We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures.

Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty x diabetes) was used for analyses.

The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01–1.03) and 1.19 (95% CI 1.10–1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant (P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures.

Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail.

An association between variability in clinical parameters (HbA_1c, blood pressure, cholesterol, and uric acid) and risk of complications in type 2 diabetes has been reported. In this analysis, we investigated to what extent such variability is associated with overall quality of care.

The quality of care summary score (Q-score) represents a validated, overall quality of care indicator ranging between 0 and 40; the higher the score, the better the quality of care provided by the diabetes center. We identified patients with five or more measurements of clinical parameters after the assessment of the Q-score. Multiple linear regression analyses assessed the role of the Q-score in predicting the variability of the different parameters.

Overall, 273,888 patients were analyzed. The variability of all the parameters systematically increased with decreasing Q-score values. At multivariate linear regression analysis, compared with a Q-score >25, a score <15 was associated with a significantly larger variation in HbA_1c, blood pressure, uric acid, total cholesterol, and LDL cholesterol and a lower variation in HDL cholesterol. The analysis of standardized β coefficients show that the Q-score has a larger impact on the variability of HbA_1c (0.34; P < 0.0001), systolic blood pressure (0.21; P < 0.0001), total cholesterol (0.21; P < 0.0001), and LDL cholesterol (0.20; P < 0.0001).

The variability of risk factors for diabetic complications is associated with quality of care. Quality of care improvement initiatives should be targeted to increase the achievement of the recommended target while reducing such variability.

Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM).

Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min.

In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009).

The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.

Depression is common in patients with type 2 diabetes and adversely affects quality of life and diabetes outcomes. We assessed whether light therapy, an antidepressant, improves mood and insulin sensitivity in patients with depression and type 2 diabetes.

This randomized, double-blind, placebo-controlled trial included 83 patients with depression and type 2 diabetes. The intervention comprised 4 weeks of light therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and insulin sensitivity (M-value derived from the results of a hyperinsulinemic-euglycemic clamp). Secondary outcomes were related psychological and glucometabolic measures.

Intention-to-treat analysis showed that light therapy was not superior to placebo in reducing depressive symptoms (–3.9 IDS points [95% CI –9.0 to 1.2]; P = 0.248) and had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI –0.41 to 0.70]; P = 0.608). Analyses incorporating only those participants who accurately adhered to the light therapy protocol (n = 51) provided similar results, but did suggest positive effects of light therapy on depression response rates (≥50% reduction in IDS points) (26% more response; P = 0.031). Prespecified analysis showed effect moderation by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication (P = 0.023). Light therapy did not affect depressive symptoms in participants with higher insulin sensitivity or those who use only oral glucose-lowering medication or none at all, but it did produce a relevant effect in participants with lower insulin sensitivity (–12.9 IDS points [95% CI –21.6 to –4.2]; P = 0.017) and a trend toward effectiveness in those using insulin (–12.2 IDS points [95% CI –21.3 to –3.1]; P = 0.094). Light therapy was well tolerated.

Although this trial is essentially inconclusive, secondary analyses indicate that light therapy might be a promising treatment for depression among a subgroup of highly insulin-resistant individuals with type 2 diabetes.

To estimate long-term cumulative risk of end-stage renal disease (ESRD) after diagnosis of type 2 diabetes.

This nationwide population-based inception cohort study included 421,429 patients with type 2 diabetes diagnosed in 1990–2011; patients were followed until the end of 2013. Data linkage between several national health care registers in Finland, covering 100% of the population, enabled the inclusion of almost all inhabitants who started taking diabetes medication or were hospitalized for diabetes. Cumulative risk of ESRD and hazard ratios [HR] for ESRD and death were estimated according to age, sex, and time period of diabetes diagnosis.

Among 421,429 patients with type 2 diabetes, 1,516 developed ESRD and 150,524 died during 3,458,797 patient-years of follow-up. Cumulative risk of ESRD was 0.29% at 10 years and 0.74% at 20 years from diagnosis of diabetes. Risk was higher among men than among women (HR 1.93 [95% CI 1.72–2.16]), decreased with older age at diagnosis (HR 0.70 [95% CI 0.60–0.81] for age 60–69 vs. 40–49 years), and was lower for those diagnosed in 2000–2011 than in 1990–1994 (HR 0.72 [95% CI 0.63–0.81]). Patients diagnosed with diabetes in 2000–2011 had lower risk of death during follow-up than those diagnosed in 1990–1994 (HR 0.64 [95% CI 0.63–0.65]).

Cumulative risk of ESRD is minimal among patients with type 2 diabetes compared with their risk of death. Patients diagnosed with diabetes at an older age have a lower risk of ESRD due to higher competing mortality.

To investigate real-world costs of continuous insulin pump therapy compared with multiple daily injection (MDI) therapy for type 1 diabetes.

Individuals with type 1 diabetes and pump therapy in the Swedish National Diabetes Register (NDR) since 2002 were eligible. Control subjects on MDI were matched 2:1 using time-varying propensity scores. Longitudinal data on health care resource use, antidiabetes treatment, sickness absence, and early retirement were taken from national registers for 2005–2013. Mean annual costs were analyzed using univariate analysis. Regression analyses explored the role of sociodemographic factors. Subgroup and sensitivity analyses were performed.

A total of 14,238 individuals with type 1 diabetes entered in the NDR between 2005 and 2013 (insulin pump n = 4,991, MDI n = 9,247, with switches allowed during the study) were included. Mean age at baseline was 34 years, with 21 years of diabetes duration and a mean HbA_1c of 8.1% (65 mmol/mol). We had 73,920 person-years of observation with a mean follow-up of 5 years per participant. Mean annual costs were higher for pump therapy than for MDI therapy ($12,928 vs. $9,005, respectively; P < 0.001; mean difference $3,923 [95% CI $3,703–$4,143]). Health care costs, including medications and disposables, accounted for 73% of the costs for pump therapy and 63% of the costs for MDI therapy. Regression analyses showed higher costs for low education, low disposable income, women, and older age.

Nine years of real-world data on all measurable diabetes-related resource use show robust results for additional costs of insulin pump therapy in adults by subgroup and alternative propensity score specifications. Identification of tangible and intangible benefits of pump therapy over time remain important to support resource allocation decisions.

Circumstantial evidence links 25-hydroxy vitamin D [25(OH)D], vitamin D–binding protein (DBP), vitamin D–associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D.

From a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography–tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, and VDR). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders.

Higher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 [95% CI 0.74–0.98] per μmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 [95% CI 0.77–0.98] per 10 nmol/L increase) in children carrying the VDR rs11568820 G/G genotype (P_interaction = 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions.

Higher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on VDR genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include VDR genotype and DBP levels.

The nature of the independent relationship between polycystic ovary syndrome (PCOS) and type 2 diabetes remains unclear. Few studies have aimed to clarify this relationship independent of obesity in longitudinal population-based cohorts.

We used the Australian Longitudinal Study on Women’s Health (ALSWH) (2000–2015) database to estimate nationwide incidence rates and predictors of type 2 diabetes among women aged 18–42 using person-time and survival analysis.

Over a follow-up of 1,919 person-years (PYs), 186 women developed type 2 diabetes. The incidence rate was 4.19/1,000 PYs and 1.02/1,000 PYs (P < 0.001) in PCOS and control subjects. On subgroup analyses across healthy-weight, overweight, and obese categories of women, the incidence rates for type 2 diabetes were 3.21, 4.67, and 8.80, whereas incidence rate ratios were 4.68, 3.52, and 2.36 (P < 0.005) in PCOS versus age-matched control subjects. PCOS was one of the most influential predictors for type 2 diabetes in the entire cohort (hazard ratio 3.23, 95% CI 2.07–5.05, P < 0.001) adjusting for BMI, education, area of residence, and family history of type 2 diabetes.

Women with PCOS are at an increased risk of type 2 diabetes, irrespective of age and BMI. The incidence of type 2 diabetes increases substantially with increasing obesity; yet, PCOS adds a greater relative risk in lean women. Based on the overall moderate absolute clinical risk demonstrated here, guideline recommendations suggest type 2 diabetes screening every 1–3 years in all women with PCOS, across BMI categories and age ranges, with frequency influenced by additional type 2 diabetes risk factors.

To estimate the causal association between intake of dairy products and incident type 2 diabetes.

The analysis included 21,820 European individuals (9,686 diabetes cases) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a single nucleotide polymorphism (SNP) for lactase persistence (LP) that enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression.

Each additional LP allele was associated with a higher intake of milk (β 17.1 g/day, 95% CI 10.6–23.6) and milk beverages (β 2.8 g/day, 95% CI 1.0–4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (β –7.0 g/day, 95% CI –12.4 to –1.7 per additional LP allele), nonalcoholic beverages (β –18.0 g/day, 95% CI –34.4 to –1.6), and wine (β –4.8 g/day, 95% CI –9.1 to –0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratio_{per 15 g/day} 0.99, 95% CI 0.93–1.05).

rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations, we consider it unlikely that this caused the observed null result.

Screening involves the presumptive identification of asymptomatic individuals at increased risk for unrecognized disease. We examined changes in screening practices for prediabetes and diabetes since January 2010, when HbA_1c was first recommended as an option for screening and diagnosis.

We studied members without diabetes of an HMO ≥45 years of age continuously enrolled for ≥3 years and assigned to primary care clinicians affiliated with a large academic health system. We defined screening as the first oral glucose tolerance test, HbA_1c, or glucose test performed between 2010 and 2014.

Of 12,772 eligible patients, 9,941 (78%) were screened at least once over 3 years. HbA_1c was the initial screening test 14% of the time and glucose 86% of the time. Of those screened with HbA_1c, 63% had abnormal results defined as HbA_1c ≥5.7% (≥39 mmol/mol). Of those tested with glucose, 30% had abnormal results defined as glucose ≥100 mg/dL, and 5% had abnormal results defined as glucose ≥126 mg/dL. Patients with abnormal HbA_1c levels and those with glucose levels ≥126 mg/dL were equally likely to be scheduled for follow-up appointments (41% vs. 39%), but those with abnormal HbA_1c levels were more likely to be diagnosed with prediabetes or diabetes (36% vs. 26%).

As we observed in 2004, rates of screening are high. HbA_1c is still used less frequently than glucose for screening but is more likely to result in a clinical diagnosis. Evidence to support guidelines to define the role of random glucose screening, including definition of appropriate cut points and follow-up, is needed.

To evaluate the safety and efficacy of IONIS-GCGR_Rx, a 2'-O-methoxyethyl antisense oligonucleotide targeting the glucagon receptor (GCGR), and the underlying mechanism of liver transaminase increases in patients with type 2 diabetes on stable metformin therapy.

In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGR_Rx (50–200 mg) or placebo for 13 or 26 weeks.

Significant reductions in HbA_1c were observed after IONIS-GCGR_Rx treatment versus placebo at week 14 (–2.0% 200 mg, –1.4% 100 mg, –0.3% placebo; P < 0.001) or week 27 (–1.6% 75 mg, –0.9% 50 mg, –0.2% placebo; P < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGR_Rx, which were attenuated at lower doses and remained mostly within the normal reference range at the 50-mg dose. There were no other significant safety observations and no symptomatic hypoglycemia or clinically relevant changes in blood pressure, LDL cholesterol, or other vital signs. At week 14, IONIS-GCGR_Rx 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. –20.2 mmol/L, respectively; P = 0.093) but significantly increased hepatic lipid content (4.2 vs. –2.7%, respectively; P = 0.005) in the presence of transaminase increases.

IONIS-GCGR_Rx is a potent inhibitor of hepatic glucagon receptor expression with a potential to improve glycemic control at low weekly doses in combination with metformin. Significant reductions in HbA_1c occurred across the full-dose range tested, with minimal transaminase elevations at lower doses. Furthermore, novel results suggest that despite inhibition of glycogenolysis after GCGR antagonism, IONIS-GCGR_Rx did not increase hepatic glycogen content.

We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1–7 years as well as evaluate the role of diluted insulin on glucose control.

In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3–6] and mean ± SD HbA_1c 7.4 ± 0.7% [57 ± 8 mmol/mol] and total insulin 13.2 ± 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used.

The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean ± SD 72 ± 8% vs. 70 ± 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; P = 0.16). There was no difference in mean glucose levels (8.0 ± 0.8 vs. 8.2 ± 0.6 mmol/L; P = 0.14), glucose variability (SD of sensor glucose 3.1 ± 0.5 vs. 3.2 ± 0.4 mmol/L; P = 0.16), or the proportion of time spent with sensor glucose <3.9 mmol/L (4.5 ± 1.7% vs. 4.7 ± 1.4%; P = 0.47) or <2.8 mmol/L (0.6 ± 0.5% vs. 0.6 ± 0.4%; P > 0.99). Total daily insulin delivery did not differ (17.3 ± 5.6 vs. 18.9 ± 6.9 units/day; P = 0.07). No closed-loop–related severe hypoglycemia or ketoacidosis occurred.

Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin.

We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).

During the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA_1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs).

During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA_1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD –4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD –0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA_1c, metformin was more effective in subjects with higher baseline HbA_1c by RD, with metformin RD –1.03 cases/100 person-years with baseline HbA_1c <6.0% (42 mmol/mol) and –3.88 cases/100 person-years with 6.0–6.4% (P = 0.0001).

Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA_1c and women with a history of GDM.

To evaluate sex, age at diabetes onset, puberty, and HbA_1c, with subjects followed from diabetes diagnosis and during different time periods, as risk factors for developing diabetic simplex and proliferative retinopathy.

In a population-based observational study, HbA_1c for 451 patients diagnosed with diabetes before 35 years of age during 1983–1987 in southeast Sweden was followed for up to 18–24 years from diagnosis. Long-term mean weighted HbA_1c (wHbA_1c) was calculated. Retinopathy was evaluated by fundus photography and analyzed in relation to wHbA_1c levels.

Lower wHbA_1c, diabetes onset ≤5 years of age, and diabetes onset before puberty, but not sex, were associated with longer time to appearance of simplex retinopathy. Proliferative retinopathy was associated only with wHbA_1c. The time to first appearance of any retinopathy decreased with increasing wHbA_1c. Lower wHbA_1c after ≤5 years’ diabetes duration was associated with later onset of simplex retinopathy but not proliferative retinopathy. With time, most patients developed simplex retinopathy, except for those of the category wHbA_1c ≤50 mmol/mol (6.7%), for which 20 of 36 patients were without any retinopathy at the end of the follow-up in contrast to none of 49 with wHbA_1c >80 mmol/mol (9.5%).

Onset at ≤5 years of age and lower wHbA_1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy. There is a strong positive association between long-term mean HbA_1c measured from diagnosis and up to 20 years and appearance of both simplex and proliferative retinopathy.

Type 2 diabetes exerts a deleterious effect on lung function. However, it is unknown whether an improvement in glycemic control ameliorates pulmonary function.

Prospective interventional study with 60 patients with type 2 diabetes and forced expiratory volume in 1 s (FEV1) ≤90% of predicted. Spirometric maneuvers were evaluated at baseline and after a 3-month period in which antidiabetic therapy was intensified. Those with an HbA_1c reduction of ≥0.5% were considered to be good responders (n = 35).

Good responders exhibited a significant improvement in spirometric values between baseline and the end of the study (forced vital capacity [FVC]: 78.5 ± 12.6% vs. 83.3 ± 14.7%, P = 0.029]; FEV1: 75.6 ± 15.3% vs. 80.9 ± 15.4%, P = 0.010; and peak expiratory flow [PEF]: 80.4 ± 21.6% vs. 89.2 ± 21.0%, P = 0.007). However, no changes were observed in the group of nonresponders when the same parameters were evaluated (P = 0.586, P = 0.987, and P = 0.413, respectively). Similarly, the initial percentage of patients with a nonobstructive ventilatory defect and with an abnormal FEV1 decreased significantly only among good responders. In addition, the absolute change in HbA_1c inversely correlated to increases in FEV1 (r = –0.370, P = 0.029) and PEF (r = –0.471, P = 0.004) in the responders group. Finally, stepwise multivariate regression analysis showed that the absolute change in HbA_1c independently predicted increased FEV1 (R² = 0.175) and PEF (R² = 0.323). In contrast, the known duration of type 2 diabetes, but not the amelioration of HbA_1c, was related to changes in forced expiratory flow between 25% and 75% of the FVC.

In type 2 diabetes, spirometric measurements reflecting central airway obstruction and explosive muscle strength exhibit significant amelioration after a short improvement in glycemic control.

The kinetics and risk factors of diabetic nephropathy after kidney transplantation remain unclear. This study investigated the posttransplant occurrence of diabetic nephropathy and the contribution of posttransplant glycemic control.

We performed a single-center prospective cohort study of 953 renal allograft recipients and 3,458 protocol-specified renal allograft biopsy specimens up to 5 years after transplantation. The effects of pretransplant diabetes and glycemic control (glycated hemoglobin levels) on the posttransplant histology were studied.

Before transplantation, diabetes was present in 164 (17.2%) renal allograft recipients, primarily type 2 (n = 146 [89.0%]). Despite intensive glycemic control (glycated hemoglobin 7.00 ± 1.34% [53 ± 14.6 mmol/mol], 6.90 ± 1.22% [52 ± 13.3 mmol/mol], and 7.10 ± 1.13% [54 ± 12.4 mmol/mol], at 1, 2, and 5 years after transplantation), mesangial matrix expansion reached a cumulative incidence of 47.7% by 5 years in the pretransplant diabetes group versus 27.1% in patients without diabetes, corresponding to a hazard ratio of 1.55 (95% CI 1.07–2.26; P = 0.005). Mesangial matrix expansion was not specific for diabetic nephropathy and associated independently with increasing age. Pretransplant diabetes was associated with posttransplant proteinuria but not with estimated glomerular filtration rate, graft failure, or any other structural changes of the glomerular, vascular, or tubulointerstitial renal compartments. The occurrence of diabetic nephropathy was independent of posttransplant glycated hemoglobin levels.

Mesangial matrix expansion, an early indicator of diabetic nephropathy, can occur rapidly in patients with diabetes before transplantation, despite intensive glycemic control. Prevention of diabetic nephropathy requires more than pursuing low levels of glycated hemoglobin.

Childhood and young adulthood may represent time periods in which cardiovascular risk factors (CVRFs) and their cumulative exposure lay the foundation for future risk of chronic diseases. We examined the longitudinal burden of CVRFs since childhood in men and women in whom diabetes did and did not develop at follow-up.

We included 1,530 participants (mean [SD] follow-up time 33.1 [8.2] years), who participated in the Bogalusa Heart Study and had been examined at least four times starting in childhood (mean age [SD] at first examination 9.4 [3.1] years). The area under the growth curve was used as a measure of cumulative exposure to CVRFs since childhood.

In childhood, boys and girls in whom diabetes did and did not develop at follow-up had similar CVRFs. Yet, over time, women during the transition from normoglycemia to diabetes experienced greater adverse changes in total cholesterol (TC), LDL cholesterol, and fasting plasma glucose (FPG) (noted as early as 23.5 years old and persisting across adulthood up to the age of the diagnosis of diabetes); a higher burden of exposure to BMI, TC, LDL cholesterol, and FPG from childhood to midlife; and a greater change in rates of BMI, TC, LDL cholesterol, and FPG since childhood than men during the same transition (interaction P values <0.05).

The greater exposure of women to and burden of CVRFs associated with diagnosis of diabetes may help to explain the stronger impact of diabetes as a major risk factor for cardiovascular events in women compared with men.

Individualized treatment of patients with diabetes requires detailed evaluation of risk factor dynamics at the population level. This study evaluated the persistent glycemic and cardiovascular (CV) risk factor burden over 2 years after treatment intensification (TI).

From U.S. Centricity Electronic Medical Records, 276,884 patients with incident type 2 diabetes who intensified metformin were selected. Systolic blood pressure (SBP) ≥130/140 mmHg and LDL ≥70/100 mg/dL were defined as uncontrolled for those with/without a history of CV disease at TI. Triglycerides ≥150 mg/dL and HbA_1c ≥7.5% (58 mmol/mol) were defined as uncontrolled. Longitudinal measures over 2 years after TI were used to define risk factor burden.

With 3.7 years’ mean follow-up, patients were 59 years; 70% were obese; 22% had a history of CV disease; 60, 30, 50, and 48% had uncontrolled HbA_1c, SBP, LDL, and triglycerides, respectively, at TI; and 81% and 69% were receiving antihypertensive and lipid-modifying therapies, respectively. The proportion of patients with consistently uncontrolled HbA_1c increased from 31% in 2005 to 41% in 2014. Among those on lipid-modifying drugs, 41% and 37% had consistently high LDL and triglycerides over 2 years, respectively. Being on antihypertensive therapies, 29% had consistently uncontrolled SBP. Among patients receiving cardioprotective therapies, 63% failed to achieve control in HbA_1c + LDL, 57% in HbA_1c + SBP, 55% in LDL + SBP, and 63% in HbA_1c + triglycerides over 2 years after TI.

Among patients on multiple therapies for risk factor control, more than one-third had uncontrolled HbA_1c, lipid, and SBP levels, and more than one-half had two CV risk factors that were simultaneously uncontrolled after TI.

To determine the diagnostic accuracy in a real-world primary care setting of a deep learning–enhanced device for automated detection of diabetic retinopathy (DR).

Retinal images of people with type 2 diabetes visiting a primary care screening program were graded by a hybrid deep learning–enhanced device (IDx-DR-EU-2.1; IDx, Amsterdam, the Netherlands), and its classification of retinopathy (vision-threatening [vt]DR, more than mild [mtm]DR, and mild or more [mom]DR) was compared with a reference standard. This reference standard consisted of grading according to the International Clinical Classification of DR by the Rotterdam Study reading center. We determined the diagnostic accuracy of the hybrid deep learning–enhanced device (IDx-DR-EU-2.1) against the reference standard.

A total of 1,616 people with type 2 diabetes were imaged. The hybrid deep learning–enhanced device’s sensitivity/specificity against the reference standard was, respectively, for vtDR 100% (95% CI 77.1–100)/97.8% (95% CI 96.8–98.5) and for mtmDR 79.4% (95% CI 66.5–87.9)/93.8% (95% CI 92.1–94.9).

The hybrid deep learning–enhanced device had high diagnostic accuracy for the detection of both vtDR (although the number of vtDR cases was low) and mtmDR in a primary care setting against an independent reading center. This allows its’ safe use in a primary care setting.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated the beneficial effects of intensive therapy on atherosclerosis and clinical cardiovascular disease (CVD) outcomes. The current analyses evaluated the relationship between longitudinal changes in insulin dose and CVD risk factors and outcomes.

A total of 1,441 participants were randomly assigned to intensive or conventional diabetes therapy during the DCCT. After an average of 6.5 years of follow-up, 96% of the surviving cohort enrolled in the EDIC observational study, which included annual visits with detailed medical history, physical examination, and laboratory testing. CVD events were adjudicated by a review committee. Generalized linear mixed models and Cox proportional hazards regression models were used to assess the association between insulin dose and cardiometabolic risk factors and CVD risk, respectively, over a total of 30 years.

Higher insulin doses were significantly associated with a less favorable cardiometabolic risk profile (higher BMI, pulse rate, and triglycerides and lower HDL cholesterol) with the exception of lower diastolic blood pressure and lower LDL cholesterol. In a minimally adjusted model, a 0.1 unit/kg body wt/day increase in insulin dose was associated with a 6% increased risk of any CVD (95% CI 3, 9). However, the association with insulin dose was no longer significant after adjustment for other CVD risk factors.

During DCCT/EDIC, higher insulin doses were associated with adverse trends in several cardiometabolic risk factors, even after multivariable adjustment, but not with incident CVD outcomes.

People with type 1 diabetes and kidney failure have an increased risk for major adverse cardiovascular events (MACE). Simultaneous pancreas and kidney transplantation (SPKT) improves survival, but the long-term risk for MACE is uncertain.

We assessed the frequency and risk factors for MACE (defined as fatal cardiovascular disease and nonfatal myocardial infarction or stroke) and related nonfatal MACE to allograft failure in SPKT recipients with type 1 diabetes who underwent transplantation between 2001 and 2015 in the U.K. In a subgroup, we related a pretransplant cardiovascular risk score to MACE.

During 5 years of follow-up, 133 of 1,699 SPKT recipients (7.8%) experienced a MACE. In covariate-adjusted models, age (hazard ratio 1.04 per year [95% CI 1.01–1.07]), prior myocardial infarction (2.6 [1.3–5.0]), stroke (2.3 [1.2–4.7]), amputation (2.0 [1.02–3.7]), donor history of hypertension (1.8 [1.05–3.2]), and waiting time (1.02 per month [1.0–1.04]) were significant predictors. Nonfatal MACE predicted subsequent allograft failure (renal 1.6 [1.06–2.6]; pancreas 1.7 [1.09–2.6]). In the subgroup, the pretransplant cardiovascular risk score predicted MACE (1.04 per 1% increment [1.02–1.06]).

We report a high rate of MACE in SPKT recipients. There are a number of variables that predict MACE, while nonfatal MACE increase the risk of subsequent allograft failure. It may be beneficial that organs from hypertensive donors are matched to recipients with lower cardiovascular risk. Pretransplant cardiovascular risk scoring may help to identify patients who would benefit from risk factor optimization or alternative transplant therapies and warrants validation nationally.

Acute glucose fluctuations are associated with hypoglycemia and are emerging risk factors for cardiovascular outcomes. However, the relationship between glycemic variability (GV) and the occurrence of midterm major cardiovascular events (MACE) in patients with diabetes remains unclear. This study investigated the prognostic value of GV in patients with diabetes and acute coronary syndrome (ACS).

This study included consecutive patients with diabetes and ACS between January 2015 and November 2016. GV was assessed using SD during initial hospitalization. MACE, including new-onset myocardial infarction, acute heart failure, and cardiac death, were recorded. The predictive effects of GV on patient outcomes were analyzed with respect to baseline characteristics and cardiac status.

A total of 327 patients with diabetes and ACS were enrolled. MACE occurred in 89 patients (27.2%) during a mean follow-up of 16.9 months. During follow-up, 24 patients (7.3%) died of cardiac causes, 35 (10.7%) had new-onset myocardial infarction, and 30 (9.2%) were hospitalized for acute heart failure. Multivariable logistic regression analysis showed that GV >2.70 mmol/L, a Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score >34, and reduced left ventricular ejection fraction of <40% were independent predictors of MACE, with odds ratios (ORs) of 2.21 (95% CI 1.64–2.98; P < 0.001), 1.88 (1.26–2.82; P = 0.002), and 1.71 (1.14–2.54; P = 0.009), respectively, whereas a Global Registry of Acute Coronary Events (GRACE) risk score >140 was not (OR 1.07 [0.77–1.49]; P = 0.69).

A GV cutoff value of >2.70 mmol/L was the strongest independent predictive factor for midterm MACE in patients with diabetes and ACS.

To examine the association of diabetes and glycated hemoglobin (HbA_1c) with the risk of intracerebral hemorrhage (ICH) in a large population-based cohort.

The computerized database of the largest health care provider in Israel was used to identify adult members aged 40 years or older and alive at 1 January 2010 (297,486 with diabetes and 1,167,585 without diabetes). The cohort was followed until 31 December 2017 for incidence of ICH. Multivariable Cox proportional hazards regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio (HR) of ICH.

Overall 4,170 ICH cases occurred during 10,730,915 person-years of follow-up. Diabetes was independently associated with increased ICH risk, with hazard ratio (HR) 1.36 (95% CI 1.27–1.45), and increased with longer diabetes duration: 1.23 (1.12–1.35) and 1.44 (1.34–1.56) for diabetes duration ≤5 years and >5 years, respectively. The increased ICH risk associated with diabetes was more pronounced in patients ≤60 years old (P_interaction <0.001). Among patients with diabetes, HbA_1c had a nonlinear J-shaped relationship with ICH (P for nonlinearity = 0.0186). Compared to the fourth HbA_1c decile, 6.5–6.7% (48–50 mmol/mol), the HR for ICH was 1.27 (1.01–1.59) and 2.19 (1.75–2.73) in the lowest HbA_1c decile, ≤6.0% (≤42 mmol/mol), and highest HbA_1c decile, >9.3% (>78 mmol/mol), respectively.

Diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA_1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.

Changes in heart rate variability (HRV) occur at the initiation of hypoglycemia due to sympathetic nervous system activity. We investigated the use of HRV detection by a wearable device as an early alert for hypoglycemia.

This proof-of-principle study included 23 patients with type 1 diabetes (14 women, mean age 42 ± 11 years). Patients wore a VitalConnect HealthPatch for 5 days. Hypoglycemia was defined as glucose ≤70 mg/dL (≤3.9 mmol/L) by fingerstick measurement. HRV was analyzed in standardized periods before the hypoglycemic event.

Sixty-six hypoglycemic events were recorded. Hypoglycemia caused a typical HRV pattern in 36 (55%) of the hypoglycemic events. Eighteen events (27%) showed an atypical pattern. Ten events were unclassified (15%), and two did not display a change in HRV (3%).

Hypoglycemia causes early changes in HRV that can be detected by a wearable device. Measuring real-time HRV seems promising for early hypoglycemia detection.

Sodium–glucose cotransporter (SGLT)-2 inhibitors lower clinic and ambulatory blood pressure (BP), possibly through their natriuretic action. However, it remains unclear whether this BP-lowering effect is dose dependent and different from that of low-dose hydrochlorothiazide. The purpose of this meta-analysis was to quantify the association of the dose with response of ambulatory BP to SGLT-2 inhibition and to provide comparative evaluation with low-dose hydrochlorothiazide.

PubMed/MEDLINE, Embase, and Cochrane database of clinical trials from inception of each database through 22 August 2018. Randomized controlled trials (RCTs) reporting treatment effects of SGLT-2 inhibitors on ambulatory BP. We extracted data on the mean difference between the active treatment and placebo groups in change from baseline (CFB) of ambulatory systolic and diastolic BP.

We identified seven RCTs (involving 2,381 participants) comparing SGLT-2 inhibitors with placebo. Of these, two RCTs included low-dose hydrochlorothiazide as active comparator. CFB in 24-h systolic BP between SGLT-2 inhibitor and placebo groups was –3.62 mmHg (95% CI –4.29, –2.94) and in diastolic BP was –1.70 mmHg (95% CI –2.13, –1.26). BP lowering with SGLT-2 inhibition was more potent during daytime than during nighttime. The CFB in ambulatory BP was comparable between low-dose and high-dose subgroups and was similar to that for low-dose hydrochlorothiazide. Eligible RCTs did not evaluate cardiovascular outcomes/mortality.

This meta-analysis shows that SGLT-2 inhibitors provoke an average reduction of systolic/diastolic BP 3.62/1.70 mmHg in 24-h ambulatory BP. This BP-lowering effect remains unmodified regardless of the dose of SGLT-2 inhibitor and is comparable with BP-lowering efficacy of low-dose hydrochlorothiazide.