery to 55.10(11.60) kg at 6 months (P < 0.001) with BMI decreasing from 22.67 (2.90) to 19.77 (3.48); While in the Non-T2DM group, weight decreased from 61.42 (8.46) to 53.19 (9.26) kg at 6 months after surgery with BMI decline from 22.49 (2.77) before operation to 19.45 (3.08) at 6 months after surgery. Fasting plasma glucose levels showed a significant decrease (P = 0.035) in the T2DM group at a six-month point of 7.00 (2.21) mmol/L compared to preoperative levels of 7.67 (2.32) mmol/L. HDL levels increased significantly in the Non-T2DM group at six months postoperatively at 1.52 (0.05) with P < 0.001 compared to preoperative levels of 1.22(0.04) mmol/L. TG, LDL, and TC levels decreased significantly in both groups from the preoperative to the 6-month point. Conclusions: Esophagectomy induces weight loss in T2DM and Non-T2DM groups, improves long-term glucose metabolism in the T2DM group, and enhances lipid metabolism in both groups. Further research is needed to understand their mechanisms. [ABSTRACT FROM AUTHOR]

The aim of this study was to provide a scoping and comprehensive review for the clinical outcomes from the cross-link of Type 2 diabetes mellitus (T2DM), COVID-19, and sarcopenia. By using PRISMA guidelines and searching through different databases that could provide findings of evidence on the association of T2DM, COVID-19, and sarcopenia. Thirty-three studies reported a relationship between sarcopenia with T2DM, twenty-one studies reported the prognosis COVID-19 in patients with T2DM, ten studies reported the prognosis of COVID-19 in patients with sarcopenia, five studies discussed the outcomes of sarcopenia in patients with COVID-19, and one study reported sarcopenia outcomes in the presence of T2DM and COVID-19. There is an obvious multidimensional relationship between T2DM, COVID-19 and sarcopenia which can cause prejudicial effects, poor prognosis, prolonged hospitalisation, lowered quality of life and a higher mortality rate during the current COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Western diet and unhealthy lifestyle have contributed to the continued growth of type 2 diabetes mellitus (T2DM). T2DM is associated with dysbacteriosis, and studies have found that altering the gut microbiota has a positive effect on treatment. In addition to hyperglycaemia, T2DM often causes damage to multiple organs. However, there are few studies on organ damage from faecal microbiota transplantation (FMT). T2DM mice were divided into four groups and were given phosphate buffered saline (PBS) (T2DM group), FMT (FMT group), Lactobacillus (LAB group), and Bifidobacterium (BIO group) by gavage for six weeks, respectively. Mice on a normal diet (control group) were gavaged with PBS for six weeks. After gavage treatment, FMT, LAB, and BIO groups were similar in lowering glucose, endotoxemia was slightly reduced, and the colonic mucus layer and liver lobules developed towards normal tissue. Surprisingly, we found that the FMT group had unique effects on islet cell regeneration, increased functional β cells, and insulin sensitivity. Lactobacillus has the best glucose-lowering effect, but FMT has obvious advantages in β-cell regeneration, which provides new treatment ideas for tissue damage caused by T2DM. [ABSTRACT FROM AUTHOR]

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium‐glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK‐UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration‐time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5‐2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%‐82% and 89%‐93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK‐UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP. [ABSTRACT FROM AUTHOR]

Introduction: People with obesity have high circulating bile acids (BA). Although aerobic fitness favors low circulating BA, the effect of training intensity before clinically meaningful weight loss on BA is unclear. This study aimed to test the hypothesis that 2 wk of interval (INT) versus continuous (CONT) exercise would lower plasma BA in relation to insulin sensitivity. Methods: Twenty-three older adults with prediabetes (ADA criteria) were randomized to 12 work-matched bouts of INT (n = 11, 60.3 ± 2.4 yr, 32.1 ± 1.2 kg⋅m-2) at 3 min at 50% HRpeak and 3 min at 90% HRpeak or CONT (n = 12, 60.8 ± 2.4 yr, 34.0 ± 1.7 kg⋅m-2) at 70% HRpeak cycling training for 60 min⋅d-1 over 2 wk. A 180-min 75-g oral glucose tolerance test (OGTT) was performed to assess glucose tolerance (tAUC), insulin sensitivity (Siis), and metabolic flexibility (RERpostprandial-RERfast; indirect calorimetry). BA (n = 8 conjugated and 7 unconjugated) were analyzed at 0, 30, and 60 min of the OGTT. Anthropometrics and fitness (...O2peak) were also assessed. Results: INT and CONT comparably reduced body mass index (BMI; P < 0.001) and fasting RER (P < 0.001) but raised insulin sensitivity (P = 0.03). INT increased ...O2peak as compared with CONT (P = 0.01). Exercise decreased the unconjugated BA chenodeoxycholic acid iAUC60min (P < 0.001), deoxycholic acid iAUC60min (P < 0.001), lithocholic acid iAUC60min (P < 0.001), and glycodeoxycholic acid (GCDCA) iAUC60min (P < 0.001). Comparable reductions were also seen in the conjugated BA hyodeoxycholic acid iAUC60min (P = 0.01) and taurolithocholic acid iAUC60min (P = 0.007). Increased ...O2peak was associated with lowered UDCA0min (r = -0.56, P = 0.02) and cholic acid iAUC60min (r = -0.60, P = 0.005), whereas reduced BMI was related to higher GDCA0min (r = 0.60, P = 0.005) and GCDCA0min (r = 0.53, P = 0.01). Improved insulin sensitivity correlated with lower GCDCA iAUC60min (r = -0.45, P = 0.03) and GDCA iAUC60min (r = -0.48, P = 0.02), whereas increased metabolic flexibility was related to deoxycholic acid iAUC60min (r = 0.64, P = 0.004) and GCDCA iAUC60min (r = 0.43, P = 0.05). Conclusions: Short-term training lowers some BA in relation to insulin sensitivity independent of intensity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (−0.72, 95% CI −0.95 to −0.48) compared with the control group (−0.37, 95% CI −0.60 to −0.15) (diet vs. control −0.34, 95% CI −0.58 to −0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (−0.46, 95% CI −0.70 to −0.23) did not significantly differ from the control group (exercise vs. control −0.09, 95% CI −0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This post hoc analysis assessed change from baseline to week 52 in glycemic parameters for tirzepatide (5, 10, 15 mg) versus insulin degludec (SURPASS-3 trial) and glargine (SURPASS-4 trial) in people with type 2 diabetes and different baseline glycemic patterns, based on fasting serum glucose (FSG) and postprandial glucose (PPG) values. RESEARCH DESIGN AND METHODS: Participant subgroups with low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, and high FSG/high PPG were defined according to the median values of these measures. RESULTS: All tirzepatide doses and basal insulins were associated with decreased HbA1c, FSG, and PPG values from baseline to week 52 in all subgroups (P < 0.05). Within each subgroup, HbA1c and PPG decreases were greater with tirzepatide than insulin (P < 0.05). FSG decreases were generally similar. There were no differential treatment effects by FSG/PPG subgroup. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with superior glycemic control compared with insulin, irrespective of baseline glycemic pattern. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. RESEARCH DESIGN AND METHODS: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. RESULTS: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (−2.6% vs. −2.4%), BW (−14 vs. −13 kg), WC (−10 vs. −10 cm), triglycerides (−26% vs. −24%), HDL (7% vs. 7%), and systolic BP (−6 vs. −7 mmHg) were observed in both subgroups with tirzepatide. CONCLUSIONS: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine trends in incidence of acute diabetes complications in individuals with type 1 or type 2 diabetes with and without severe mental illness (SMI) in Denmark by age and calendar year. RESEARCH DESIGN AND METHODS: We conducted a cohort study using nationwide registers from 1996 to 2020 to identify individuals with diabetes, ascertain SMI status (namely, schizophrenia, bipolar disorder, or major depression) and identify the outcomes: hospitalization for hypoglycemia and diabetic ketoacidosis (DKA). We used Poisson regression to estimate incidence rates (IRs) and incidence rate ratios (IRRs) of recurrent hypoglycemia and DKA events by SMI, age, and calendar year, accounting for sex, diabetes duration, education, and country of origin. RESULTS: Among 433,609 individuals with diabetes, 8% had SMI. Risk of (first and subsequent) hypoglycemia events was higher for individuals with SMI than for those without SMI (for first hypoglycemia event, IRR: type 1 diabetes, 1.77 [95% CI 1.56–2.00]; type 2 diabetes, 1.64 [95% CI 1.55–1.74]). Individuals with schizophrenia were particularly at risk for recurrent hypoglycemia events. The risk of first DKA event was higher in individuals with SMI (for first DKA event, IRR: type 1 diabetes, 1.78 [95% CI 1.50–2.11]; type 2 diabetes, 1.85 [95% CI 1.64–2.09]). Except for DKA in the type 2 diabetes group, IR differences between individuals with and without SMI were highest in younger individuals (<50 years old) but stable across the calendar year. CONCLUSIONS: SMI is an important risk factor for acute diabetes complication and effective prevention is needed in this population, especially among the younger population and those with schizophrenia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648 , hazard ratio [HR] 1.23, P = 3.6 × 10−9), rs77142250 (near HS3ST1 , HR 1.89, P = 9.9 × 10−9), and rs335407 (near TFB1M/NOX3 , HR 1.25, P = 1.5 × 10−8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison–adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10−16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate whether the sex disparities in type 2 diabetes–associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. RESEARCH DESIGN AND METHODS: We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. RESULTS: Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03–1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). CONCLUSIONS: Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the excess in diabetes-related CVD risk for women but may benefit from intensive BP control. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the longitudinal development of neurofilament light chain (NfL) levels in type 2 diabetes with and without diabetic polyneuropathy (+/−DPN) and to explore the predictive potential of NfL as a biomarker for DPN. RESEARCH DESIGN AND METHODS: We performed retrospective longitudinal case-control analysis of data from 178 participants of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care-Denmark (ADDITION-Denmark) cohort of people with screen-detected type 2 diabetes. Biobank samples acquired at the ADDITION-Denmark 5- and 10-year follow-ups were analyzed for serum NfL (s-NfL) using single-molecule array, and the results were compared with established reference material to obtain NfL z- scores. DPN was diagnosed according to Toronto criteria for confirmed DPN at the 10-year follow-up. RESULTS: s-NfL increased over time in +DPN (N = 39) and −DPN participants (N = 139) at levels above normal age-induced s-NfL increase. Longitudinal s-NfL change was greater in +DPN than in −DPN participants (17.4% [95% CI 4.3; 32.2] or 0.31 SD [95% CI 0.03; 0.60] higher s-NfL or NfL z -score increase in +DPN compared with −DPN). s-NfL at the 5-year follow-up was positively associated with nerve conduction studies at the 10-year follow-up (P = 0.02 to <0.001), but not with DPN risk. Areas under the curve (AUCs) for s-NfL were not inferior to AUCs for the Michigan Neuropathy Screening Instrument questionnaire score or vibration detection thresholds. Higher yearly s-NfL increase was associated with higher DPN risk (odds ratio 1.36 [95% CI 1.08; 1.71] per 1 ng/L/year). CONCLUSIONS: Our findings suggest that preceding s-NfL trajectories differ slightly between those with and without DPN and imply a possible biomarker value of s-NfL trajectories in DPN. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis -protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. RESULTS: Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73–0.82) to 0.88 (0.85–0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. CONCLUSIONS: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011–2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS: Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS: In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53–3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23–1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57–2.71). CONCLUSIONS: Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease. [ABSTRACT FROM AUTHOR]

Background: Effective self‐management of type 2 diabetes requires adequate health literacy (HL) and a supportive network. Diabetes self‐management education and support programmes play a crucial role in improving these factors. However, limited research exists on how such programmes can support health literacy among migrants and facilitate the dissemination of knowledge within their social networks. Aim: This study aimed to investigate the perspectives of Arabic‐speaking informants with a migrant background in relation to how their type 2 diabetes‐related health literacy was acquired, applied and distributed within social networks through participation in a culturally sensitive diabetes self‐management education and support (DSMES) programme. Methods: Semi‐structured interviews were conducted with 12 informants during the programme and three to 7 months later, from September 2019 to May 2020. Abductive analysis was applied using HL and distributed health literacy (DHL) theory as frameworks. Results: The analysis generated three themes: (1) sources of health information and the development of health literacy; (2) changes towards active self‐management; and (3) distributed health literacy. Prior to programme participation, informants faced challenges in navigating conflicting information from family, friends and social media. After participating in the programme, they reported improvements in HL, particularly in knowledge acquisition. Many became more actively engaged in decision‐making and exhibited improved health behaviours, such as dietary choices. Nonetheless, some informants continued to struggle with choosing appropriate prevention and treatment strategies. Notably, certain informants acted as HL mediators, sharing their newly acquired knowledge within their social networks in Denmark and abroad. Conclusion: Culturally sensitive diabetes self‐management education programmes have the potential to enhance HL among migrants, leading to the distribution of relevant diabetes knowledge within their social networks. Future studies should explore how members of migrants' social networks perceive their supportive role in type 2 diabetes management. Programmes can benefit from emphasising critical HL and exploring how participant‐informants effectively communicate diabetes‐related knowledge within their networks to address misinformation and conflicting information. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of type 2 diabetes has surged to epidemic proportions and despite treatment administration/adherence, some individuals experience poorly controlled diabetes. While existing literature explores metabolic changes in type 2 diabetes, understanding metabolic derangement in poorly controlled cases remains limited. Objective: This investigation aimed to characterize the urine metabolome of poorly controlled type 2 diabetes in a South African cohort. Method: Using an untargeted proton nuclear magnetic resonance metabolomics approach, urine samples from 15 poorly controlled type 2 diabetes patients and 25 healthy controls were analyzed and statistically compared to identify differentiating metabolites. Results: The poorly controlled type 2 diabetes patients were characterized by elevated concentrations of various metabolites associated with changes to the macro-fuel pathways (including carbohydrate metabolism, ketogenesis, proteolysis, and the tricarboxylic acid cycle), autophagy and/or apoptosis, an uncontrolled diet, and kidney and liver damage. Conclusion: These results indicate that inhibited cellular glucose uptake in poorly controlled type 2 diabetes significantly affects energy-producing pathways, leading to apoptosis and/or autophagy, ultimately contributing to kidney and mild liver damage. The study also suggests poor dietary compliance as a cause of the patient's uncontrolled glycemic state. Collectively these findings offer a first-time comprehensive overview of urine metabolic changes in poorly controlled type 2 diabetes and its association with secondary diseases, offering potential insights for more targeted treatment strategies to prevent disease progression, treatment efficacy, and diet/treatment compliance. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is one of the most common complications of type 2 diabetes, which can lead to impaired balance and walking. Innovative footwear devices designed to stimulate foot sensory receptors, such as vibrating insoles, could offer a new route to improve motor impairments in people with diabetic peripheral neuropathy (DPN). Does wearing vibrating insoles for the first time alter measures of balance, walking, and ankle-foot muscle activity, in people with DPN? A randomised cross-over study was conducted with 18 ambulant men and women with a diagnosis of DPN. Participants performed tests of standing balance (Bertec® force platform) under four conditions (foam/firm surface, eyes open/closed) and level-ground walking (GAITRite® instrumented walkway), whilst wearing vibrating and non-vibrating (control) insoles on two separate occasions (one insole/session). Electromyography (EMG) was used to assess soleus, medial gastrocnemius, tibialis anterior, peroneus longus activity during balance tests. Outcomes included centre of pressure (CoP) sway, EMG amplitude, spatiotemporal gait patterns, and Timed Up and Go test. One sample t-tests were used to explore %differences in outcomes between insole conditions. Wearing vibrating insoles led to a reduction (improvement) in CoP elliptical area, when standing on a foam surface with eyes closed, relative to non-vibrating insoles (P =0.03). Applying perceptible vibrations to the soles of the feet also reduced the EMG amplitude in soleus (P =0.01 and P=0.04) and medial gastrocnemius (P =0.03 and P=0.09) when standing with eyes closed on firm and foam surfaces. Our findings of signs of improved balance and altered muscle activity with suprasensory vibrating insoles provides new insights into how these devices can be used to inform innovative rehabilitation approaches in individuals with DPN. This will be strengthened by further research into possible clinical benefits of these devices – given that the effects we detected were small with uncertain clinical meaning. • Wearing vibrating insoles may alter centre of pressure measures during standing. • Perceptible vibrations at the feet reduce the amplitude of plantarflexor activity. • Altered muscle activity may be one underlying mechanism of vibrating insoles. [ABSTRACT FROM AUTHOR]

Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases. • Proteostasis is emerging as a fundamental process that is altered during ageing. • Protein misfolding and ER stress functionally contributes to the ageing process. • Protein homeostasis hold therapeutic promise for delaying many age-onset diseases. • Understanding misfolding will open new ways in attaining healthy ageing & longevity. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of β-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR. Article Highlights: Type 2 diabetes can be subcategorized on the basis of β-cell function and insulin sensitivity, but little is known about the association of subtypes of type 2 diabetes with risk of diabetic retinopathy (DR). Do individuals with hyperinsulinemic or insulinopenic type 2 diabetes have an increased risk of DR compared with individuals with classical type 2 diabetes? Individuals with hyperinsulinemic type 2 diabetes had almost half the risk of prevalent or incident DR or progression of DR compared with individuals with classical type 2 diabetes. These results suggest that more individualized screening intervals for DR may be possible within subgroups of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat. Article Highlights: The relationship between excess adiposity and type 2 diabetes is complex. Can genetic subtypes of adiposity reveal distinct pathways linking adiposity with type 2 diabetes? Higher adiposity increases type 2 diabetes risk via different mechanisms (e.g., cholesterol pathways or inflammation) but decreases risk via other mechanisms (lower liver fat and improved insulin sensitivity, or increased body size and enhanced muscle quality). These insights could improve precision medicine for type 2 diabetes via treating adiposity. [ABSTRACT FROM AUTHOR]

Normal-weight individuals with usual-onset type 2 diabetes have reduced β-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of β-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0–10 min) and steady-state (100–120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state β-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse β-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals. Article Highlights: The metabolic architecture of normal-weight young-onset type 2 diabetes (YOD) remains unclear. We investigated the relative contribution of β-cell dysfunction and insulin resistance to normal-weight YOD. Normal-weight individuals with YOD had worse β-cell responses and preserved insulin sensitivity than obese counterparts with YOD and normal-weight healthy control individuals. Our results confirm the pivotal role of β-cell defects in normal-weight YOD and emphasize the importance of preserving β-cell function in this group. [ABSTRACT FROM AUTHOR]

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11 , T-C-G-T-T , as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11 , *12 , and *22 , where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [ *22 ] and 0.78 [ *12 ]); an added interaction term was statistically significant (OR 0.49 [ *12 ]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30–41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes. Article Highlights: This study enlarged our sample of high-resolution HLA-DRB1 alleles and 5 individually typed mutations for the SLC16A11 locus and used these to test for protection, risk, and interaction for type 2 diabetes. We confirmed our earlier reports of protection (DRB1*16:02) and risk (SLC16A11) and used all genotypes in a sensitivity analysis for BMI. HLA-DRB1*16:02 was found to be protective, and sensitivity analysis demonstrated that SLC16A11 is a risk in lower BMI strata and protective in higher ones. Epistasis for individuals with DRB1*16:02 and T-C-G-T-T reduces the odds for type 2 diabetes in a BMI range of 30–41 kg/m2, and binding studies implicate core peptide FSAFASGLL. [ABSTRACT FROM AUTHOR]

The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium–glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of −0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of −0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of −0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes Article Highlights: Loss-of-function variant of SGLT1 is associated with reduced intestinal SGLT1 expression and early postload glucose response. Mendelian randomization supports the causal relationship between intestinal glucose absorption and postprandial glucose. Modulating intestinal SGLT1 expression/function is a promising avenue for the prevention and treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multiomics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially l-tryptophan, in the diabetic mice. Notably, l-tryptophan upregulated the mRNA level of glucagon-like peptide 1 (GLP-1) production–related gene (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L cells, and it increased the supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplant of fecal microbiota from dapagliflozin-treated mice, supplementation of l-tryptophan, or treatment with dapagliflozin upregulated l-tryptophan, GLP-1, and insulin or C-peptide levels and promoted β-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism. Article Highlights: Sodium–glucose cotransporter 2 inhibitors, novel and efficacious antidiabetic agents, can preserve β-cell mass in type 2 diabetic animals, but the mechanism remains unclear. We find that dapagliflozin reshapes gut microbiota, improves microbiotic and plasmatic metabolites related to tryptophan metabolism, and increases glucagon-like peptide 1 (GLP-1) production mediated via tryptophan metabolism. GLP-1−GLP-1 receptor signaling participates in the dapagliflozin-induced β-cell regeneration. Our study reveals that the gut microbiota–tryptophan metabolism–GLP-1 axis is a novel mechanism of β-cell regeneration induced by dapagliflozin and provides experimental evidence for its β-cell protection in treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Acute and chronic sodium–glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ—liver versus kidney—responsible for the increase in EGP has not been identified. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-3H]glucose infusion (to measure total EGP) combined with arterial and renal vein catheterization and para -aminohippuric acid infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 h after dapagliflozin (DAPA) and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 min, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in NGT or T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P < 0.05 vs. placebo). The increase in renal glucose uptake was entirely explained by the increase in glucosuria. A single dose of DAPA significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis. Article Highlights: Sodium–glucose cotransporter 2 (SGLT2) inhibitors increase endogenous glucose production (EGP) but the organ—liver versus kidney—responsible for the increase in EGP is unknown. Total EGP ([3-3H]glucose), net renal arteriovenous balance (renal vein catheterization), and renal glucose production were measured in 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) before and 4 h after dapagliflozin and placebo administration. Dapagliflozin increased EGP in both T2D and NGT subjects. All of the increase in EGP was derived from an increase in hepatic glucose output. These results establish the existence of a novel renal-hepatic axis. [ABSTRACT FROM AUTHOR]

Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes, eGlx dysfunction occurs before podocyte damage; hence, we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signaling in human GEnCs through AdipoR1. It significantly reduced eGlx shedding and the tumor necrosis factor-α (TNF-α)–mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnCs in vitro. It protected against increased TNF-α mRNA expression in glomeruli isolated from db/db mice and against expression of genes associated with glycocalyx shedding (namely, SDC4, MMP2, and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps'alb) in glomeruli isolated from db/db mice when administered intraperitoneally and when applied directly to glomeruli (ex vivo). Ps'alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes. Article Highlights: Adiponectin protects against diabetic kidney disease (DKD). Understanding its role on glomerular endothelial barrier properties should help formulate a strategic therapeutic approach. This study shows adiponectin protects against endothelial glycocalyx shedding and restores albumin permeability in experimental diabetes. Activation of the glomerular endothelial cell adiponectin signaling pathway may be an early treatment strategy for patients with diabetes who are at risk of DKD. [ABSTRACT FROM AUTHOR]

African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Here, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA-focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method. We further tested the score in three independent studies with a total of 7,275 AAs and compared the PRSAA with other published scores. Results show that a 1-SD increase in the PRSAA was associated with 40–60% increase in the odds of T2D (odds ratio [OR] 1.60, 95% CI 1.37–1.88; OR 1.40, 95% CI 1.16–1.70; and OR 1.45, 95% CI 1.30–1.62) across three testing cohorts. These models captured 1.0–2.6% of the variance (R 2) in T2D on the liability scale. The positive predictive values for three calculated score thresholds (the top 2%, 5%, and 10%) ranged from 14 to 35%. The PRSAA, in general, performed similarly to existing T2D PRS. The need remains for larger data sets to continue to evaluate the utility of within-ancestry scores in the AA population. Article Highlights: This study aimed to better understand the performance of existing and a novel polygenic risk scores (PRS) for type 2 diabetes in African American (AA) populations. A PRS was developed using only genetic data from AA populations (PRSAA) and compared with scores developed using genetic data from other ancestral populations. The performance metrics of the PRSAA were comparable to a published multiancestry PRS developed using training data from much larger study samples. The utility of single-ancestry PRS in AAs should be reevaluated when larger AA training data sets are available. [ABSTRACT FROM AUTHOR]

This study aimed to assess the correlation between glycemic status (prediabetes and type 2 diabetes mellitus) and the risk of gastric cancer according to menopausal status. A total of 982,559 pre/peri-menopausal and 1445,419 postmenopausal women aged ≥ 40, who underwent the Korean national health screening in 2009, were included and followed up until 2018. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for development of gastric cancers according to hyperglycemic status in both groups using Cox proportional hazards models. Over a mean follow-up period of 8.3 years, 3259 (0.33%) pre/peri-menopausal women and 13,245 (0.92%) postmenopausal women were diagnosed with gastric cancer. In postmenopausal women, only diabetes mellitus conferred a higher risk of gastric cancer compared to normal glycemic status (HR, 1.15; 95% CI, 1.09–1.20), with an increasing trend of gastric cancers from prediabetes to diabetes (P for trend < 0.001) observed regardless of menopausal status. Obesity, smoking, and heavy alcohol consumption was associated with increased gastric cancer risk mainly in the postmenopausal period. The risk of gastric cancer escalates with deteriorating glycemic status in a dose-response manner. Diabetes mellitus is linked with an elevated risk of gastric cancer in postmenopausal women. [ABSTRACT FROM AUTHOR]

Up to 25% of people with type 2 diabetes (T2D) may binge eat which is almost 10 times as many as in the general population. Binge eating is associated with depression, anxiety, and social isolation. Moreover, binge eating may increase the risk of obesity and high blood glucose levels, both of which can accelerate the onset of complications to diabetes and death in people with T2D. Still, little is known about the experiences, needs, and preferences of people with T2D and binge eating that can inform and develop current and future treatment efforts. The aim of the study was therefore to gain in-depth insights into the experiences and biopsychosocial support needs of women and men with T2D and binge eating. Twenty semi-structured individual interviews (65% with females) were conducted and analyzed according to the methodology of Interpretive Description. Four themes were identified: (a) T2D and binge eating: Feeling trapped in a vicious circle; (b) Unwanted outcasts: Responding to continuous criticism; (c) Biomedical relief: Blaming and adjusting the body; and, (d) Silent struggles: Wanting to cease the secrecy. Pertinent to all themes were the guilt, shame, and worries about developing complications that the participants experienced when binge eating despite having T2D. Although binge eating triggered emotional distress, binge eating was at the same time a way of coping with such distress. Implications for treatment and future research are discussed, including the need to systematically assess and address binge eating in routine T2D care. [ABSTRACT FROM AUTHOR]

Aim: To assess sleep quality in relation to perceived stress in patients with type 2 diabetes (T2DM) and age- and sex-matched controls. Methods: Perceived stress level and sleep quality assessed in 154 patients with T2DM (58 men, 96 women, age 58.3 ± 11.9 years), 154 matched controls (58 men, 96 women, age 56.8 ± 12.2 years) using Perceived Stress Scale and Pittsburgh Sleep Quality Index. Results: Patients with T2DM had worse subjective sleep quality (p < 0.001), sleep latency (p = 0.047) than controls. Patients with high stress level had worse subjective sleep quality (p = 0.027), higher use of sleeping medication (p = 0.023), daytime dysfunction (p < 0.001) than those with low stress level. No significant differences in sleep quality between controls with high and low perceived stress level. Perceived stress level in patients with T2DM correlated with subjective sleep quality (r = 0.260, p = 0.002), sleep duration (r = 0.228, p = 0.005), use of sleep medication (r = 0.245, p = 0.004), daytime dysfunction (r = 0.326, p < 0.001), in age- and sex-matched controls—to daytime dysfunction (r = 0.191, p = 0.037). Conclusion: Sleep quality (subjective sleep quality, sleep latency) is worse in patients with type 2 diabetes than in age- and sex-matched controls. Patients with high perceived stress level have worse subjective sleep quality, higher use of sleeping medication, daytime dysfunction than patients with low perceived stress level; no significant differences in sleep quality between controls with high and low stress level. Perceived stress level in patients with type 2 diabetes is related to subjective sleep quality, sleep duration, use of sleep medication, daytime dysfunction, in age- and sex-matched controls—to daytime dysfunction. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to explore the causal association between inflammatory bowel disease (IBD) and the risk of type 2 diabetes (T2D) based on a two-sample Mendelian randomization (MR) study. Methods: Summary single nucleotide polymorphism (SNP)-phenotype association data were obtained from published two genome-wide association studies (GWAS) including SNPs related to IBD, UC, or CD in European participants (n = 71,997) and East Asian participants (n = 16,805). Two GWAS including SNPs associated with T2D included 655,666 Europeans and 433,540 East Asians. A series of screening processes were performed to select qualified instrumental SNPs strongly related to exposure. We applied the inverse variance weighted (IVW), the MR-Egger regression, and the weighted median to estimate the causal effects of IBD, ulcerative colitis (UC) or Crohn' disease (CD) on T2D. Cochran's Q test was conducted to evaluate the statistical heterogeneity between SNPs in the IVW method. The leave-one-out analysis was employed to assess whether the results were caused by any single SNP associated with IBD, UC, or CD. Odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: The IVW results demonstrated that IBD could increase the risk of T2D in the European population (OR = 1.0230, 95%CI: 1.0073–1.0390). UC was positively associated with the risk of T2D according to the weighted median (OR = 1.0274, 95%CI: 1.0009–1.0546) and IVW (OR = 1.0244, 95%CI: 1.0071–1.0421) results in the European population. The IVW results indicated that the CD was positively associated with the risk of T2D in the European population (OR = 1.0187, 95%CI: 1.0045–1.0330). In the East Asian population, there are no associations between the IBD, UC, or CD and the risk of T2D (all P > 0.05). MVMR results revealed that the causal effect UC on T2D was still statistically significant after including body mass index (BMI) or low-density lipoprotein (LDL). Conclusion: IBD, UC, or CD had causal effects on the risk of T2D in the European population, which might provide evidence for the prevention of T2D in patients with IBD, UC, or CD. [ABSTRACT FROM AUTHOR]

Background: Variability in biological parameters may be associated with adverse outcomes. The aim of the study was to determine whether variability in body mass index (BMI) and blood pressure is associated with all-cause, cardiovascular mortality and cancer mortality or with renal disease progression in subjects with type 2 diabetes. Methods: The diabetes database was accessed, and all the information on patient visits (consultations) carried out in the study period (1 January 2008–31 December 2019) was extracted and linked to the laboratory database and the mortality register. Results: The total number of patients included in the study population was 26,261, of whom 54.4% were male. Median (interquartile range, IQR) age was 60.2 (51.8–68.3) years. The coefficient of variability of BMI was independently associated with increased all-cause and cardiovascular, but not cancer, mortality. Glycated haemoglobin (HbA1c) was associated with increased all-cause, cardiovascular, and cancer mortality as well as with renal progression. Variability in systolic blood pressure, diastolic blood pressure, and pulse pressure was associated with increased all-cause and cardiovascular mortality in bivariate, but not in multivariate, analyses. Conclusions: Variability in BMI was associated with increased all-cause and cardiovascular, but not cancer, mortality in a large real-world contemporary population. Our results also confirm the association of HbA1c with increased all-cause, cardiovascular, and cancer mortality as well as with renal progression. [ABSTRACT FROM AUTHOR]

Aims: The Gompertz law of mortality proclaims that human mortality rates in middle to old ages grow log-linearly with age and this law has been confirmed at multiple instances. We investigated if diabetes mortality in Germany also obeys to the Gompertz law and how this information helps to communicate diabetes mortality more intuitively. Methods: We analyzed all statutory health-insured persons in Germany in 2013 that were aged 30 years or older. Deaths in 2014 were recorded and given in 5-year age groups. We fitted weighted linear regression models (separately for females and males and for people with and without diabetes) and additionally computed the probability that a person with diabetes dies before a person of the same age and sex without diabetes, and the "diabetes age", that is, the additional years of mortality risk added to an individual's chronological age due to diabetes-related excess mortality. Results: We included N = 47,365,120 individuals, 6,541,181 of them with diabetes. In 2014, 763,228 deaths were recorded, among them 288,515 with diabetes. Diabetes mortality followed nearly perfectly Gompertz distributions. The probability that a person with diabetes dies before a person without diabetes was 61.9% for females and 63.3% for males. Conclusions: Diabetes mortality for females and males aged 30 years or older in Germany in 2014 followed the Gompertz law of mortality. The survival information of the population with diabetes during a large part of the lifespan can thus be reduced to the two parameters of the Gompertz distribution. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG). Methods: We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). Results: Changes in LECT2 were correlated with the percentage of total weight loss (ρ = − 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601). Conclusions: SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications. [ABSTRACT FROM AUTHOR]

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302–1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237–1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395–1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019–1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007–1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02–1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%–12.10%) for any stroke, 11.77% (95% CI: 10.58%–12.97%) for IS, 10.62% (95% CI: 8.04%–13.20%) for LAS, and 7.57% (95% CI: 6.79%–8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes is a prevalent condition. The change in glucose control and body weight with the use of once-weekly semaglutide was evaluated in individuals with Type 2 diabetes in Colombia. Methods: This was a real-world, multi-centre, single-arm study involving adults in Colombia with Type 2 diabetes treated with once-weekly subcutaneous semaglutide for approximately 26 weeks. The primary endpoint assessed the change in glycated hemoglobin (HbA1c) from baseline to end of study. Secondary endpoints included changes in body weight from baseline to end of study. The study also explored the proportion of participants achieving predefined HbA1c targets and weight-loss responses at the end of the study. Results: Data from 225 patients across 11 centers were collected. Most patients were women (65%), and the mean age of the population was 57 years with a median HbA1c of 7.6% and a median body weight of 86 kg. After approximately 26 weeks, semaglutide was associated with a significant reduction in HbA1c of − 0.88 and a body weight reduction of − 4.04kg. The proportion of patients with HbA1c < 7% increased from 32 to 66% at end of study. Conclusion: Patients treated with once-weekly semaglutide experienced a clinically significant reduction in HbA1c and body weight. These results are in line with previous clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: In people with type 2 diabetes (PwT2D) who also have obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. The objective of this study was to explore the relationship between glycemic control and obesity among PwT2D in Europe and Australia using recent real-world data and applying consistent methodology across countries. Methods: Retrospective study utilizing IQVIA electronic medical records (EMR) databases grouped into panels based on specialty of contributing physicians. General practitioner (GP) and endocrinologist/diabetologist (E/D) panels were used in Germany and France, while GP panels were used in Italy, UK and Australia. The Spanish database included all physician specialties. The sample included PwT2D with glycated hemoglobin A1c (HbA1c) and body mass index (BMI) values measured within 90 days of each other between January 2015 and December 2018 (second record termed the 'index date'). PwT2D had a 1-year baseline period and a recorded HbA1c at the end of the 1-year post-index period. Results: The final sample comprised 194,729 PwT2D. At baseline, across countries/panels, 36.8–58.0% were above HbA1c target (HbA1c ≥ 7%) and 39.4–56.7% had obesity (BMI ≥ 30.0 kg/m2). Mean HbA1c ranged from 6.9 to 7.6% and mean BMI ranged from 29.3–31.6 kg/m2. At baseline, a higher proportion of PwT2D with obesity (40.8–64.2%) were above HbA1c target compared to their counterparts without obesity (32.2–52.4%). A higher proportion of patients with obesity at baseline (38.1–60.6%) had post-index HbA1c above target compared to their counterparts without obesity (30.9–56.0%). In logistic regression, patients with obesity had substantially lower odds of post-index HbA1c below target compared to those without obesity in all countries/panels except for France (E/D), Spain and Australia. Conclusions: This study presents data on HbA1c and BMI among type 2 diabetes (T2D) populations in Europe and Australia. A notable proportion of PwT2D had obesity and were above HBA1c target. Higher BMI was associated with poorer glycemic control. [ABSTRACT FROM AUTHOR]