Type 2 Diabetes Mortality Research Articles

Serum T50 predicts cardiovascular mortality in individuals with type 2 diabetes: A prospective cohort study.

Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors. We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all-cause mortality. Causes of death were categorized according to ICD-10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T50. RESULTS: The mean age was 64.2±9.8 years, and 61% were male. The average serum T50 time was 323±63min. Higher age, alcohol use, high-sensitive C-reactive protein, and plasma phosphate were associated with lower serum T50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow-up of 7.5[5.4-10.7] years, each 60min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08-1.50, and p=0.01) and all-cause mortality (HR 1.15, 95%CI 1.00-1.38, and p=0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60mL/min/1.73m2 and higher plasma phosphate levels. Serum T50 improves prediction of cardiovascular and all-cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D.

Triglyceride glucose index as a predictor of mortality in middle-aged and elderly patients with type 2 diabetes in the US

Despite a wealth of research linking the triglyceride glucose index (TyG index) to metabolic diseases. However, little evidence links the TyG index to all-cause or CVD mortality in middle-aged and elderly individuals with type 2 diabetes (T2D). This study analyzed data from 2998 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. The TyG index and mortality in middle-aged and elderly T2D patients were investigated using Cox regression models. The nonlinear association between the TyG index and mortality can be understood with the help of a restricted cubic spline (RCS). During a median follow-up period of 82 months, 883 fatalities were observed from all causes and 265 from CVD. The TyG index was found to have a U-shaped relationship with all-cause and CVD mortality in T2D, with cutoffs of 8.95 and 9, respectively, according to the RCS. After controlling for other factors, an increase of 1 unit in the TyG index was related to an increase of 33% in all-cause mortality and 50% in CVD mortality when TyG was ≥ 8.95 and 9. When TyG < 8.95 and 9, with the change in the TyG index, the change in all-cause and CVD death was insignificant. Patients with T2D who are middle-aged or older, especially elderly patients, have higher TyG levels associated with increased mortality. In middle-aged and elderly patients with T2D, the TyG index may predict the probability of death from any cause and death from CVD.

MG53 does not mark cardiovascular risk and all-cause mortality in subjects with type 2 diabetes: A prospective, observational study

AimsSubjects with type 2 diabetes (T2D) are characterized by a high cardiovascular morbidity and mortality. MG53, a marker of peripheral insulin resistance, has been linked with impaired β-cell function and decreased β-cell survival, and its circulating levels are increased in T2D. Its relationship with the cardiovascular risk profile and mortality in T2D is currently unknown. MethodsIn this longitudinal study, MG53 was measured in serum samples collected at baseline for 296 Caucasian participants in the MIND.IT study, relating its circulating levels with the cardiovascular risk profile and all-cause mortality over a 17-years follow up. ResultsAs compared to a reference cohort of 234 healthy subjects, MG53 levels were higher in T2D individuals (p < 0.001), and higher in T2D women than in men (p = 0.001). In the whole study cohort, MG53 levels were directly related to HbA1c (r2 0.029; p = 0.006) and systolic blood pressure (r2 0.032; p = 0.004). There was no difference in baseline MG53 levels between deceased and alive participants, neither predict all-cause mortality. ConclusionsMG53 does not mark the cardiovascular risk profile neither predict long-term mortality in Caucasian T2D individuals.

Dietary Diversity and Inflammatory Diet Associated with All-Cause Mortality and Incidence and Mortality of Type 2 Diabetes: Two Prospective Cohort Studies.

A higher dietary diversity score (DDS) and a lower energy-adjusted dietary inflammatory index (E-DII) may be associated with lower risks of type 2 diabetes (T2D) and mortality. This cohort study aimed to investigate the associations of DDS and E-DII with all-cause mortality, incidence of T2D, and mortality of T2D, as well as the joint effects of these two dietary factors. A total of 181,360 participants without all types of diabetes at baseline from the UK Biobank and 42,139 participants from the US NHANES were included. Cox proportional hazards models were used to assess the associations of DDS and E-DII with outcomes. In the UK Biobank data, 8338 deaths, 3416 incident T2D cases, and 353 T2D deaths occurred during a median follow-up of 12.5 years. In the US NHANES data, 6803 all-cause deaths and 248 T2D-specific deaths were recorded during a median follow-up of 9.6 years. We observed that higher DDS and lower E-DII were significantly associated with lower risks of total mortality and incident T2D. Compared with low DDS, the hazard ratios (HRs) and 95% confidence intervals (CIs) of high DDS were 0.69 (0.64, 0.74) for all-cause mortality, 0.79 (0.70, 0.88) for incident T2D in the UK Biobank, and 0.69 (0.61, 0.78) for all-cause mortality in the US NHANES. Compared with participants in tertile 3 of E-DII, those in tertile 1 had a lower risk of overall death [HR 0.86 (95% CI: 0.81, 0.91) in UK Biobank; 0.83 (0.77, 0.88) in US NHANES] and incident T2D [0.86 (0.79, 0.94)] in UK Biobank. No evidence was observed of the interactive effects of DDS and E-DII on either all-cause mortality or the incidence and mortality of T2D. There was no significant association found between any exposure and T2D mortality in this study. In conclusion, our results revealed that higher DDS and lower E-DII were associated with both total mortality and incident T2D in UK and US adults.

The STC2-PAPP-A-IGFBP4-IGF1 axis and its associations to mortality and CVD in T2D.

Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2-PAPP-A-IGFBP4-IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). We followed 1284 participants with T2D from the ADDITION trial for 5 years. Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model. During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09-3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98-3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11-1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91-4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16-2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34-0.76); P = 0.001. This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A-IGF1 axis. PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2-PAPP-A-IGFBP4-IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2-PAPP-A-IGFBP4-IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

Differential effects of treatment targets on risks of adverse outcomes according to diabetes duration, age and complications: Can these characteristics be used to individualize diabetes treatment? The Rio de Janeiro type 2 diabetes cohort

AimsTo investigate interactions between more/less strict treatment targets (HbA1c, systolic blood pressure, LDL-cholesterol) and clinical characteristics (age, diabetes duration and presence of complications) for occurrence of cardiovascular/microvascular complications and mortality in type 2diabetes. Methods690 individuals were followed-up for 10 years (median). Interactions between treatment targets, estimated as mean values during the first 2-years, and clinical characteristics were tested in multivariable Cox regressions adjusted for other risk factors. Hazard ratios (HRs) were estimated in stratified analyses for cardiovascular/microvascular outcomes and mortality. ResultsDuring follow-up, 214 patients had a cardiovascular event (175 MACEs); and 265 died (132 cardiovascular deaths); there were 206 renal, 161 retinopathy and 181 peripheral neuropathy events. There were interactions between treatment parameters and clinical characteristics, in most of them the HRs were higher in older individuals, in those with longer diabetes durations and with complications, particularly for the cardiovascular outcomes and mortality. For microvascular outcomes the opposite was observed. For cardiovascular mortality, the HRs of higher HbA1c were 1.31 (1.08–1.58) and 1.09 (0.88–1.34), respectively with longer/shorter diabetes duration (p-for-interaction 0.11); and 1.43 (1.14–1.79) and 1.02 (0.85–1.23) in older/younger individuals (p-for-interaction 0.019). ConclusionsOur findings do not support less strict treatment targets for older individuals, with longer diabetes duration or with complications, particularly for cardiovascular and mortality prevention.

Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists.

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

Circulating Trimethylamine N-Oxide Is Associated with Increased Risk of Cardiovascular Mortality in Type-2 Diabetes: Results from a Dutch Diabetes Cohort (ZODIAC-59).

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), p <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (adjHR) 1.93 (95% CI 1.11; 3.34), p = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: adjHR 1.32 (95% CI 1.07; 1.63), p = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.

Multimorbidity, mortality, and HbA1c in type 2 diabetes: A cohort study with UK and Taiwanese cohorts.

There is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient's individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D. We studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p <0.001). HRs for NDCMP were similar to those from UK Biobank for all multimorbidity counts. For those with two conditions in addition to T2D, cardiovascular diseases featured in 18 of the top 20 combinations most highly associated with mortality in UK Biobank and 12 of the top combinations in the Taiwan NDCMP. In UK Biobank, a combination of coronary heart disease and heart failure in addition to T2D had the largest effect size on mortality, with a HR (95% CI) of 4.37 (3.59-5.32) p < 0.001, whereas in the Taiwan NDCMP, a combination of painful conditions and alcohol problems had the largest effect size on mortality, with an HR (95% CI) of 4.02 (3.08-5.23) p < 0.001. One limitation to note is that we were unable to model for changes in multimorbidity during our study period. Multimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care.

Epicardial adipose tissue: an emerging biomarker of cardiovascular complications in type 2 diabetes?

Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease and heart failure, which highlights the need for improved understanding of factors contributing to the pathophysiology of these complications as they are the leading cause of mortality in T2D. Patients with T2D have high levels of epicardial adipose tissue (EAT). EAT is known to secrete inflammatory factors, lipid metabolites, and has been proposed to apply mechanical stress on the cardiac muscle that may accelerate atherosclerosis, cardiac remodeling, and heart failure. High levels of EAT in patients with T2D have been associated with atherosclerosis, diastolic dysfunction, and incident cardiovascular events, and this fat depot has been suggested as an important link coupling diabetes, obesity, and cardiovascular disease. Despite this, the predictive potential of EAT in general, and in patients with diabetes, is yet to be established, and, up until now, the clinical relevance of EAT is therefore limited. Should this link be established, importantly, studies show that this fat depot can be modified both by pharmacological and lifestyle interventions. In this review, we first introduce the role of adipose tissue in T2D and present mechanisms involved in the pathophysiology of EAT and pericardial adipose tissue (PAT) in general, and in patients with T2D. Next, we summarize the evidence that these fat depots are elevated in patients with T2D, and discuss whether they might drive the high cardiometabolic risk in patients with T2D. Finally, we discuss the clinical potential of cardiac adipose tissues, address means to target this depot, and briefly touch upon underlying mechanisms and future research questions.

Peripheral monocyte count is an independent predictor of all-cause mortality in type 2 diabetes with macro-vascular complications.

The relationship between monocyte count and mortality seemed to be varied in different diseases, and it remains unclear in type 2 diabetes (T2D). We conducted a prospective study to investigate whether monocyte count predict all-cause mortality in patients with T2D.In this prospective study, a total of 1073 patients with T2D were enrolled at baseline and 880 patients completed the follow up. The median follow-up time was 47 months. At baseline, clinical characteristics including height, weight, waist circumference, blood pressure were recorded. Biochemical parameters including counts of white blood cells (WBCC), neutrophil (NC) and monocyte (MC), lipid profiles, glycated hemoglobin (HbA1c), serum creatinine were measured. Charlson comorbidity index (CCI) was calculated based on age and comorbidities. Participants were stratified into low, median, and high tertiles according to the baseline MC. Regression models were used to analyze the associations of peripheral MC and the all-cause mortality.Compared to the survived subjects, the baseline MC was significantly higher in patients who deceased during the follow-up (0.45 ± 0.16 vs 0.37 ± 0.15 × 109/L, P = .003). In the multivariate Cox hazard models, subjects in higher MC tertile showed higher risks of all-cause mortality (low tertile as the reference, hazard ratio [HR] 95%CI 2.65 [0.84,8.31] and 3.73 [1.14,12.24] for middle and high MC tertile, respectively) after adjusted for gender, body mass index, CCI, duration of T2D, history of hypertension and metabolic syndrome, drugs, levels of high-sensitivity C-reactive protein, systolic blood pressure, HbA1c, WBCC, and NC. In T2D patients with macro-vascular complications at baseline, 1-SD increment of MC resulted in 1.92-fold higher risk of all-cause mortality. However, the relationship disappeared in subjects without macro-vascular complications at baseline (1.13 [0.72, 1.78], P = .591).Peripheral monocyte count is an independent predictor of all-cause mortality in T2D, especially for subjects with macro-vascular complications.

Standard mortality rates and years of life lost for serologically defined adult-onset type 1 and type 2 diabetes – A fifteen year follow-up

AimsThe Diabetes Incidence in Kronoberg (DIK) study of adult-onset diabetes used serological classification. Standard Mortality Rates (SMR) and Years of Life Lost (YLL) 15 years after adult-onset (18–100 years) of diabetes were compared to the population of Kronoberg. MethodsOf 1609/1660 (97%) patients, 112 (7%) had type 1 (T1D) (GADA+ and/or ICA+, and/or C-peptide < 0.25 nmol/l), and 1497 (93%) had type 2 diabetes (T2D) (antibody- and C-peptide ≥ 0.25 nmol/l). The National Swedish Mortality Register provided time of death. ResultsFor T1D SMR did not differ from the Kronoberg population in any age group. In T2D SMR was 1.20 (1.12–1.29). After 15 years 26% (29/112) T1D and 52% (785/1497) T2D patients had died, p < 0.0001. In T2D SMR was 5.6 (30–39 years), 2 (40–59 years), 1.4 (60–69 years), and thereafter no difference. There were no significant sex differences in mortality, and no YLL to adult-onset T1D, but five YLL to T2D for onset at ages 20–60 years. ConclusionsFor adult-onset T1D SMR did not differ from the general population, in contrast to previous findings in childhood-onset (< 30 years of age) T1D. The difference in mortality between persons with diabetes and the general population was due to higher mortality in T2D.

1610-P: On the Combined Effect of C-Reactive Protein (CRP) and Serum Amyloid Component P (SAP) on Mortality Risk in Type 2 Diabetes

CRP and SAP are the two short, strongly homologous pentraxins produced in response to inflammation. Though their common contribution to innate immunity, they seem to differently affect atherosclerosis and related clinical outcomes. In the specific context of mortality rate i) CRP is a recognized risk biomarker; ii) data on SAP are sparse and conflicting; iii) no data are available on their possibly combined effect. Accordingly, the combined effect of CRP and SAP on mortality risk was investigated in the high-risk subset of patients with type 2 diabetes (T2D). Four cohorts of patients with T2D [i.e., Gargano Heart Study (GHS; n=358; follow-up (f-u)=5±3 years; 81 events); Gargano Mortality Study (n=650; f-u=11±4 years; 190 events); Foggia Mortality Study (n=530; f-u=7±3 years; 146 events) and Pisa Mortality Study (n=986; f-u=13±3 years; 230 events)] were analyzed by Cox proportional hazard models. In the pooled sample, with a total of 2,524 individuals experiencing 647 events, hs-CRP was positively [HR=1.53 (95% CI 1.41-1.66)] whereas SAP was negatively [HR=0.80 (95% CI 0.74-0.86)] associated with all-cause mortality. Similar results were observed on cardiovascular death in GHS: HR (95% CI) being 1.90 (1.48-2.44) and 0.78 (0.61-0.98) for hs-CRP and SAP, respectively. The whole sample was then stratified according to relatively low and high hs-CRP and SAP (&amp;lt; or &amp;gt; the median value), so to obtain four groups: low/high (1), low/low (2), high/high (3), and high/low (4) hs-CRP/SAP levels. As compared to group 1, group 2, 3 and 4 had HRs (95% CIs) of 1.25 (0.96-1.64), 1.80 (1.39-2.33) and 2.40 (1.81-3.17) for all-cause mortality (p for trend=1.1x10-11 or, in a model comprising study sample, age, sex, smoking habit, BMI, HbA1c, diabetes duration and all ongoing treatments, p=4.1x10-8). In conclusion, in patients with T2D, hs-CRP and SAP show a combined effect on all-cause death. Whether their simultaneous use may prove to be useful in predicting mortality in T2D needs further investigation. Disclosure M. Scarale: None. M. Copetti: None. M. Garofolo: None. L. Salvemini: None. S. De Csomo: None. O. Lamacchia: None. G. Penno: None. V. Trischitta: None. C. Menzaghi: None. Funding Italian Ministry of Health (RF-2013-02356459)

The paradoxical association of adiponectin with mortality rate in patients with type 2 diabetes: evidence of synergism with kidney function

BackgroundThe paradoxical relationship between high adiponectin and increased mortality, described in several clinical subsets, has been reported only once in type 2 diabetes (T2D) and only in selected elderly patients.We investigated this relationship in unselected patients with T2D and, then, addressed its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. MethodsPatients from the Gargano Mortality Study (GMS; N = 897, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 529, follow-up = 7.1 ± 2.5 years; 143 events), were investigated. ResultsFor each SD adiponectin increase, HRs (95% CI) for all-cause mortality were 1.30 (1.19–1.43) in GMS, 1.43 (1.26–1.64) in FMS and 1.34 (1.24–1.45) in the combined studies. This association was independent of the possible confounding effect of demographics, adiposity measures, diabetes-related features, kidney function-related parameters and medications (p = 9.34 × 10−9). While no interaction was observed between adiponectin and sex, age, smoking habits, BMI, waist circumference, HbA1c, diabetes duration, micro-/macro-albuminuria and medications, a strong interaction was observed with GFR, with a significant adiponectin-mortality association observed in individuals with GFR≥ but not those with GFR < 60 ml/min/1.73 m2; p for adiponectin-by-GFR status interaction = 2.13 × 10−6). ConclusionThis is the first study reporting a paradoxical association of adiponectin with all-cause mortality in a large sample of unselected diabetic patients and indicating that such counterintuitive effect is observed only among patients with preserved kidney function. Further studies are needed to address if the strong interwoven effect of adiponectin and GFR turns to be useful in improving previously validated tools for predicting mortality in T2D.

Abstract 13920: Impact of Diabetes on Acute Kidney Injury After Myocardial Infarction: Possible Involvement of Toll-like Receptor in the Kidney

Background: Comorbid acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI). Although type 2 diabetes (T2D) is a well-known risk factor of AKI after MI, the mechanism of the increased risk remains unclear. Here we hypothesized that T2D increases AKI after MI via toll-like receptor (TLR)-mediated inflammation. Methods and Results: OLETF, a rat model of obese T2D, and LETO, non-diabetic controls, at 25-30 weeks of age were randomized into sham and permanent coronary ligation (MI) groups. At baseline, body weight (617±23 vs. 537±13 g), fasting plasma glucose (267±32 vs. 153±15 mg/dl) and urinary protein level (6.4 vs. 0.6 g/gCr), but not serum creatinine, were significantly higher in OLETF than in LETO. Histologically, glomerular size was increased by 17% without mesangial proliferation in OLETF compared to that in LETO, indicating that OLETF developed early-stage nephropathy by this age. At 12 h after MI, mRNA levels of TLR2, TLR4, IL-6 and TNF-α in the kidney were increased by 1.6-, 1.2-, 2.6-, 1.5-fold, respectively, in OLETF but not in LETO. Furthermore, immunoblot analyses showed that phosphorylation levels of p38 MAPK and JNK, downstream mediators of the TLR signal, were significantly elevated by MI in OLETF. Histological abnormalities in the kidney or increase in serum creatinine were not detected in either LETO or OLETF 12 h after MI. However, in immunohistochemical analyses, areas positive for neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were significantly increased by 4.0- and 5.3-fold, respectively, and NGAL mRNA level was increased by 1.8-fold after MI in OLETF but not in LETO. In sham-operated LETO and OLETF, areas positive for NGAL and KIM-1 were barely detected. Infarct sizes were similar and cardiac BNP mRNA levels in the non-infarcted left ventricle were equally elevated at 12 h after MI in LETO and OLETF, suggesting that MI-induced cardiac loads were comparable in the two groups. However, mortality at 48 h after MI was significantly higher in OLETF than in LETO (68% vs. 18%, P&lt;0.05). Conclusion: The results suggest that AKI after MI is enhanced in T2D via TLR-mediated inflammation. The cardio-renal interaction may underlie increased post-MI mortality in T2D.

Predictors of all-cause and cardiovascular disease mortality in type 2 diabetes: Diabetes Heart Study.

BackgroundMany studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question.MethodsAssociations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models.ResultsThe all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10−4 ≤ p ≤ 0.001) and UACR (1.99 × 10−8 ≤ p ≤ 2.23 × 10−8). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed.ConclusionsThis analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-015-0055-y) contains supplementary material, which is available to authorized users.

The Effect Of Exercise On Vascular Function In Type 2 Diabetes

Individuals with type 2 diabetes (T2D) have a two to four-fold greater risk of cardiovascular disease (CVD). This is due to vascular maladaptations resulting from chronic hyperglycaemia and hyperinsulinaemia, along with comorbid hypertension, proinflammatory cytokines, and the presence of excess free fatty acids. To date, the primary treatment for vascular dysfunction is pharmacological interventions. Regular exercise has been shown to produce physiological changes in the cardiovascular system and reduce risk factors associated with CVD, leading to overall reductions in cardiovascular morbidity and mortality in T2D. Current studies assessing the effect of exercise on vascular function have used different techniques usually on vessel structure, or endothelial function, making it difficult to conclude on the efficacy of exercise in vascular function. PURPOSE: The aim of this study was to assess the effect of exercise on vascular function in T2D. METHODS: Electronic database searches were performed in AMED, MEDLINE, MEDLINE Daily Update, PREMEDLINE, SPORTDiscus, CINAHL, EMBASE and Web of Science. Studies that were eligible for this review performed controlled trials (CTs) and completed an exercise intervention of ≥ 4 weeks in individuals with T2D. The effect size (ES), and 95% confidence intervals (CIs) of eligible studies were calculated. RESULTS: Of the studies employing an aerobic exercise (AEx) intervention alone, three used pulse wave velocity (PWV), three used endothelial-independent dilation (EID), and three used flow-mediated dilation (FMD), and had sufficient data for calculation of ES and 95% CIs for the purpose of meta-analyses. Results found that AEx had a significant effect in vascular stiffness (PWV: ES = -0.402, 95% CI: -0.716 to -0.088; P = 0.012) and a non-significant benefit in endothelial function measures (EID: ES =-0.262, 95% CI: -0.615 to 0.091; FMD: ES =-0.029, 95% CI: -0.384 to 0.326; P= 0.873). There were limited studies using resistance training, or in combination with aerobic exercise, to assess a pooled effect. CONCLUSIONS: Exercise therapy may be considered as a primary intervention to treat vascular stiffness as it targets the pathology associated with vascular maladaptation. Future research is needed in controlled trials targeting aerobic, resistance or combined exercise to provide guidelines in exercise prescription to manage vascular health in T2D.

Association of Serum Concentration of TNFR1 With All-Cause Mortality in Patients With Type 2 Diabetes and Chronic Kidney Disease: Follow-up of the SURDIAGENE Cohort

Renal dysfunction is a key risk factor for all-cause mortality in patients with type 2 diabetes (T2D). Circulating tumor necrosis factor receptor 1 (TNFR1) was recently suggested as a strong biomarker for end-stage renal failure in T2D. However, its relevance regarding all-cause death has yet to be conclusively established. We aimed to assess the prognostic value of serum TNFR1 concentration for all-cause death in T2D and diabetic kidney disease (DKD) from the SURDIAGENE (Survie, Diabete de type 2 et Genetique) study. A total of 522 T2D patients with DKD (estimated glomerular filtration rate [eGFR] <60 and/or urinary albumin-to-creatinine ratio [uACR] >30 mg/mmol) were followed for a median duration of 48 months, and 196 deaths occurred. Incidence rate (95% CI) for death increased as quartiles of TNFR1 concentration increased (first quartile: 4.7% patient-years [3.0-6.3%]; second quartile: 7.7% [5.4-10.0%]; third quartile: 9.3% [6.7-11.9%]; fourth quartile: 15.9% [12.2-19.5%]). In multivariate analysis taking age, diabetes duration, HbA1c, uACR, and eGFR into account, compared with the first quartile, patients from the fourth quartile had an adjusted hazard ratio for death of 2.98 (95% CI 1.70-5.23). The integrated discrimination improvement index was statistically significant when adding TNFR1 concentration to the UK Prospective Diabetes Study outcome equation (P = 0.031). TNFR1 is a strong prognostic factor for all-cause mortality in T2D with renal dysfunction, and its clinical utility is suggested in addition to established risk factors for all-cause mortality.

Albuminuria and renal function as predictors of cardiovascular events and mortality in a general population of patients with type 2 diabetes: A nationwide observational study from the Swedish National Diabetes Register

Reduced renal function and albuminuria predict cardiovascular (CV) events and mortality in type 2 diabetes (T2D). In addition, we evaluated the role of co-existing congestive heart failure (CHF) and other CV risk factors on CV events in a large observational population-based cohort of T2D patients. We included 66,065 patients with T2D who were reported to the National Diabetes Register (NDR) in Sweden between 2003-2006 with a follow-up of 5.7 years. Data on outcomes were collected from the cause of death and hospital discharge registers. A total of 10% of patients experienced a CV event and 3.7% of these were fatal. Increasing levels of albuminuria and renal impairment were independently associated with increasing risk of CV events and all-cause mortality also when adjusting for CHF. In normoalbuminuric patients, a reduction in renal function is an important predictor of CV events and all-cause mortality. Glycaemic control (high HbA1c), smoking and hyperlipidaemia had important effects on risk for CV events in patients with albuminuria, while high blood pressure, but not glycaemic control, had an effect in patients with normoalbuminuric renal impairment. Albuminuria and renal impairment are independent risk factors for CV outcomes and mortality in T2D, albuminuria being the strongest risk factor and relevant at all levels of renal function. In normoalbuminuric patients, a reduction in renal function is an important predictor of CV events and all-cause mortality.

Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study

ObjectiveA negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality. MethodsThis investigation included 1220 self-described European American (EA) individuals from the DHS, a family-based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome-wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality. ResultsA genome-wide association study detected 18 SNPs within the UGT1A gene family associated with TBili at p < 5 × 10−8. The top hit was rs887829 (p = 8.67 × 10−20). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p = 0.05–0.88). There was, however, evidence of association with all-cause mortality (p = 0.0004–0.06), the top hit being rs2741034. ConclusionThese findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required.