Type 2 Diabetes Subjects Research Articles

Type 2 diabetes: basic clinical and laboratory parameters and risk of cardiovascular death

Aim. To evaluate the basic clinical and laboratory parameters and their relationship with the 14-year risk of cardiovascular death in individuals with type 2 diabetes (T2D).Material and methods. A prospective case-control study of a sample of Novosibirsk residents with T2D was performed. An initial examination was conducted as part of the HAPIEE project in 2003-2005. The follow-up period lasted until 2017 and amounted to 13,7±0,7 years. The case group consisted of 145 people (mean age — 62,0±5,7 years) with recorded cardiovascular death. Control group — 272 people (mean age — 57,9±6,6 years) without recorded death as of December 31, 2017. Persons with a history of non-fatal myocardial infarction and/or stroke at the initial examination were excluded. Blood pressure (BP), biochemical, anthropometric and socio-demographic data were determined. Logistic regression models were used to analyze the association of clinical and laboratory parameters with the risk of cardiovascular death.Results. T2D subjects with recorded cardiovascular death at the initial examination had a longer duration of the disease, higher fasting plasma glucose (FPG) and anthropometric parameters (body mass index (BMI), waist circumference (WC) (in women)), systolic blood pressure (SBP) and diastolic blood pressure (DBP). In individuals of both sexes, the risk of cardiovascular death increased 2,2 times with WC >95 cm, 2,3 times with an increased WC/HC ratio, 2,2 times with a BMI ≥30 kg/m2, 1,9 times with physical activity <3 hours/week, 2 times for smokers and those with a single marital status, 3,5 times for hypertensive people, 2 times with FPG ≥7,5 mmol/L and longer duration of diabetes.Conclusion. Fourteen-year follow-up revealed that individuals with T2D have associations of cardiovascular death with both conventional risk factors such as hypertension, abdominal obesity, low level of physical activity, smoking, single marital status, and diabetes-related ones — FPG and the duration of diabetes.

SUN-624 Low Risk of Major Adverse Cardiovascular Events After Pancreas Transplantation Alone

INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure. OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period. METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation). RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact. CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.

MON-030 Intermediate Hyperglycemia and Type 2 Diabetes in Women with Polycystic Ovary Syndrome: Findings from Large Caucasian Cohort

Background: Insulin secretory defects and insulin resistance exists in women with polycystic ovary syndrome (PCOS) and are prerequisites for the development of type 2 diabetes (T2D). Objective: To determine the prevalence of T2D, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), as well as the factors associated with these dysglycemic conditions. Participants: 1614 women with PCOS of Caucasian origin (Rotterdam criteria) with a mean age 25.14±5.56 years and BMI 27.34±7.09 kg/m2 comprised the study group, whereas 359 normally ovulating, not hyperandrogenic women of comparable age and BMI, served as controls. Design: Observational study. Setting: Outpatient clinics of tertiary hospitals. Main Outcome and Measures: Clinical, biochemical, hormonal and ovarian ultrasound as well oral glucose tolerance test were performed in all subjects participating in the study. Diabetes and intermediate hypeglycemia was categorised according to WHO criteria and PCOS subgroups was based on the Rotterdam criteria. Results: In the PCOS group 2.2%, 9.5% and 12,4% of subjects had T2D, IGT and IFG, respectively. In control group 1,11%, 7.5% and 8.9% had T2D, IGT and IFG, respectively. When the existence of T2D was stratified according to age and BMI, no difference was found among age and BMI subgroups or PCOS subgroups. Namely in patients aged 17-22 years, T2D was detected in 3 lean and 2 obese subjects. The corresponding distribution for patients aged 22-30 years was 4 lean, one overweight and 2 obese, whereas in those older than 31 years, 2 overweight and 5 obese suffered from T2D. Free Androgen Index (FAI), waist to hip ratio (WHR) and LDL levels were significantly higher in T2D subjects in comparison to PCOS women with normal glucose metabolism. Diagnosis of T2D was significantly associated with Free Androgen Index (r: 0.469, p<0.05), while subjects with either IFG and IGT had positive association with BMI, WHR, FAI and HOMA-IR. In controls, T2D, IGT and IFG were positively associated with BMI and androgen concentrations. Conclusions: The prevalence of T2D and IGT is significantly higher in our large cohort of PCOS women in comparison to controls. The existence of T2D is irrespective of age and BMI, and seems to be inherent for PCOS women. Hence, the evaluation of glycemic status in women with PCOS using OGTT is supported.

SAT-LB111 Improving Classification of Diabetes Etiology in Electronic Resources Using Phenotype Algorithms and Polygenic Risk Scores

Electronic Health Records (EHR) contain rich data to identify and study diabetes. Many phenotype algorithms have been developed to identify research subjects with type 2 diabetes (T2D), but very few accurately identify type 1 diabetes (T1D) cases or more rare forms of monogenic and atypical metabolic presentations. Polygenetic risk scores (PRS) quantify risk of a disease using common genomic variants well for both T1D and T2D. In this study, we apply validated phenotyping algorithms to EHRs linked to a genomic biobank to understand the independent contribution of PRS to classification of diabetes etiology and generate additional novel markers to distinguish subtypes of diabetes in EHR data. Using a de-identified mirror of medical center’s electronic health record, we applied published algorithms for T1D and T2D to identify cases, and used natural language processing and chart review strategies to identify cases of maturity onset diabetes of the young (MODY) and other more rare presentations. This novel approach included additional data types such as medication sequencing, ratio and temporality of insulin and non-insulin agents, clinical genetic testing, and ratios of diagnostic codes. Chart review was performed to validate etiology. To calculate PRS, we used genome wide genotyping from our BioBank, the de-identified biobank linking EHR to genomic data using coefficients of 65 published T1D SNPS and 76,996 T2D SNPS using PLINK in Caucasian subjects. In the dataset, we identified 82,238 cases of T2D but only 130 cases of T1D using the most cited published algorithms. Adding novel structured elements and natural language processing identified an additional 138 cases of T1D and distinguished 354 cases as MODY. Among over 90,000 subjects with genotyping data available, we included 72,624 Caucasian subjects since PRS coefficients were generated in Caucasian cohorts. Among those subjects, 248, 6,488, and 21 subjects were identified as T1D, T2D, and MODY subjects respectively in our final PRS cohort. The T1D PRS did significantly discriminate well between cases and controls (Mann-Whitney p-value is 3.4 e-17). The PRS for T2D did not significantly discriminate between cases and controls using published algorithms. The atypical case count was too low to calculate PRS discrimination. Calculation of the PRS score was limited by quality inclusion of variants available, and discrimination may improve in larger data sets. Additionally, blinded physician case review is ongoing to validate the novel classification scheme and provide a gold standard for machine learning approaches that can be applied in validation sets.

Novel Insights Into Effects of Cortisol and Glucagon on Nocturnal Glucose Production in Type 2 Diabetes.

The effect of physiological changes in night-time cortisol and glucagon on endogenous glucose production (EGP) and nocturnal glycemia are unknown. To determine the effects of changes in cortisol and glucagon on EGP during the night. Two overnight protocols were conducted. In Protocol 1, endogenous cortisol was blocked with metyrapone and hydrocortisone infused either at constant (constant) or increasing (variable) rates to mimic basal or physiological nocturnal cortisol concentrations. In Protocol 2, endogenous glucagon was blocked with somatostatin and exogenous glucagon was infused at either basal or elevated rates to mimic nocturnal glucagon concentrations observed in nondiabetic (ND) and type 2 diabetes (T2D) individuals. EGP was measured using [3-3H] glucose and gluconeogenesis estimated with 2H2O in all studies. Mayo Clinic Clinical Research Trials Unit, Rochester, MN, US. In Protocol 1, 34 subjects (17 ND and 17 T2D) and in Protocol 2, 39 subjects (21 ND and 18 T2D) were studied. Endogenous glucose production. EGP, gluconeogenesis, and glycogenolysis were higher with variable than with constant cortisol at 7 am in T2D subjects. In contrast, nocturnal EGP did not differ in ND subjects between variable and constant cortisol. While elevated glucagon increased EGP, glycogenolysis, and gluconeogenesis in ND, the data in T2D subjects indicated that EGP and gluconeogenesis but not glycogenolysis were higher during the early part of the night. Nocturnal hyperglucagonemia, but not physiological rise in cortisol, contributes to nocturnal hyperglycemia in T2D due to increased gluconeogenesis.

Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels

It is not known how ghrelin affects insulin secretion in human islets from patients with type 2 diabetes (T2D) or whether islet ghrelin expression or circulating ghrelin levels are altered in T2D. Here we sought out to identify the effect of ghrelin on insulin secretion in human islets and the impact of T2D on circulating ghrelin levels and on islet ghrelin cells.The effect of ghrelin on insulin secretion was assessed in human T2D and non-T2D islets. Ghrelin expression was assessed with RNA-sequencing (n = 191) and immunohistochemistry (n = 21). Plasma ghrelin was measured with ELISA in 40 T2D and 40 non-T2D subjects. Ghrelin exerted a glucose-dependent insulin-suppressing effect in islets from both T2D and non-T2D donors. Compared with non-T2D donors, T2D donors had reduced ghrelin mRNA expression and 75% less islet ghrelin cells, and ghrelin mRNA expression correlated negatively with HbA1c. T2D subjects had 25% lower fasting plasma ghrelin levels than matched controls.Thus, ghrelin has direct insulin-suppressing effects in human islets and T2D patients have lower fasting ghrelin levels, likely as a result of reduced number of islet ghrelin cells. These findings support inhibition of ghrelin signaling as a potential therapeutic avenue for stimulation of insulin secretion in T2D patients.

Dynamic Change of β to α Ratio in Islets of Chinese People With Prediabetes and Type 2 Diabetes Mellitus.

The present study aimed to investigate the dynamic change of α cells and β cells, and their ratios in prediabetes and type 2 diabetes in the Chinese population. Pancreata from 27 nondiabetic (ND), 8 prediabetic (PreD), and 19 type 2 diabetic (T2D) organ donors were subjected to immunofluorescence staining with insulin and glucagon. The β to α ratio in islets (β/α) in PreD was significantly higher than that in ND, resulting from an increase of β cells and a decrease of α cells per islet, but that in T2D was significantly lower than that in ND, resulting from a decrease of β cells and an increase of α cells per islet. The β-cell percentage and β/α ratio positively correlated and α-cell percentage negatively correlated with HbA1c (glycated hemoglobin) in ND and PreD, but these correlations disappeared when T2D subjects were included. The islet β to α ratio increased in PreD individuals because of a relative α-cell loss and β-cell compensation and decreased after T2D onset because of both β-cell loss and α-cell reexpansion.

Blood-based analysis of 84 microRNAs identifies molecules deregulated in individuals with type-2 diabetes, risk factors for the disease or metabolic syndrome

AimMicro-RNAs (miRNAs) are implicated in insulin-signaling and the development of type-2 diabetes (T2D). Their deregulated expression is mostly described in the pancreas, liver, skeletal muscle, or adipose tissue of diabetic animals. Relevant studies in humans are limited due to difficulties in accessing tissue-biopsies. Though, circulating miRNAs are indicators of organ-specific pathophysiological events and could potentially serve as disease biomarkers. We explored the profile of 84 T2D-related miRNAs in peripheral blood of subjects with or without the disease. Methods: An RT-qPCR array screening 84 T2D-related miRNAs was applied in samples of T2D (n = 6) versus non-T2D (n = 6) subjects. The deregulated miRNAs were thereafter analyzed in peripheral blood samples of a validation cohort of 40 T2D and 37 non-T2D individuals [16 controls and 21 subjects with metabolic syndrome (Met-S) and/or T2D risk factors (T2D-RF)], using specific RT-qPCR assays. Correlations with clinicopathological parameters and risk factors were evaluated. Results: Subjects with the disease displayed decreased levels of miR-214-3p, miR-24-3p and let-7f-5p, compared to those without. MiRNA levels correlated with serum insulin and HbA1c levels in individuals with T2D or Met-S/T2D-RF, and with higher BMI, dyslipidemia and family history in controls. Conclusions: Blood levels of miR-214-3p, miR-24-3p and let-7f-5p are down-regulated in T2D- and Met-S/T2D-RF subjects. Future studies are needed to evaluate their potential as disease biomarkers and elucidate the associated tissue-specific pathogenetic mechanisms.

Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport

IntroductionInsulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.MethodsWe applied the pancreatic...

Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a MIR499A Gene Polymorphism.

Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the MIR499A. T2D patients show a decrease in the number of mtDNA copies compared to healthy controls (p = 2 × 10-10). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without (p = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of MIR499A correlates with a decrease in the number of mtDNA copies, particularly in T2D patients (p = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of MIR499A with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.

Effect of Lifestyle Intervention in the Concentration of Adipoquines and Branched Chain Amino Acids in Subjects with High Risk of Developing Type 2 Diabetes: Feel4Diabetes Study.

Introduction: The global prevalence of type 2 diabetes (T2D) is increasing rapidly, especially in low- and middle-income countries and has a high number of associated comorbidities. Plasmatic concentrations of branched chain amino acids (BCAA) and retinol-binding protein 4 (RBP4) have been shown to be elevated in T2D subjects in cross-sectional studies. However, the effect of lifestyle community-based interventions on BCAA and RBP4 concentrations has not yet been analyzed. Material and methods: The Feel4Diabetes study is a school and community-based intervention that identified 360 European families with a high risk of developing T2D according to the FINDRISC questionnaire. Families were randomized in control and intervention groups were followed-up from 2016 to 2018. In the Spanish families, the concentration of BCAA and RBP4 was determined in 266 subjects (115 control and 151 intervention group) that attended the three time-point assessments by colorimetric and ELISA reaction, respectively. Results: Baseline BCAA levels showed positive correlations with the FINDRISC score and glucose impairment (baseline glucose, insulin, and glycated hemoglobin), body mass index, and body weight. The participants receiving the community-based intervention showed a significant decrease in glycated hemoglobin and BCAA levels compared to the control group (p = 0.011 and p < 0.001, respectively). However, baseline RBP4 did not show significant correlations with anthropometric and glycemic parameters, and no significant change was observed in anthropometric parameters and RBP4 concentrations throughout the follow-up. Conclusion: A community-based intervention on lifestyle led to a significant reduction in BCAA levels regardless of weight loss. These findings suggest that this interventional approach could be promising in T2D prevention.

Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion.

Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation. Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r = 0.824; P < 0.001) was observed. Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.

Different β-cell secretory phenotype in non-obese compared to obese early type 2 diabetes.

Type 2 diabetes (T2D) is characterized by impaired tissue sensitivity to insulin action (ie, insulin resistance) and impaired β-cell insulin secretion. Because obesity contributes importantly to the development of insulin resistance, we sought to determine whether insulin secretory defects would predominate in non-obese compared to obese T2D. We measured β-cell function and secretory capacity using the glucose-potentiated arginine test in T2D subjects early in the disease course classified as non-obese (BMI <30; n = 12) or obese (BMI ≥30 kg/m2 ; n = 28) and additionally compared responses from non-obese T2D with a non-diabetic control group (n = 12). The acute insulin response to glucose potentiation of arginine-induced insulin release was less in non-obese T2D than in controls and associated with impaired β-cell sensitivity to glucose (PG50 ). Proinsulin secretory ratios were increased in non-obese T2D when compared to obese T2D. Obese T2D subjects had reduced insulin sensitivity (M/I) while non-obese T2D subjects had insulin sensitivity that was comparable to controls. In non-obese T2D, insulin secretory defects predominate with impaired β-cell sensitivity to glucose and proinsulin processing in the absence of insulin resistance. Future studies should consider whether different β-cell secretory phenotypes and tissue sensitivity to insulin explain the varying responsiveness to T2D interventions.

In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis

Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder.

Modulation of adiponectin receptors AdipoR1 and AdipoR2 by phage display-derived peptides in in vitro and in vivo models

Type 2 diabetes (T2D) is often linked to metabolic syndrome, which assembles various risk factors related to obesity. Plasma levels of adiponectin are decreased in T2D and obese subjects. Aiming to develop a peptide able to bind adiponectin receptors and modulate their signalling pathways, a 12-amino acid sequence homologous in AdipoR1/R2 has been targeted by phage display with a linear 12-mer peptide library. The selected peptide P17 recognises AdipoR1/R2 expressed by skeletal muscle, liver and pancreatic islets. In HepaRG and C2C12 cells, P17 induced the activation of AMPK (AMPKα-pT172) and the expression of succinate dehydrogenase and glucokinase; no cytotoxic effects were observed on HepaRG cells. In db/db mice, P17 promoted body weight and glycaemia stabilisation, decreased plasma triglycerides to the range of healthy mice and increased adiponectin (in high fat-fed mice) and insulin (in chow-fed mice) levels. It restored to the range of healthy mice the tissue levels and subcellular distribution of AdipoR1/R2, AMPKα-pT172 and PPARα-pS12. In liver, P17 reduced steatosis and apoptosis. The docking of P17 to AdipoR is reminiscent of the binding mechanism of adiponectin. To conclude, we have developed an AdipoR1/AdipoR2-targeted peptide that modulates adiponectin signalling pathways and has therapeutic relevance for T2D and obesity associated pathologies.

Structural and Functional Abnormalities in Early-stage Diabetic Retinopathy

ABSTRACT Purpose To evaluate the relationship between microperimetric (MP) sensitivity and retinal thickness measured at co-registered retinal locations in individuals who have mild or no diabetic retinopathy. Methods Fifty non-diabetic control subjects and 50 type-2 diabetic subjects participated (25 had no clinically apparent DR [NDR] and 25 had mild nonproliferative DR [MDR]). MP sensitivity was measured at 36 retinal locations that were arranged in three concentric rings centered on the fovea (radii of 3°, 6°, and 12°). Optical coherence tomography (OCT) images were obtained, and total retinal thickness (TRT), inner retinal thickness (IRT), and outer retinal thickness (ORT) were quantified from the OCT images at locations that matched the MP measures. Linear quantile mixed models (LQMMs) and linear quantile models (LQMs) were used to compare MP and thickness values for the three subject groups and to quantify structure–function relationships. Results The statistical models indicated significant TRT and IRT reductions in the NDR and MDR groups, relative to the controls, that were most apparent in the 3° ring. By contrast, ORT was not reduced significantly for either diabetic group. MP sensitivity was reduced significantly within each ring and for both diabetic groups. Despite reductions in both thickness and sensitivity, the structure–function associations were generally weak with borderline statistical significance. For example, a TRT or IRT reduction of approximately 27 µm was predicted to result in approximately 1 dB of MP sensitivity loss for the MDR group (p = .03 and 0.05, respectively) Conclusions The results support previous findings of early retinal neurodegeneration in diabetics who have NDR or MDR. Interestingly, the structural and functional deficits appear to be only weakly associated, suggesting that mechanisms in addition to retinal thinning underlie the functional defects in early-stage DR.

Glycemic profile is improved by High Slowly Digestible Starch diet in type 2 diabetic patients

AbstractIntroductionConsidering the dramatically increasing incidence of type 2 diabetes (T2D), decreasing glycemic variability in T2D patients is a key challenge to limit the occurrence of diabetic complications. Diet appears as one potential lever that can be set up above medications. Particularly, the ingestion of foods with a high content in slowly digestible starch (SDS) demonstrated both lower postprandial glycemic and insulin responses in healthy and insulin resistant subjects. This study aimed at designing a full high-SDS diet by selecting high-SDS starchy food products and at studying its impact on glycemic response and variability in T2D.Materials and methodsThis pilot randomized controlled cross-over study included eight T2D patients (HbA1c = 7.0 ± 0.2%, BMI = 31.7 ± 2.1 kg/m2, treated by Metformin &amp; Sitagliptin) who consumed twice, for one week a controlled diet containing starchy food products screened and selected to be either High (High-SDS) or Low (Low-SDS) in SDS, as determined by the SDS in-vitro method developed by Englyst et al. During each diet period, the glycemic profile was monitored for 6 days using a Continuous Glucose Monitoring System (CGMS). Multiple metrics related to variability and glycemic responses were calculated.Results222 SDS analyses were realized on commercial food products as consumed. 23 High-SDS and 20 Low-SDS food items with associated specific cooking instructions were selected to design two diets consistent with local T2D recommendations. The High-SDS diet demonstrated a significantly higher SDS content compared to the Low-SDS diet (61.6 vs 11.6 g/day; p &lt; 0.0001), mainly driven by selected pasta, rice and high-SDS biscuits (75.6% of the consumed SDS content). The % of total daily energy intake (TDEI) for all macronutrients remained similar between diets (p &gt; 0.05) and the carbohydrate content specifically represented 49 ± 1 % and 47 ± 2 % of the TDEI for High-SDS and Low-SDS diets, respectively. With the high-SDS diet, the Mean Amplitude of Glycemic Excursion, a key parameter of glycemic variability, was significantly decreased (79.6 for Low-SDS vs 61.6 mg/dL for High-SDS; p = 0.0067). The significant correlation between the meals SDS contents and various glycemic parameters such as postprandial iAUC, tAUC (up to 180 min) or peak value strengthen this finding (p &lt; 0.05 for all).DiscussionIt was the first demonstration that a diet including selected starchy food items and cooking recommendations designed to favor products’ high SDS content beneficially impacts glycemic profile in T2D subjects. Carefully selecting starchy food may be a simple and valuable tool to improve glycemic control in T2D.

Chicoric acid does not restore palmitate-induced decrease in irisin levels in PBMCs of newly diagnosed patients with T2D and healthy subjects

Targeting irisin as a myokine/adipokine is a new therapeutic approach in the improvement of insulin-resistance (IR) during type 2 diabetes (T2D). In present study we evaluated the effects of palmitate and chicoric acid (CA) on irisin production in peripheral blood mononuclear cells (PBMCs) of patients with T2D. This study performed on 20 newly diagnosed patients with T2D and 20 healthy subjects. PBMCs treated with palmitate and CA. PPARGC1A and FNDC5 genes expression assessed using qRT-PCR. Irisin levels in cell culture medium measured by ELISA. Palmitate decreased PPARGC1A and FNDC5 genes expression, as well as irisin levels in PBMCs from T2D and healthy volunteers. CA significantly restored palmitate-induced decrease in PPARGC1A gene expression in PBMCs of healthy subjects. Although, FNDC5 gene expression and irisin levels were not induced significantly by CA. In conclusion, palmitate decreases irisin production through down-regulation of PPARGC1A and FNDC5 expressions. However, CA does not effect on irisin pathway. Key points Palmitate reduced PPARGC1A and FNDC5 genes expression, as well as irisin secretion in PBMCs. Palmitate-induced decrease in PPARGC1A gene expression significantly has been reversed by CA in PBMCs of healthy subjects. CA did not return palmitate-decreased in FNDC5 gene expression and irisin levels in PBMCs.

Augmented pressor and sympathoexcitatory responses to the onset of isometric handgrip in patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) exhibit greater daytime blood pressure (BP) variability, increasing their cardiovascular risk. Given the number of daily activities that incorporate short-duration isometric muscle contractions (e.g., carrying groceries), herein we investigated BP and muscle sympathetic nerve activity (MSNA) responses at the onset of isometric handgrip (HG). We tested the hypothesis that, relative to control subjects, patients with T2D would exhibit exaggerated pressor and MSNA responses to the immediate onset of HG. Mean arterial pressure (MAP) and MSNA were quantified during the first 30 s of isometric HG at 30% and 40% of maximal voluntary contraction (MVC) and during a cold pressor test (CPT), a nonexercise sympathoexcitatory stimulus. The onset of 30% MVC HG evoked similar increases in MAP between groups (P = 0.17); however, the increase in MSNA was significantly greater in patients with T2D versus control subjects with the largest group difference at 20 s (P < 0.001). At the onset of 40% MVC HG, patients with T2D demonstrated greater increases in MAP (e.g., 10 s, T2D: 9 ± 1 mmHg, controls: 5 ± 2 mmHg; P = 0.04). MSNA was also greater in patients with T2D at 40% MVC onset but differences were only significant at the 20-30 s timepoint (T2D: 15 ± 3 bursts/min, controls: -2 ± 4 bursts/min; P < 0.001). Similarly, MAP and MSNA responses were augmented during the onset of CPT in T2D patients. These findings demonstrate exaggerated pressor and MSNA reactivity in patients with T2D, with rapid and robust responses to both isometric contractions and cold stress. This hyper-responsiveness may contribute to daily surges in BP in patients with T2D, increasing their short-term and long-term cardiovascular risk.

A composite immune signature parallels disease progression across T1D subjects.

At diagnosis, most people with type 1 diabetes (T1D) produce measurable levels of endogenous insulin, but the rate at which insulin secretion declines is heterogeneous. To explain this heterogeneity, we sought to identify a composite signature predictive of insulin secretion, using a collaborative assay evaluation and analysis pipeline that incorporated multiple cellular and serum measures reflecting β cell health and immune system activity. The ability to predict decline in insulin secretion would be useful for patient stratification for clinical trial enrollment or therapeutic selection. Analytes from 12 qualified assays were measured in shared samples from subjects newly diagnosed with T1D. We developed a computational tool (DIFAcTO, Data Integration Flexible to Account for different Types of data and Outcomes) to identify a composite panel associated with decline in insulin secretion over 2 years following diagnosis. DIFAcTO uses multiple filtering steps to reduce data dimensionality, incorporates error estimation techniques including cross-validation and sensitivity analysis, and is flexible to assay type, clinical outcome, and disease setting. Using this novel analytical tool, we identified a panel of immune markers that, in combination, are highly associated with loss of insulin secretion. The methods used here represent a potentially novel process for identifying combined immune signatures that predict outcomes relevant for complex and heterogeneous diseases like T1D.