Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria).

EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m² [95% CI –0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74–0.98]). Retinopathy rates did not differ by treatment group or in the HbA_1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m² did not differ by group. Those with eGFR ≥60 mL/min/1.73 m² had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58–0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85–1.38]; P for interaction = 0.031).

EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m² in analyses unadjusted for multiplicity.

This retrospective cohort study analyzed patients from Tayside and Fife in the Scottish Care Information–Diabetes Collaboration (SCI-DC) who were observable from the diagnosis of diabetes and had at least five HbA_1c measurements before the outcomes were evaluated. We used the previously reported HbA_1c variability score (HVS), calculated as the percentage of the number of changes in HbA_1c >0.5% (5.5 mmol/mol) among all HbA_1c measurements within an individual. The association between HVS and 10 outcomes was assessed using Cox proportional hazards models.

We included 13,111–19,883 patients in the analyses of each outcome. The patients with HVS >60% were associated with elevated risks of all outcomes compared with the lowest quintile (for example, HVS >80 to ≤100 vs. HVS ≥0 to ≤20, hazard ratio 2.38 [95% CI 1.61–3.53] for major adverse cardiovascular events, 2.4 [1.72–3.33] for all-cause mortality, 2.4 [1.13–5.11] for atherosclerotic cardiovascular death, 2.63 [1.81–3.84] for coronary artery disease, 2.04 [1.12–3.73] for ischemic stroke, 3.23 [1.76–5.93] for heart failure, 7.4 [3.84–14.27] for diabetic retinopathy, 3.07 [2.23–4.22] for diabetic peripheral neuropathy, 5.24 [2.61–10.49] for diabetic foot ulcer, and 3.49 [2.47–4.95] for new-onset chronic kidney disease). Four sensitivity analyses, including adjustment for time-weighted average HbA_1c, confirmed the robustness of the results.

Our study shows that higher HbA_1c variability is associated with increased risks of all-cause mortality, cardiovascular events, and microvascular complications of diabetes independently of high HbA_1c.

We performed a cross-sectional study in severely obese individuals before bariatric surgery. Lean control subjects were recruited from a research website. Cognitive deficits were defined by the National Institutes of Health (NIH) Toolbox (<5th percentile for lean control subjects). Cardiovascular autonomic neuropathy (CAN) was defined by an expiration-to-inspiration (E-to-I) ratio of <5th percentile for lean control subjects. Retinopathy was based on retinal photographs and nephropathy on the estimated glomerular filtration rate (<60 mg/dL) and/or the albumin-to-creatinine ratio (ACR) (≥30 mg/g). NIH Toolbox, E-to-I ratio, mean deviation on frequency doubling technology testing, and ACR were used as sensitive measures of these outcomes. We used multivariable linear regression to explore associations between metabolic factors and these outcomes.

We recruited 138 severely obese individuals and 46 lean control subjects. The prevalence of cognitive deficits, CAN, retinopathy, and nephropathy were 6.5%, 4.4%, 0%, and 6.5% in lean control subjects; 22.2%, 18.2%, 0%, and 6.1% in obese participants with normoglycemia; 17.7%, 21.4%, 1.9%, and 17.9% in obese participants with prediabetes; and 25.6%, 31.9%, 6.1%, and 16.3% in obese participants with diabetes. Waist circumference was significantly associated with cognitive function (–1.48; 95% CI –2.38, –0.57) and E-to-I ratio (–0.007; 95% CI –0.012, –0.002). Prediabetes was significantly associated with retinal function (–1.78; 95% CI –3.56, –0.002).

Obesity alone is likely sufficient to cause cognitive deficits but not retinopathy or nephropathy. Central obesity is the key metabolic risk factor.

We identified 8,528 patients with diabetes (self-report, medication use, or electronic medical record diagnosis) from the Henry Ford Exercise Testing Project (FIT Project). Patients with a BMI <18.5 kg/m² or cancer were excluded. Fitness was measured as the METs achieved during a physician-referred treadmill stress test and categorized as low (<6), moderate (6–9.9), or high (≥10). Adjusted hazard ratios for mortality were calculated using standard BMI (kilograms per meter squared) cutoffs of normal (18.5–24.9), overweight (25–29.9), and obese (≥30). Adjusted splines centered at 22.5 kg/m² were used to examine BMI as a continuous variable.

Patients had a mean age of 58 ± 11 years (49% women) with 1,319 deaths over a mean follow-up of 10.0 ± 4.1 years. Overall, obese patients had a 30% lower mortality hazard (P < 0.001) compared with normal-weight patients. In adjusted spline modeling, higher BMI as a continuous variable was predominantly associated with a lower mortality risk in the lowest fitness group and among patients with moderate fitness and BMI ≥30 kg/m². Compared with the lowest fitness group, patients with higher fitness had an ~50% (6–9.9 METs) and 70% (≥10 METs) lower mortality hazard regardless of BMI (P < 0.001).

Among patients with diabetes, the obesity paradox was less pronounced for patients with the highest fitness level, and these patients also had the lowest risk of mortality.

The myocardial metabolic rate of glucose (MRGlu) was measured by using dynamic ¹⁸F-fluorodeoxyglucose positron emission tomography combined with a euglycemic-hyperinsulinemic clamp in 30 volunteers without coronary artery disease. Three groups were studied: 1) those with 1-h postload glucose <155 mg/dL (NGT 1-h low) (n = 10), 2) those with NGT 1-h high (n = 10), 3) and those with IGT (n = 10).

After adjusting for age, sex, and BMI, both subjects with NGT 1-h high (23.7 ± 6.4 mmol/min/100 mg; P = 0.024) and those with IGT (16.4 ± 6.0 mmol/min/100 mg; P < 0.0001) exhibited a significant reduction in global myocardial MRGlu; this value was 32.8 ± 9.7 mmol/min/100 mg in subjects with NGT 1-h low. Univariate correlations showed that MRGlu was positively correlated with insulin-stimulated whole-body glucose disposal (r = 0.441; P = 0.019) and negatively correlated with 1-h (r = –0.422; P = 0.025) and 2-h (r = –0.374; P = 0.05) postload glucose levels, but not with fasting glucose.

This study shows that myocardial insulin resistance is an early defect that is already detectable in individuals with dysglycemic conditions associated with an increased risk of type 2 diabetes, such as IGT and NGT 1-h high.

Based on the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort (n = 27,548), we constructed case-cohorts including a random subsample of 2,500 participants and all physician-verified incident cases of type 2 diabetes (n = 820; median follow-up time 6.5 years) and CVD (n = 508; median follow-up time 8.2 years). Information on the relative abundance of 39 N-glycan groups in baseline plasma samples was generated by chromatographic profiling. We selected predictive N-glycans for type 2 diabetes and CVD separately, based on cross-validated machine learning, nonlinear model building, and construction of weighted prediction scores. This workflow for CVD was applied separately in men and women.

The N-glycan–based type 2 diabetes score was strongly predictive for diabetes risk in an internal validation cohort (weighted C-index 0.83, 95% CI 0.78–0.88), and this finding was externally validated in the Finland Cardiovascular Risk Study (FINRISK) cohort. N-glycans were moderately predictive for CVD incidence (weighted C-indices 0.66, 95% CI 0.60–0.72, for men; 0.64, 95% CI 0.55–0.73, for women). Information on the selected N-glycans improved the accuracy of established and clinically applied risk prediction scores for type 2 diabetes and CVD.

Selected N-glycans improve type 2 diabetes and CVD prediction beyond established risk markers. Plasma protein N-glycan profiling may thus be useful for risk stratification in the context of precisely targeted primary prevention of cardiometabolic diseases.

EarlyBird is a nonintervention prospective cohort study that recruited 307 healthy U.K. children at 5 years of age and followed them throughout childhood. We genotyped 121 single nucleotide polymorphisms (SNPs) previously associated with diabetes risk, identified in the adult population. Association of SNPs with fasting insulin and glucose and HOMA indices of insulin resistance and β-cell function, available from 5 to 16 years of age, were tested. Association analysis with hormones was performed on selected SNPs.

Several candidate loci influenced the course of glycemic and insulin traits, including rs780094 (GCKR), rs4457053 (ZBED3), rs11257655 (CDC123), rs12779790 (CDC123 and CAMK1D), rs1111875 (HHEX), rs7178572 (HMG20A), rs9787485 (NRG3), and rs1535500 (KCNK16). Some of these SNPs interacted with age, the growth hormone–IGF-1 axis, and adrenal and sex steroid activity.

The findings that genetic markers influence both elevated and average courses of glycemic traits and β-cell function in children during puberty independently of BMI are a significant step toward early identification of children at risk for diabetes. These findings build on our previous observations that pancreatic β-cell defects predate insulin resistance in the onset of prediabetes. Understanding the mechanisms of interactions among genetic factors, puberty, and weight gain would allow the development of new and earlier disease-management strategies in children.

In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs.

SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94–1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38–2.42], P < 0.001), CV death (1.60 [1.11–2.30], P = 0.012), and hHF (2.09 [1.37–3.17], P = 0.001), while nonfatal MI (2.02 [1.35–3.01], P = 0.001), nonfatal stroke (2.30 [1.25–4.23], P = 0.007), hACS (2.00 [1.39–2.90], P < 0.001), and hHF (3.24 [1.98–5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without.

These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.

This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank.

Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18–3.41) for retinopathy, 2.15 (1.38–3.35) for neuropathy, 1.58 (1.04–2.40) for diabetic nephropathy, 0.97 (0.84–1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², 1.19 (0.90–1.58) for PAD, and 1.49 (1.02–2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26–9.15) for retinopathy, 1.48 (0.83–2.66) for peripheral neuropathy, 0.98 (0.94–1.01) for eGFR <60 mL/min/1.73 m², and 1.23 (0.57–2.67) for PAD per 1 mmol/L higher glucose level.

Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m², PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m².

In this large-scale retrospective cohort study in Japan, new users of antidepressants (exposure group) and nonusers (nonexposure group), aged 20–79 years, were included between 1 April 2006 and 31 May 2015. Patients with a history of diabetes or receipt of antidiabetes treatment were excluded. Covariates were adjusted by using propensity score matching; the associations were analyzed between risk of new-onset type 2 diabetes and the duration of antidepressant use/dose of antidepressant in the exposure and nonexposure groups by using Cox proportional hazards models. Changes in glycated hemoglobin (HbA_1c) level were examined in groups with continuous use, discontinuation, or a reduction in the dose of antidepressants.

Of 90,530 subjects, 45,265 were in both the exposure and the nonexposure group after propensity score matching; 5,225 patients (5.8%) developed diabetes. Antidepressant use was associated with the risk of diabetes onset in a time- and dose-dependent manner. The adjusted hazard ratio was 1.27 (95% CI 1.16–1.39) for short-term low-dose and 3.95 (95% CI 3.31–4.72) for long-term high-dose antidepressant use. HbA_1c levels were lower in patients who discontinued or reduced the dose of antidepressants (F[2,49] = 8.17; P < 0.001).

Long-term antidepressant use increased the risk of type 2 diabetes onset in a time- and dose-dependent manner. Glucose tolerance improved when antidepressants were discontinued or the dose was reduced after diabetes onset.

The Swedish Obese Subjects study is a prospective matched study performed at 25 surgical departments and 480 primary health care centers. Participants aged 37–60 years with BMI ≥34 kg/m² (men) or ≥38 kg/m² (women) were recruited between 1987 and 2001; 2,007 participants received bariatric surgery and 2,040 usual care. Self-reported body weight at 20 years of age was used to stratify patients into subgroups with normal BMI (<25 kg/m²), overweight (BMI 25–29.9 kg/m²), or obesity (BMI ≥30 kg/m²). Body weight, energy intake, and type 2 diabetes status were examined over 10 years, and incidence of cardiovascular and microvascular disease was determined over up to 26 years using data from health registers.

There were small but statistically significant differences in reduction of body weight among the subgroups after bariatric surgery (interaction P = 0.032), with the largest reductions among those with obesity aged 20 years. Bariatric surgery increased type 2 diabetes remission (odds ratios 4.51, 4.90, and 5.58 in subgroups with normal BMI, overweight, or obesity at 20 years of age, respectively; interaction P = 0.951), reduced type 2 diabetes incidence (odds ratios 0.15, 0.13, and 0.15, respectively; interaction P = 0.972), and reduced microvascular complications independent of obesity status at 20 years of age (interaction P = 0.650). The association between bariatric surgery and cardiovascular disease was similar in the subgroups (interaction P = 0.674). Surgical complications were similar in the subgroups.

The treatment benefits of bariatric surgery in adults are similar regardless of obesity status at 20 years of age.

A total of 2,287 patients with type 2 diabetes who underwent metabolic surgery between 1998 and 2017 in the Cleveland Clinic Health System were propensity-matched 1:5 to 11,435 nonsurgical patients with BMI ≥30 kg/m² and type 2 diabetes who received usual care with follow-up through December 2018. Multivariable time-to-event regression and random forest machine learning models were built and internally validated using fivefold cross-validation to predict the 10-year risk for four outcomes of interest. The prediction models were programmed to construct user-friendly web-based and smartphone applications of Individualized Diabetes Complications (IDC) Risk Scores for clinical use.

The prediction tools demonstrated the following discrimination ability based on the area under the receiver operating characteristic curve (1 = perfect discrimination and 0.5 = chance) at 10 years in the surgical and nonsurgical groups, respectively: all-cause mortality (0.79 and 0.81), coronary artery events (0.66 and 0.67), heart failure (0.73 and 0.75), and nephropathy (0.73 and 0.76). When a patient’s data are entered into the IDC application, it estimates the individualized 10-year morbidity and mortality risks with and without undergoing metabolic surgery.

The IDC Risk Scores can provide personalized evidence-based risk information for patients with type 2 diabetes and obesity about future cardiovascular outcomes and mortality with and without metabolic surgery based on their current status of obesity, diabetes, and related cardiometabolic conditions.

In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation—a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD^– (clean coronaries) and CAD⁺ (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD.

Though CAD⁺ was more prevalent among participants with T2D (HbA_1c 6.7 ± 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 15, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were "protected" from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02).

We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD.

A total of 24 T1D patients (median age 5.1 years) received a single intravenous infusion of autologous UCB cells and underwent metabolic and immunologic assessments.

No infusion-related adverse events were observed. β-Cell function declined after UCB infusion. Area under the curve C-peptide was 24.3% of baseline 1 year postinfusion (P < 0.001) and 2% of baseline 2 years after infusion (P < 0.001). Flow cytometry revealed increased regulatory T cells (Tregs) (P = 0.04) and naive Tregs (P = 0.001) 6 and 9 months after infusion, respectively.

Autologous UCB infusion in children with T1D is safe and induces changes in Treg frequency but fails to preserve C-peptide.

In this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.d. before meals (a.c.). This study included an initial 14-week, dose-ranging phase followed by a 40-week treatment phase during which patients were to be uptitrated as tolerated to 40 mg (or placebo) t.i.d. a.c. The primary efficacy end point was change from baseline in A1C at Week 14.

At Week 14, A1C and 2-h postmeal glucose (PMG) improved significantly versus placebo with all MK-0941 doses. Maximal placebo-adjusted least squares mean changes from baseline in A1C (baseline A1C 9.0%) and 2-h PMG were –0.8% and –37 mg/dL (–2 mmol/L), respectively. No significant effects on fasting plasma glucose were observed at any dose versus placebo. By 30 weeks, the initial glycemic responses noted at 14 weeks were not sustained. MK-0941 at one or more doses was associated with significant increases in the incidence of hypoglycemia, triglycerides, systolic blood pressure, and proportion of patients meeting criteria for predefined limits of change for increased diastolic blood pressure.

In patients receiving stable-dose insulin glargine, the GKA MK-0941 led to improvements in glycemic control that were not sustained. MK-0941 was associated with an increased incidence of hypoglycemia and elevations in triglycerides and blood pressure.