Well-controlled Type 2 Diabetes Mellitus Research Articles

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2024 American College of Cardiology Conference.

To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2024 Scientific Session of the American College of Cardiology (ACC) conference. The LIBerate-HR trial showed the efficacy and safety of lerodalcibep, a subcutaneous injection that prevents binding of Pro-Protein Convertase Subtilisin/Kexin (PCSK) 9 to low-density lipoprotein (LDL)-receptors resulting in LDL-cholesterol (LDL-C) lowering in patients at very high risk or high risk of atherosclerotic CV disease (ASCVD). The AEGIS-II randomized patients with type 1 myocardial infarction (MI) with multivessel coronary artery disease and additional CV risk factors and found no benefit in major adverse CV events (MACE) with CSL112, an apolipoprotein A1 infusion shown to increase cholesterol efflux capacity. The Bridge-TIMI 73a trial showed a significant reduction in triglyceride (TG) levels with olezarsen, an antisense mRNA, in patients with moderate hyperTG with elevated CV risk. The BE ACTIVE trial showed significant improvement in step counts in patients given behavioral and financial incentives. The DRIVE study showed a significant increase in the prescription of either sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus (T2DM) at elevated CV or renal risk with a remote team-based, non-licensed navigator and clinical pharmacist approach. The TACTiC trial showed increased and sustained use of statin therapy by patient-driven use of a web-based portal that calculated the ASCVD risk score and gave prompts. The VICTORIAN-INITIATE trial showed efficacy and safety in early use of inclisiran in patients with ASCVD who did not reach target LDL-C < 70mg/dL despite maximally tolerated statin therapy. The ARISE-HF trial showed no difference in change of peak oxygen consumptionwith the use of an oral aldose reductase inhibitor, AT-001, in patients with well-controlled T2DM and diabetic cardiomyopathy with high-risk features compared to placebo. The PREVENT trial showed a significant reduction in target vessel failure at 2years in patients with non-flow limiting vulnerable plaques with percutaneous coronary intervention and optimal medical therapy (OMT) compared to OMT alone. The late-breaking clinical science presented at the 2024 Scientific Session of the ACC paves the way for an evidence-based alternative to statin therapy and provides data on several common clinical scenarios encountered in daily practice.

Optimal Coefficient of Variance Threshold to Minimize Hypoglycemia Risk in Individuals with Well-Controlled Type 1 Diabetes Mellitus.

This study investigated the optimal coefficient of variance (%CV) for preventing hypoglycemia based on real-time continuous glucose monitoring (rt-CGM) data in people with type 1 diabetes mellitus (T1DM) already achieving their mean glucose (MG) target. Data from 172 subjects who underwent rt-CGM for at least 90 days and for whom 439 90-day glycemic profiles were available were analyzed. Receiver operator characteristic analysis was conducted to determine the cut-off value of %CV to achieve time below range (%TBR)<54 mg/dL <1 and =0. Overall mean glycosylated hemoglobin was 6.8% and median %TBR<54 mg/dL was 0.2%. MG was significantly higher and %CV significantly lower in profiles achieving %TBR<54 mg/dL <1 compared to %TBR<54 mg/dL ≥1 (all P<0.001). The cut-off value of %CV for achieving %TBR<54 mg/dL <1 was 37.5%, 37.3%, and 31.0%, in the whole population, MG >135 mg/dL, and ≤135 mg/dL, respectively. The cut-off value for %TBR<54 mg/dL=0% was 29.2% in MG ≤135 mg/dL. In profiles with MG ≤135 mg/dL, 94.2% of profiles with a %CV <31 achieved the target of %TBR<54 mg/dL <1, and 97.3% with a %CV <29.2 achieved the target of %TBR<54 mg/ dL=0%. When MG was >135 mg/dL, 99.4% of profiles with a %CV <37.3 achieved %TBR<54 mg/dL <1. In well-controlled T1DM with MG ≤135 mg/dL, we suggest a %CV <31% to achieve the %TBR<54 mg/dL <1 target. Furthermore, we suggest a %CV <29.2% to achieve the target of %TBR<54 mg/dL =0 for people at high risk of hypoglycemia.

Upregulation of Anti-Angiogenic miR-106b-3p Correlates Negatively with IGF-1 and Vascular Health Parameters in a Model of Subclinical Cardiovascular Disease: Study with Metformin Therapy.

Well-controlled type 1 diabetes mellitus (T1DM) is regarded as a model of subclinical cardiovascular disease (CVD), characterized by inflammation and adverse vascular health. However, the underlying mechanisms are not fully understood. We investigated insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, their correlation to miR-106b-3p expression in a subclinical CVD model, and the cardioprotective effect of metformin. A total of 20 controls and 29 well-controlled T1DM subjects were studied. Plasma IGF-1, IGFBP-3 levels, and miR-106b-3p expression in colony-forming unit-Hills were analyzed and compared with vascular markers. miR-106b-3p was upregulated in T1DM (p < 0.05) and negatively correlated with pro-angiogenic markers CD34+/100-lymphocytes (p < 0.05) and IGF-1 (p < 0.05). IGF-1 was downregulated in T1DM (p < 0.01), which was associated with increased inflammatory markers TNF-α, CRP, and IL-10 and reduced CD34+/100-lymphocytes. IGFBP-3 had no significant results. Metformin had no effect on IGF-1 but significantly reduced miR-106b-3p (p < 0.0001). An Ingenuity Pathway analysis predicted miR-106b-3p to inhibit PDGFA, PIK3CG, GDNF, and ADAMTS13, which activated CVD. Metformin was predicted to be cardioprotective by inhibiting miR-106b-3p. In conclusion: Subclinical CVD is characterized by a cardio-adverse profile of low IGF-1 and upregulated miR-106b-3p. We demonstrated that the cardioprotective effect of metformin may be via downregulation of upregulated miR-106b-3p and its effect on downstream targets.

Study of Glycemic Variability in Well-controlled Type 2 Diabetic Patients Using Continuous Glucose Monitoring System.

The world has changed tremendously for patients suffering from diabetes mellitus with the development of cutting-edge technologies like continuous glucose monitoring and flash glucose monitoring systems. Now, the details of constant fluctuations of glucose in their blood can be monitored not only by medical professionals but also by patients, and this is called glycemic variability (GV). Traditional metrics of glycemic control measurement, such as glycated hemoglobin (HbA1c), fail to reflect various short-term glycemic changes like postprandial hyperglycemia and hypoglycemic episodes, paving the way to the occurrence of various diabetic complications even in asymptomatic, well-controlled diabetic patients. This need for advanced management of diabetes and effective monitoring of these swings in blood glucose can be met by using a continuous glucose monitoring system (CGMS). To evaluate the extent of GV in well-controlled type 2 diabetes mellitus (T2DM) patients using a flash CGMS and to assess the correlation between GV and HbA1c. A hospital-based prospective observational study was carried out from May 2020 to Oct 2021 at the Department of Medicine, SMS Hospital, Jaipur, Rajasthan (India), after approval from the Ethics Committee of the institution. A total of 30 patients with well-controlled T2DM (HbA1c was ≥6.5, but ≤7.5) were included in the study using simple random techniques after written informed consent from patients. Patients were studied for glycemic excursions over a period of 7 days by using FreeStyle® Libre Pro™, which is a flash glucose monitoring system. The CGM sensor was attached to the left upper arm of the patient on day 0 and removed on day 7. The data recorded in the sensor was then retrieved using pre-installed computer software and analyzed using standard CGM metrics like standard deviation (SD), percentage coefficient of variation (%CV), time above range (TAR), time below range (TBR), and time in range (TIR), out of which %CV was used to quantify GV. %CV has been used to cluster patients into four cohorts from best to worst, namely: best/low CV ≤ 10%, intermediate CV from 10 to 20%, high CV from 20 to 30%, and very high CV of >30%. Scatterplots are used to establish correlations between various parameters. Data from a total of 30 patients were analyzed using CGMS and thus used for calculating standard CGM metrics; glucose readings every 15 minutes were recorded consecutively for 7-day periods, making it a total of 672 readings for each patient. Interpreting the CGM data of all 30 patients, the following results were found: the mean blood glucose of all cases is 134.925 ± 22.323 mg/dL, the mean SD of blood glucose of all cases is 35.348 ± 9.388 mg/dL, the mean of %CV of all cases is 26.376 ± 6.193%. CGM parameters of time are used in the form of percentages, and the following results were found: the mean of TAR, TBR, and TIR is 14.425 ± 13.211, 5.771 ± 6.808, and 82.594 ± 12.888%, respectively. Clustering the patients into cohorts, the proportion of patients exhibiting best/low %CV (10%) is 0, intermediate %CV (10-20%) is 16.67% (five out of 30 patients), high %CV (20-30%) is 50% (15 out of 30 patients) and very high %CV (>30%) is 33.33% (10 out of 30 patients). Also, there is no significant correlation found between HbA1c and %CV (ρ = 0.076, p-value = 0.690); a significant negative correlation was found between %CV and TIR (ρ = -0.604, p < 0.001S); a positive correlation of %CV with TAR and TBR is significant (ρ = 0.816, p-value of <0.001). Using a flash CGMS device and considering %CV as the parameter and primary measure of GV, the study demonstrated the overall instability of a person's glycemic control, making note of unrecognized events of hypoglycemia and hyperglycemia in asymptomatic well-controlled T2DM patients, revealing the overall volatile glycemic control. The most important finding of this study is that even those diabetics who are considered well-controlled experience a great degree of GV as assessed by CGM-derived metrics. This study also demonstrated that there is no significant correlation between HbA1c and GV, suggesting that patients may not have optimal control of their diabetes despite having "normal HbA1c" values; hence, GV can be considered an HbA1c-independent danger factor, having more harmful effects than sustained hyperglycemia in the growth of diabetic complications. So, by using CGM-derived metrics, the measurement of GV has the potential to complement HbA1c data. In this manner, a more comprehensive assessment of glycemic excursions can be provided for better treatment decisions, thereby facilitating optimal glycemic control, which is essential for reducing overall complications and promoting good quality of life.

Impacts of Chemerin Levels and Antioxidant Capacity on the Severity of Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes and Prediabetes.

Existing evidence supports an association between chemerin levels and cardiovascular risk, while reduced thiol levels are linked to diabetes mellitus. It is hypothesized that chemerin may contribute to autonomic dysfunction and cardiovascular risk in type 2 diabetes mellitus (T2DM), potentially mediated by the antioxidant capacity of patients with well-controlled T2DM and prediabetes. Comprehensive cardiovascular autonomic testing and biomarker assessments were conducted for all participants. The severity of cardiovascular autonomic neuropathy (CAN) was evaluated using the composite autonomic scoring scale (CASS). A mediation model was employed to explore the potential relationships among chemerin levels, antioxidant capacity (indicated by thiol levels), and CAN severity (indicated by CASS values). A total of 184 participants were enrolled in this study, comprising 143 individuals with T2DM and 40 individuals with prediabetes. The findings reveal a significant negative association between thiols levels (r = -0.38, p < 0.0001) and the CASS values, while a positive association is observed between chemerin levels (r = 0.47, p < 0.0001) and the CASS values. Linear regression analysis identified chemerin and thiols as independent variables significantly associated with CASS values. Subsequent mediation analysis elucidated that thiols levels act as mediators in the relationship between elevated chemerin levels and an increased CASS value. This study shows that poor cardiovascular function, higher chemerin levels, and reduced antioxidant capacity coexist in individuals with T2DM and prediabetes. Mediation analysis suggests a pathophysiological link between high chemerin levels and low antioxidant capacity, adversely impacting CAN severity.

The association between serum ferritin and bilirubin with glycemic control among patients with type 2 diabetes mellitus.

Previous evidence has shown an association between serum ferritin and bilirubin levels in the development of type 2 diabetes mellitus (T2DM) and glycemic control. However, the evidence is scarce in Saudi Arabia. In this study, we aimed to evaluate the association between serum ferritin and bilirubin levels with glycemic control in patients with T2DM. This was a cross-sectional study that involved 153 patients with T2DM recruited from outpatient diabetes clinics. Participants were categorized into two groups: well-controlled and uncontrolled T2DM, based on their glycemic status. We focused on comparing the iron profile and bilirubin levels between these two groups and examining the influence of antidiabetic medications on these parameters. A total of 153 patients with T2DM were included (58.2% women and 41.8% men). In both univariate and multivariate analyses, ferritin levels did not have a statistically significant association with glycemic control. However, patients with well-controlled T2DM had a significantly higher median level of total bilirubin and direct bilirubin than those with uncontrolled T2DM. Only direct bilirubin showed a statistically significant association with FBG less than 130 mg/dl and HbA1c level less than 7.0%. Ferritin level was not associated with glycemic control in patients with T2DM. On the other hand, direct bilirubin level was an independent predictor of better glycemic control. Monitoring direct bilirubin levels could aid in predicting glycemic control in T2DM and could be a potential target for developing antidiabetic medications.

Improvement of Global Longitudinal Strain and Myocardial Work in Type 2 Diabetes Patients on Sodium-Glucose Cotransporter 2 Inhibitors Therapy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a novel class of oral hypoglycemic agents currently used among patients with type 2 diabetes mellitus (T2DM). The effects of SGLT2-i inhibitors on cardiac structure and function are not fully understood. The aim of this study is to evaluate the echocardiographic changing among patients with well-controlled T2DM treated with SGLT2-i in real-world setting. Thirty-five well-controlled T2DM patients (65 ± 9 years, 43.7% male) with preserved left ventricular ejection fraction (LVEF) and 35 age and sex-matched controls were included. T2DM patients underwent clinical and laboratory evaluation; 12-lead surface electrocardiogram; 2-dimensional color Doppler echocardiography at enrolment, before SGLT2-i administration, and at 6 months follow-up after an uninterrupted 10 mg once daily of empagliflozin (n: 21) or dapagliflozin (n: 14). Standard echocardiographic measurements, LV global longitudinal strain (LV-GLS), global wasted work, and global work efficiency were calculated. T2DM patients showed higher E\E' ratio (8.3 ± 2.5 vs. 6.3 ± 0.9; P < 0.0001 ) and lower LV-GLS (15.8 ± 8.1 vs. 22.1 ± 1.4%; P < 0.0001 ) and global myocardial work efficiency (91 ± 4 vs. 94 ± 3%; P: 0.0007 ) compared with age and sex-matched controls. At 6-month follow-up, T2DM patients showed a significant increase in LVEF (58.9 ± 3.2 vs. 62 ± 3.2; P < 0.0001 ), LV-GLS (16.2 ± 2.8 vs. 18.7 ± 2.4%; P = 0.003 ), and global work efficiency (90.3 ± 3.5 vs. 93.3 ± 3.2%; P = 0.0004 ) values; conversely, global wasted work values (161.2 ± 33.6 vs. 112.72 ± 37.3 mm Hg%; P < 0.0001 ) significantly decreased. Well-controlled T2DM patients with preserved LVEF who are treated with a SGLT2-i on top of the guidelines direct medical therapy showed a favorable cardiac remodeling, characterized by the improvement of LV-GLS and myocardial work efficiency.

Impact of scaling and root planing on salivary and serum plasminogen activator inhibitor-1 expression in patients with periodontitis with and without type 2 diabetes mellitus.

Plasminogen activator inhibitor-1 (PAI-1) is significantly enhanced in insulin resistance and inflammation and ascribed as a proinflammatory marker. This study aimed to compare and correlate salivary and serum PAI-1 and alpha 2-macroglobulin (α2MG) in patients with periodontitis with and without type 2 diabetes mellitus (T2DM) and also appraise the consequence of periodontal treatment on these biomarkers. Sixty subjects enlisted were split into two groups; Group 1 consisted of 30 systemically healthy subjects with Stage II and III, generalized, Grade B, C periodontitis while Group 2 consisted of 30 patients with periodontitis and well-controlled T2DM (PDM). Salivary and serum PAI-1 and α2MG levels were estimated by enzyme-linked immunosorbent assay and allied with clinical parameters before and 3 months post non-surgical periodontal therapy (NSPT). Data were statistically analyzed using student t-test and Spearman correlation. Analogous improvements in clinical periodontal markers were experienced in both groups after initial periodontal treatment. Estimates of salivary and serum PAI-1 and α2MG were higher among the PDM group compared with periodontitis alone at baseline. Significant diminution in estimates of biomarkers was noted 3 months after NSPT. In the PDM group, there was also an improvement in glycemic control. NSPT positively impacted both groups. Noteworthy expression of salivary and serum PAI-1 in patients with periodontitis and diabetes insinuates a possible role of the adipokine in periodontal inflammation and glucose level regulation. Salivary PAI-1 could thus be used as a diagnostic biomarker to detect disease activity and to track periodontal therapy response.

Association between Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized β coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized β coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized β coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized β coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.

An Unanticipated Worsening of Glycemic Control Following a Mild COVID-19 Infection

We describe a case of acute-onset worsening of a patient’s previously well-controlled type 2 diabetes mellitus (T2DM) following his recovery from a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 78-year-old male with a three-year medical history of well-controlled T2DM (controlled by diet and metformin) presented to the outpatient clinic to discuss his regularly scheduled six-month lab work. He mentioned having a mild coronavirus disease 2019 (COVID-19) infection lasting one week which required no medical treatment approximately two months before his current visit. His labs, taken one week prior to his current visit, were notable for fasting hyperglycemia, 301mg/dL, and an elevated hemoglobin A1C (HbA1C), 11%. A fasting blood glucose level was recorded at his current in-office visit and was found to be 403mg/dL. These findings were not anticipated - our patient reported no change in his meals, medications, or exercise routines. The only notable change he reported between visits was his COVID-19 infection. This case report explores the link between this virus and our patient's exacerbation of his previously well-controlled T2DM. Whether it be through insulin resistance or deficiency (or another unknown mechanism), our patient's prior novel COVID-19 infection could potentially be associated with his unprecedented altered glucose metabolism.

Myocardial fibrosis in Type 2 Diabetes is associated with functional and metabolomic parameters

AimsTo identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis. MethodsIn this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses. ResultsPatients with T2DM (n = 49, median [interquartile range] age 61 [56–63] years, 61% male, diabetes duration 11 [7–20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9–8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8–30.0] vs 23.4 [22.4–25.5) %, p < 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VO2 (R2 = 0.48, p = 0.01), increased circulating choline (p = 0.002) and cysteamine (p = 0.002) both of which were also associated with reduced peak VO2 (p < 0.025 and 0.014 respectively). ConclusionsPatients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.

Pre-transplant Type 2 Diabetes Mellitus Is Associated With Higher Graft Failure and Increased 5-Year Mortality After Heart Transplantation.

AimsCardiac transplant recipients often suffer from type 2 diabetes mellitus (T2DM) but its influence on graft failure and post-transplant mortality remains unknown. The aim of this study was to investigate the long-term effects of pre-transplant T2DM in patients after heart transplantation (HTX).MethodsThis study included a total of 376 adult patients who received HTX at Heidelberg Heart Center between 01/01/2000 and 01/10/2016. HTX recipients were stratified by diagnosis of T2DM at the time of HTX. Patients with T2DM were further subdivided by hemoglobin A1c (HbA1c ≥ 7.0%). Analysis included donor and recipient data, immunosuppressive drugs, concomitant medications, post-transplant mortality, and causes of death. Five-year post-transplant mortality was further assessed by multivariate analysis (Cox regression) and Kaplan–Meier estimator.ResultsAbout one-third of all HTX recipients had T2DM (121 of 376 [32.2%]). Patients with T2DM showed an increased 5-year post-transplant mortality (41.3% versus 29.8%; P = 0.027) and had a higher percentage of death due to graft failure (14.9% versus 7.8%; P = 0.035). Multivariate analysis showed T2DM (HR: 1.563; 95% CI: 1.053–2.319; P = 0.027) as an independent risk factor for 5-year mortality after HTX. Kaplan–Meier analysis showed a significantly better 5-year post-transplant survival of patients with T2DM and a HbA1c < 7.0% than patients with T2DM and a HbA1c ≥ 7.0% (68.7% versus 46.3%; P = 0.008) emphasizing the clinical relevance of a well-controlled T2DM in HTX recipients.ConclusionPre-transplant T2DM is associated with higher graft failure and increased 5-year mortality after HTX.

GASTROINTESTINAL MOTILITY IN ELDERLY PATIENTS WITH WELL-CONTROLLED TYPE 2 DIABETES MELLITUS.

Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

Whey protein supplementation improves postprandial glycemia in persons with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials

Whey protein (WP) can increase insulin secretion, produce an incretin effect, delay gastric emptying, and regulate appetite, resulting in improved glycemic control. We hypothesized that WP supplementation is associated with postprandial glycemia regulation in persons with type 2 diabetes mellitus (T2DM) and conducted a quantitative meta-analysis of randomized controlled trials (RCTs) to test this hypothesis. We searched PubMed, Embase, Cochrane Library, Scopus databases, and the ClinicalTrials.gov registry for relevant RCTs published before March 2022. We assessed the pooled effects using a random-effects model on glucose and insulin levels at 60 and 120 minutes, total glucagon-like peptide-1 (tGLP-1) at 30 and 60 minutes, and the incremental area under the curve (iAUC) of glucose, insulin, tGLP-1, and glucose-dependent insulinotropic polypeptide. Five RCTs involving 134 persons were included. Postprandial glycemia was significantly lower at 60 minutes (weighted mean difference: −2.67 mmol/L; 95% confidence interval, −3.62 to −1.72 mmol/L) and 120 minutes (−1.59 mmol/L; −2.91 to −0.28 mmol/L) in WP group than in placebo group. The iAUC of insulin was significantly higher in WP group (24.66 nmol/L × min, 1.65-47.66 nmol/L × min) than in placebo group. Although other results favored the WP group, differences between the groups were not statistically significant. The present study showed that premeal WP supplementation is beneficial for postprandial glycemia in persons with mild or well-controlled T2DM without substantial adverse effects. However, the level of certainty of current evidence is not high enough. Further larger and well-designed clinical trials are warranted for evaluating optimal dose and long-term effects of WP supplementation.

Impact of continuous vs. interval training on oxygen extraction and cardiac function during exercise in type 2 diabetes mellitus

Exercise training improves exercise capacity in type 2 diabetes mellitus (T2DM). It remains to be elucidated whether such improvements result from cardiac or peripheral muscular adaptations, and whether these are intensity dependent. 27 patients with T2DM [without known cardiovascular disease (CVD)] were randomized to high-intensity interval training (HIIT, n = 15) or moderate-intensity endurance training (MIT, n = 12) for 24weeks (3sessions/week). Exercise echocardiography was applied to investigate cardiac output (CO) and oxygen (O2) extraction during exercise, while exercise capacity [([Formula: see text] (mL/kg/min)] was examined via cardiopulmonary exercise testing at baseline and after 12 and 24weeks of exercise training, respectively. Changes in glycaemic control (HbA1c and glucose tolerance), lipid profile and body composition were also evaluated. 19 patients completed 24weeks of HIIT (n = 10, 66 ± 11years) or MIT (n = 9, 61 ± 5years). HIIT and MIT similarly improved glucose tolerance (pTime = 0.001, pInteraction > 0.05), [Formula: see text] (mL/kg/min) (pTime = 0.001, pInteraction > 0.05), and exercise performance (Wpeak) (pTime < 0.001, pInteraction > 0.05). O2 extraction increased to a greater extent after 24weeks of MIT (56.5%, p1 = 0.009, pTime = 0.001, pInteraction = 0.007). CO and left ventricular longitudinal strain (LS) during exercise remained unchanged (pTime > 0.05). A reduction in HbA1c was correlated with absolute changes in LS after 12weeks of MIT (r = - 0.792, p = 0.019, LS at rest) or HIIT (r = - 0.782, p = 0.038, LS at peak exercise). In patients with well-controlled T2DM, MIT and HIIT improved exercise capacity, mainly resulting from increments in O2 extraction capacity, rather than changes in cardiac output. In particular, MIT seemed highly effective to generate these peripheral adaptations. NCT03299790, initially released 09/12/2017.

Indocyanine-mediated antimicrobial photodynamic therapy promotes superior clinical effects in stage III and grade C chronic periodontitis among controlled and uncontrolled diabetes mellitus: A randomized controlled clinical trial

Background: The aim of this randomized controlled clinical trial was to evaluate the efficacy of indocyanine-green mediated antimicrobial photodynamic therapy (ICG-aPDT) in the treatment of stage III grade C periodontitis in terms of clinical, microbiological, and immune-inflammatory parameters in patients with well-controlled and poorly-controlled form of type-2 diabetes mellitus (T2DM). Materials and methods: Subjects with a diagnosis of chronic periodontitis according to the new classification and case definition of periodontitis [probing depth (PD): ≥6 mm, interdental clinical attachment loss (CAL): ≥5 mm and bone loss extending to mid-third of root and beyond (≥3 mm)] were recruited. Subjects were grouped on the basis of well-controlled and poorly-controlled diabetic status. Two subgroups were made according to the treatment modality (RSD versus ICG-aPDT/RSD) in each group. A split-mouth design was used in which one site was designated for control (RSD alone treatment) while the other contralateral site was chosen for test treatment (ICG-aPDT/RSD) in all the patients. Periodontal parameters included the measurement of plaque score (PS), bleeding on probing (BOP), probing depth (PD), clinical attachment level (CAL) and alveolar bone levels (ABL). Identification of Porphyromonas gingivalis and Tannarella forsythia through PCR was executed using species specific primers. Gingival crevicular fluid samples were then analyzed using enzyme-linked immunosorbent assay for the quantification of interleukin (IL)-17 and interferon (IFN)-γ. All the clinical, microbiological, and immunological parameters were assessed using repeated measure ANOVA for intra and inter-group comparisons. The p-value significance was set at 0.05. Results: The mean age of the 50 patients was 44.7 ± 7.4 years. Systemic parameters suggest no significant change between the times in either HbA1c or serum CRP levels in any of the groups. A statistically significant reduction for BOP was noted for ICG-aPDT group for non-diabetic subjects at 3 months follow up only, while a significant reduction was seen at both 3 months and 6 months among well-controlled and poorly-controlled T2DM subjects (p<0.05). For PD and CAL, a significant improvement was seen for ICG-aPDT group among non-diabetic and well-controlled T2DM subjects at both 3- and 6-months follow up, while a significant reduction was seen at only 3 months among poorly-controlled T2DM subjects. A significant reduction was seen for ICG-aPDT group compared to RSD group for both bacteria in all the three groups at 6 months follow up (p<0.05). Conclusion: ICG-aPDT significantly improved clinical and antimicrobial parameters in well-controlled and poorly-controlled T2DM having stage III and grade C periodontitis. Glycemic status did not have negative impact in the reduction of periodontal parameters in either types of T2DM. Trial registration: The present RCT was registered in the clinicaltrials.gov under the identifier: NCT04857346

Upregulated anti-angiogenic miR-424-5p in type 1 diabetes (model of subclinical cardiovascular disease) correlates with endothelial progenitor cells, CXCR1/2 and other parameters of vascular health

BackgroundIn spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. Overexpression studies in animals have proven miR-424-5p to have anti-angiogenic properties. As type 1 diabetes mellitus (T1DM) without CVD displays endothelial dysfunction and reduced circulating endothelial progenitor cells (cEPCs), it offers a model of subclinical CVD. Therefore, we explored miR-424-5p, cytokines and vascular health in T1DM.MethodsTwenty-nine well-controlled T1DM patients with no CVD and 20-matched controls were studied. Cytokines IL8, TNF-α, IL7, VEGF-C, cEPCs/CD45dimCD34+CD133+ cells and ex-vivo proangiogenic cells (PACs)/fibronectin adhesion assay (FAA) were measured. MiR-424-5p in plasma and peripheral blood mononuclear cells (PBMC) along with mRNAs in PBMC was evaluated.ResultsWe found an elevation of IL7 (p = 0.008), IL8 (p = 0.003), TNF-α (p = 0.041), VEGF-C (p = 0.013), upregulation of mRNA CXCR1 (p = 0.009), CXCR2 (p < 0.001) and reduction of cEPCs (p < 0.001), PACs (p < 0.001) and FAA (p = 0.017) in T1DM. MiR-424-5p was upregulated in T1DM in PBMC (p < 0.001). MiR-424-5p was negatively correlated with cEPCs (p = 0.006), PACs (p = 0.005) and FAA (p < 0.001) and positively with HbA1c (p < 0.001), IL7 (p = 0.008), IL8 (p = 0.017), VEGF-C (p = 0.007), CXCR1 (p = 0.02) and CXCR2 (p = 0.001). ROC curve analyses showed (1) miR-424-5p to be a biomarker for T1DM (p < 0.001) and (2) significant upregulation of miR-424-5p, defining subclinical CVD, occurred at HbA1c of 46.5 mmol/mol (p = 0.002).ConclusionWe validated animal research on anti-angiogenic properties of miR-424-5p in T1DM. MiR-424-5p may be a biomarker for onset of subclinical CVD at HbA1c of 46.5 mmol/mol (pre-diabetes). Thus, miR-424-5p has potential use for CVD monitoring whilst anti-miR-424-5p-based therapies may be used to reduce CVD morbidity/mortality in T1DM.

Association of Type 2 Diabetes Mellitus and Glycemic Control With Intracranial Plaque Characteristics in Patients With Acute Ischemic Stroke.

Type 2 diabetes mellitus (T2DM) has shown to be associated with carotid plaque vulnerability. However, the impact of T2DM on intracranial artery atherosclerosis is not well-understood. To evaluate the association of diabetes and glycemic control with intracranial atherosclerotic plaque characteristics identified by three-dimensional contrast enhanced MR vessel wall imaging in patients after acute ischemic stroke. Prospective. Two hundred and eighty-eight symptomatic patients with acute ischemic stroke due to intracranial atherosclerotic plaque. T1 WI volume isotropic turbo spin-echo acquisition sequence at 3.0 T. Clinical profiles, blood biomarkers, the number of intracranial plaques, plaque enhanced score, and the features (location, luminal stenotic rate, intraplaque hemorrhage, length, burden, enhancement grade, and ratio) of culprit plaque (defined as the most stenotic lesion ipsilateral to the ischemic event) and nonculprit plaque were analyzed by three radiologists. Analysis of variance (ANOVA), Shapiro-Wilk normality test, Levene's test, ANOVA with Bonferroni post-hoc test, Kruskal Wallis H test with subsequent pairwise comparisons, chi-square with Bonferroni post-hoc test, generalized linear regression, Pearson correlation test, Kendall's W and intra-class correlation coefficient. Two hundred and twenty-five participants (age 60 ± 10 years, 58.7% male) with 958 intracranial plaques were included. More intracranial plaques were found in the T2DM group than the non-T2DM group (4.80 ± 2.22 vs. 3.60 ± 1.78, P < 0.05). Patients with poorly-controlled T2DM exhibited higher culprit plaque enhancement ratio than patients with well-controlled T2DM and non-T2DM (2.32 ± 0.61 vs. 1.60 ± 0.62 and 1.39 ± 0.39; respectively, P < 0.05). After adjusting for other clinical variables, T2DM was independently associated with increased intracranial plaque number (β=0.269, P < 0.05), and HbA1c level was independently associated with culprit plaque enhancement ratio (β=0.641, P < 0.05) in multivariate analysis. T2DM is associated with an increased intracranial plaque number. Higher HbA1c is associated with stronger plaque enhancement. 3D contrast enhanced MR vessel wall imaging may help better understand the association of T2DM and glycemic control with intracranial plaque. 1 TECHNICAL EFFICACY STAGE: 3.

Night-time heart rate variability identifies high-risk people among people with uncomplicated type 2 diabetes mellitus.

Low heart rate variability (HRV) reflects cardiac autonomic neuropathy, which is associated with increased cardiovascular mortality in people with type 2 diabetes mellitus (T2DM). Measuring HRV is challenged by environmental noise, mental stress and physical activity during daytime. Night-time HRV during sleep may be a more valid tool to measure cardiac autonomic neuropathy and therefore may improve prediction of cardiovascular (CV) events in low-risk people with T2DM. Copenhagen Holter Study included 678 community-dwelling participants aged 55-75years who were free of previous CV disease. Day and night-time HRV were available for 653 participants. The population included 133 people with well-controlled T2DM and newly recognized T2DM (mean HbA1c 55mmol/mol [7.2%]). HRV is defined as standard deviation for the mean value of normal-to-normal complexes (SDNN). Night-time HRV measurements were pre-defined from 2:00 to 2:15 AM. Cardiovascular events were defined as CV death, myocardial infarction, stroke or coronary revascularization. Median follow-up time was 14.4years. During this period, 245 death and 149 CV events (CV death 36, myocardial infarction 42, revascularisation procedures 46, stroke 70) occurred in total. Among people with T2DM, 41 CV events were observed (CV death 13, myocardial infarction 13, revascularisation procedures 17, stroke 18). Night-time SDNN was inversely associated with CV events in people with T2DM, (hazard ratio [HR]: 0.74 95% confidence interval [CI]:0.61-0.89) for each 10-millisecond increment in SDNN after adjustment for the conventional risk factors sex, age, LDL cholesterol, smoking, systolic blood pressure and by also including glucose CRP and NT-proBNP in adjustment. Twenty-four-hour HRV was not associated with CV events, but associated with all-cause mortality in people with T2DM. Conventional risk factors had a receiver operating characteristic (ROC) value of 0.704 (95% CI 0.602-0.806) to predict CV events in people with T2DM. The prediction of CV events by conventional risk factors was improved in people with T2DM by the addition of night-time SDNN; ROC 0.765 (95% CI 0.669-0.862), p=0.037, but ROC was not improved by addition of CRP and NT-proBNP in the model. In people with T2DM and night-time SDNN ≤30ms, the 10-year risk of CV death and CV event rate was 12% and 45%, respectively, which re-allocated them to a 'very high-risk' group according to current guidelines. Reduced night-time HRV predicts increased risk of CV events in people with well-controlled T2DM, thus night-time HRV may add to traditional risk factors in predicting CV events in people with T2DM.

Enlarged glycemic variability in sulfonylurea-treated well-controlled type 2 diabetics identified using continuous glucose monitoring

Time in range (TIR) is an index of glycemic control obtained from continuous glucose monitoring (CGM). The aim was to compare the glycemic variability of treatment with sulfonylureas (SUs) in type 2 diabetes mellitus (T2DM) with well-controlled glucose level (TIR > 70%). The study subjects were 123 patients selected T2DM who underwent CGM more than 24 h on admission without changing treatment. The primary endpoint was the difference in glycemic variability, while the secondary endpoint was the difference in time below range < 54 mg/dL; TBR < 54, between the SU (n = 63) and non-SU (n = 60) groups. The standard deviation, percentage coefficient of variation (%CV), and maximum glucose level were higher in the SU group than in the non-SU group, and TBR < 54 was longer in the high-dose SU patients. SU treatment was identified as a significant factor that affected %CV (β: 2.678, p = 0.034). High-dose SU use contributed to prolonged TBR < 54 (β: 0.487, p = 0.028). Our study identified enlarged glycemic variability in sulfonylurea-treated well-controlled T2DM patients and high-dose SU use was associated with TBR < 54. The results highlight the need for careful adjustment of the SU dose, irrespective of glycated hemoglobin level or TIR value.