- A Network Analysis of Biomarkers for Type 2 Diabetes. [Journal Article]
- DDiabetes 2018 Nov 08
- Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as ...
Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as well as the potential changes in the biomarker correlation network during diabetes development. We conducted a secondary analysis of 27 plasma biomarkers representing glucose metabolism, inflammation, adipokines, endothelial dysfunction, insulin-like growth factor axis and iron store plus age and BMI at blood collection from an existing case-control study nested in the Nurses' Health Study, including 1,303 incident diabetes cases and 1,627 healthy women. A correlation network was constructed based on pairwise Spearman correlations of the above factors that were statistically different between cases and non-cases using permutation tests (p<0.0005). We further evaluated the network structure separately among diabetes cases diagnosed <5 years, 5-10 years, and >10 years after blood collection versus non-cases. Although pairwise biomarker correlations tended to have similar directions comparing diabetes cases to non-cases, most correlations were stronger in non-cases than in cases, with the largest differences observed for the insulin/HbA1c and leptin/adiponectin correlations. Leptin and soluble leptin receptor were two hubs of the network, with large numbers of different correlations with other biomarkers in cases versus non-cases. When examining the correlation network by timing of diabetes onset, there were more perturbations in the network for cases diagnosed >10 years versus <5 years after blood collection, with consistent differential correlations of insulin and HbA1c. C-peptide was the most highly connected node in the early-stage network, whereas leptin was the hub for mid- or late-stage networks. Our results suggest that perturbations of the diabetes-related biomarker network may occur decades prior to clinical recognition. In addition to the persistent dysregulation between insulin and HbA1c, our results highlight the central role of the leptin system in diabetes development.
- TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic Beta-Cells via a PKA-Dependent Pathway. [Journal Article]
- DDiabetes 2018 Nov 08
- The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in beta-cells is currentl...
The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in beta-cells is currently postulated and discussed. The present study reveals that oleanolic acid (OLA) affects murine beta-cell function by TGR5 activation. Both, a Gαs inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced ATP-dependent K+ (KATP) current and elevated current through Ca2+ channels. Accordingly, in mouse and human beta-cells TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counter-regulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide-3-kinase did not prevent stimulating effects of OLA. Involvement of exchange-protein-directly-activated-by-cAMP 2 (Epac2) or farnesoid-X-receptor (FXR) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local GLP-1 secretion from alpha-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in beta-cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway which is supposed to interfere with SSC by affecting KATP and Ca2+ currents and thus membrane potential.
- Risk Factor Modeling for Cardiovascular Disease in Type I Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison to the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. [Journal Article]
- DDiabetes 2018 Nov 08
- In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) report, mean HbA1c was the strongest predictor of cardiovascular disease (C...
In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) report, mean HbA1c was the strongest predictor of cardiovascular disease (CVD) after age. In DCCT/EDIC, mean diabetes duration was 6 (median 4) years at baseline and those with high blood pressure or cholesterol were excluded. We now replicate these analyses in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (<17 years) type 1 diabetes, with similar age (mean 27 years in both studies) but longer diabetes duration (mean 19, median 18 years) and no CVD risk factor exclusion at baseline. CVD incidence (CVD death, myocardial infarction, stroke, revascularization, angina, or ischemic ECG) was associated with diabetes duration, most recent albumin excretion rate (AER), updated mean triglycerides, baseline hypertension, baseline LDLc, and most recent HbA1c. Major atherosclerotic cardiovascular events (MACE) (CVD death, myocardial infarction, or stroke) were associated with diabetes duration, most recent AER, baseline SBP, baseline smoking, and updated mean HbA1c. Compared to DCCT/EDIC, traditional risk factors similarly predict CVD, however AER predominates in EDC and HbA1c in DCCT/EDIC. Thus, the relative impact of HbA1c and kidney disease in type 1 diabetes varies according to diabetes duration.
- Sex Differences in Coronary Microvascular Function in Individuals with Type 2 Diabetes Mellitus. [Journal Article]
- DDiabetes 2018 Nov 08
- Cardiovascular (CV) disease fatality rates are higher for women compared to men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), t...
Cardiovascular (CV) disease fatality rates are higher for women compared to men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post-hoc analysis to determine if there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled Type 2 DM and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared to men. Additionally, rest MBF was positively correlated with worse diastolic function in women. We previously showed mineralocorticoid blockade improved CFR in men and women with Type 2 DM, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with Type 2 DM and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared to men. The greater aldosterone responsivity in women may be a mechanism for this sex effect.
- Erratum. SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c. Diabetes 2018;67:2227-2238. [Journal Article]
- DDiabetes 2018 Nov 06
- Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes. [Journal Article]
- DDiabetes 2018 Nov 05
- Recent studies suggest that insulin-like growth factor binding protein-2 (IGFBP-2) may protect against type 2 diabetes but population-based human studies are scarce. We aimed to investigate the prosp...
Recent studies suggest that insulin-like growth factor binding protein-2 (IGFBP-2) may protect against type 2 diabetes but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk.Within the EPIC-Potsdam cohort (n=27,548), circulating IGFBP-2 concentration was assessed in a nested case-cohort (random subcohort, n=2500, all incident type 2 diabetes cases, n=820). A nested 1:1 matched case-control sample (300 incident type 2 diabetes cases, 300 controls) was constructed for DNA-methylation profiling. Longitudinal associations were evaluated in Cox models (case-cohort) and conditional logistic models (case-control), adjusting for age, sex, anthropometry, lifestyle and a large set of type 2 diabetes-related biomarkers.Higher circulating IGFBP-2 concentrations (median 92 ng/mL) were cross-sectional linked to lower BMI, waist circumference, fatty liver index, triglycerides, fetuin A, ALT and γ-GT, and longitudinal associated with lower type 2 diabetes risk (HR per SD 0.65, 95%CI 0.53, 0.8). A methylation score based on seven type 2 diabetes-related CpGs in the IGFBP-2 gene was associated with higher type 2 diabetes risk (OR per SD 2.7, 95%CI 2.1, 3.5).Our results are consistent with a type 2 diabetes-protective effect of high circulating IGFBP-2 concentration, and suggest that epigenetic silencing of the IGFBP-2 gene might predispose for type 2 diabetes.
- Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy. Results of the EUROCONDOR Clinical Trial. [Journal Article]
- DDiabetes 2018 Nov 02
- The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in di...
The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in diabetic patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥ 5 years, and an ETDRS level ≤35 were randomly assigned to one of 3 arms: placebo, somatostatin and brimonidine. The primary outcome was the change in Implicit Time (IT) assessed by mfERG between baseline and at the end of follow-up (96 weeks). A total of 449 eligible patients were allocated to brimonidine (n=152), somatostatin (n=145) and placebo (n=152). When the primary end-point was evaluated in the whole population we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients with pre-existing retinal neurodysfunction (34.7%), IT worsened in the placebo group (p<0.001), but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of pre-existing retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit.
- GLP-1 Receptor in Pancreatic α Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner. [Journal Article]
- DDiabetes 2018 Nov 02
- Glucagon-like peptide-1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1R expression in α cells us...
Glucagon-like peptide-1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1R expression in α cells using both antibody-dependent and -independent strategies. A novel α cell specific GLP-1R knockout (αGLP-1R-/-) mouse model was then created and used to investigate its effects on glucagon secretion and glucose metabolism. Both male and female αGLP-1R-/- mice showed higher non-fasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R-/- mice exhibited mild glucose intolerance following intraperitoneal glucose administration, and showed increased glucagon secretion in response to glucose injection compared to the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with β cell function, but affected glucagon secretion in a glucose-dependent bidirectional manner-the αGLP-1R-/- islets failed to inhibit glucagon secretion at high glucose, and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels.
- DNA Sequence Variation in ACVR1C Encoding the Activin-Receptor Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes. [Journal Article]
- DDiabetes 2018 Nov 02
- A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an...
A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C, encoding the activin-receptor like kinase 7 receptor expressed on adipocytes and pancreatic beta cells, which independently associated with reduced WHRadjBMI: Asn150His (-0.09 standard deviations, p=3.4*10-17), Ile195Thr (-0.15 SD, p=1.0*10-9), Ile482Val (-0.019 SD, p=1.6*10-5) and rs72927479 (-0.035 SD, p=2.6*10-12). Carriers of these variants exhibited reduced percent abdominal fat in dual energy X-ray imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (OR 0.70, CI 0.63, 0.77; p = 5.6*10-13). In an analysis of exome sequences from 55516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46 CI 0.27, 0.81; p=0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.
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- Senescent T Cells Predict the Development of Hyperglycemia in Humans. [Journal Article]
- DDiabetes 2018 Nov 02
- Senescent T cells have been implicated in chronic inflammatory and cardiovascular diseases. Here, we explored the relationship between senescent T cells and glycemic status in a cohort of 805 partici...
Senescent T cells have been implicated in chronic inflammatory and cardiovascular diseases. Here, we explored the relationship between senescent T cells and glycemic status in a cohort of 805 participants by investigating the frequency of CD57+ or CD28null senescent T cells in peripheral blood. Normal glucose tolerance (NGT) participants with follow-up data (N = 149) were included to determine whether hyperglycemia (prediabetes or type 2 diabetes) developed during follow-up (mean 2.3 years). CD8+CD57+ and CD8+CD28null T cell frequencies were significantly higher in prediabetes and type 2 diabetes compared with NGT. Increased CD57+ or CD28null cells in the CD8+ T cell subset was independently associated with hyperglycemia. Furthermore, among participants with baseline NGT, the frequency of CD8+CD57+ T cells was an independent predictor of hyperglycemia development. Immunofluorescent analyses confirmed that CD8+CD57+ T cell infiltration was increased in visceral adipose tissue of patients with prediabetes or type 2 diabetes compared to those with NGT. Our data suggest that increased frequency of senescent CD8+ T cells in the peripheral blood is associated with development of hyperglycemia.