Well-controlled Type 2 Diabetes Research Articles

Carnosine Supplementation Has No Effect on Inflammatory Markers in Adults with Prediabetes and Type 2 Diabetes: A Randomised Controlled Trial.

In vitro studies suggest that carnosine reduces inflammation by upregulating anti-inflammatory mediators and downregulating pro-inflammatory cytokines. However, human clinical trials examining the effects of carnosine on inflammatory biomarkers are scant. We conducted a secondary analysis of a double-blind randomised controlled trial (RCT) to examine the effects of carnosine supplementation on inflammatory markers and adipokines in participants with prediabetes or well-controlled type 2 diabetes (T2D). Out of 88 participants who were recruited, 49 adults with prediabetes or well-controlled T2D (HbA1c: 6.6 ± 0.7% [mean ± SD]) who were treated with diet and/or metformin were eligible for inclusion. Participants were randomised to receive 2 g/day of carnosine or a matching placebo for 14 weeks. We measured serum concentrations of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-10, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), adiponectin, leptin, adipsin, serpin, and resistin levels at baseline and after 14 weeks. The trial was registered at clinicaltrials.gov (NCT02917928). Forty-one participants (M = 29/F = 12) aged 53 (42.6, 59.3) years [median (IQR)] completed the trial. After 14 weeks of supplementation, changes in pro- and anti-inflammatory cytokine and adipokine levels did not differ between the carnosine and placebo groups (p > 0.05 for all). The results remained unchanged after adjustment for confounders including age, sex, and anthropometric measures (e.g., body fat percentage and visceral adipose tissue). In individuals with prediabetes and well-controlled T2D, carnosine supplementation did not result in any significant changes in inflammatory markers. Larger RCTs with longer follow-up durations are needed to evaluate whether carnosine may be beneficial in individuals with poorly controlled T2D.

Lipophilic index of serum phospholipids in patients with type 2 diabetes and atherosclerotic cardiovascular disease: links with metabolic control, vascular inflammation and platelet activation

BackgroundLittle is known about the mechanisms underlying the association of the serum phospholipid lipophilic index (LI) with atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes (T2D). Therefore, we investigated whether the LI is associated with glucometabolic control, meta-inflammation, thrombin generation, fibrin clot properties, endothelial function and platelet activation in T2D patients with angiographically documented ASCVD.MethodsWe studied 74 T2D patients with ASCVD, aged 65.6 ± 6.8 years, with a median diabetes duration of 10 years and median HbA1c of 7.0%. Serum phospholipid fatty acids (FAs) were measured by gas chromatography. The serum phospholipid LI was calculated as the sum of the products of the proportion (% of total FAs) with the melting points (°C) of each individual FA, divided by the sum of the proportions of all FAs. Levels of HbA1c, insulin, leptin, adiponectin, lipid profiles, inflammatory markers (hsCRP, interleukin-6, TNF-α), Lp-PLA2 (a biomarker of vascular inflammation), endothelial function (sICAM-1, sVCAM-1, FMD, NMD), thrombin generation, fibrin clot properties and platelet activation, measured by light transmission aggregometry with arachidonic acid [AA] and adenosine diphosphate [ADP], were assessed.ResultsPatients with LI > 16.9 °C (median) had higher HbA1c concentrations by 5.9% compared to the remaining subjects (p = 0.035). In this group, HbA1c levels ≥ 7.0% were found more often than in individuals with LI ≤ 16.9 °C (62.2 vs. 35.1%; p = 0.020). Subjects with LI > 16.9 °C had higher levels of TCh by 17.1% (p = 0.012), LDL-Ch by 29.4% (p = 0.003), interleukin-6 by 22.2% (p = 0.031) and Lp-PLA2 by 32.4% (p = 0.040), compared to the remaining patients. Moreover, they had increased maximal platelet aggregation induced by AA (p = 0.045), but not by ADP. Serum phospholipid LI correlated with HbA1c (r = 0.24; p = 0.037), TCh (r = 0.36; p = 0.002), LDL-Ch (r = 0.38; p < 0.001), interleukin-6 (r = 0.27; p = 0.020) and Lp-PLA2 (r = 0.26; p = 0.026). There were no intergroup differences in endothelial function, thrombin generation and fibrin clot properties. Regression analysis showed that HbA1c ≥ 7.0% and serum levels of LDL-Ch, interleukin-6 and Lp-PLA2 were predictors of LI > 16.9 °C in adjusted models.ConclusionsIn well-controlled T2D patients with ASCVD, the higher serum phospholipid LI is associated with worse glucometabolic control, enhanced vascular inflammation and higher platelet reactivity during aspirin treatment at cyclooxygenase-1-selective doses.

Presepsin Levels in Infection-Free Subjects with Diabetes Mellitus: An Exploratory Study.

Systemic inflammation has been recognized as the cause and consequence of metabolic dysregulation in diabetes mellitus (DM). Presepsin has recently emerged as a promising biomarker for the detection of bacterial infections and sepsis. There is evidence that gut dysbiosis results in the increased circulating concentrations of Gram-negative bacteria lipopolysaccharide, the linkage of presepsin, which in turn promotes insulin resistance and correlates with the risk of diabetic complications. Thus, we hypothesized that presepsin could reflect the magnitude of systemic inflammation and metabolic decompensation in patients with DM even in the absence of infection. In this cross-sectional pilot study, we included 75 infection-free individuals with well-controlled (n = 19) and uncontrolled (n = 23) type 2 diabetes (T2D), well-controlled (n = 10) and uncontrolled (n = 10) type 1 diabetes (T1D), and normoglycemic controls (n = 13). Presepsin levels were compared between the groups and potential associations with demographic, clinical, and laboratory parameters were explored. We observed that the duration of DM was associated with presepsin values (p = 0.008). When the participants were classified into the type of DM groups, the presepsin levels were found to be lower in the patients with T2D compared to those with T1D (p = 0.008). However, significance in that case was driven by the difference between the well-controlled groups. After adjusting for the effects of DM duration, presepsin was significantly lower in the well-controlled T2D group compared to the well-controlled T1D group [1.34 (2.02) vs. 2.22 (4.20) ng/mL, p = 0.01]. Furthermore, we adjusted our findings for various confounders, including age, body mass index, and waist circumference, and found that the difference in the presepsin values between the adequately controlled groups remained significant (p = 0.048). In conclusion, our findings suggest that presepsin could potentially serve as a surrogate marker of inflammation and metabolic control in people with DM.

Blood clot properties, thrombin generation, and platelet activation in patients with dysglycemia and established atherosclerotic cardiovascular disease: The CASCARA study.

There is a strong link between coronary artery disease (CAD), type 2 diabetes (T2D) on one hand, and altered fibrin clot properties, including increased clot density, and unfavorable fibrin clot structure on the other. T2D-related changes in fibrin clots can increase cardiovascular (CV) disease risk, including future CV events. We aimed to assess fibrin clot properties, thrombin generation, and platelet activation in CAD patients with prediabetes (PD) or T2D, compared to CAD patients without glycemic disorders. We allocated patients to three groups: 1) Those with angiographically established CAD but without glycemic abnormalities (CAD group); 2) individuals with PD and established CAD (CAD+PD group); and 3) patients with T2D and CAD (CAD+T2D group). We conducted comparisons across these groups for thrombin generation, fibrin clot permeability, fibrin clot lysis, and platelet activation. The final analysis included 116 eligible patients: 1) CAD group (n = 31); 2) CAD+PD (n = 42); and 3) CAD+T2D (n = 43). The CAD+T2D patients enrolled had well-controlled T2D (median HbA1c level of 5.90%; IQR: 5.7%-6.3%). We found no significant differences in thrombin generation, fibrin clot properties, or platelet activation markers across the three analyzed groups (all P-values >0.20). However, elevated interleukin-6 (IL-6) levels were noted in both the highest and lowest glucose concentration quartiles. Additionally, a substantial increase in endogenous thrombin potential (ETP) was observed in patients in the highest glycated hemoglobin quintile. Individuals with established CAD and concomitant PD or well-controlled T2D exhibited comparable fibrin clot phenotypes, thrombin generation potential, and platelet activation when compared to CAD patients without dysglycemia.

The Relationship between the Incidence of Atrial Fibrillation and Patients with Type 2 Diabetes Mellitus: A Systematic Review

Objectives: To investigate the prevalence and mechanisms of atrial fibrillation (AF) among type 2 diabetes (T2D) patients. Methods: We conducted a thorough search of PubMed, SCOPUS, Web of Science, Google Scholar, and Science Direct to find pertinent literature. Rayyan QRCI was utilized during the entire process. Results: We included twelve studies with a total of 587,822 T2D patients and 299,957 (51%) were females. The prevalence of AF among T2D patients ranged from 0.2% to 41.63% with a total prevalence of 44936 (7.6%). The reported risk factors for developing AF among T2D patients were impaired glucose tolerance (IGT), men, obesity, elderly patients, those with lower socioeconomic backgrounds, those who currently smoked, people with reduced renal function, long-term BP fluctuation, and microvascular illness. Conclusion: Although the exact relationship between T2D and AF is still unclear, there is a significant correlation. Certain glycemic control studies indicate that therapeutic HbA1c levels in conjunction with well-controlled T2D do not significantly reduce the risk of new-onset AF in T2D patients. Further investigation is needed to fully comprehend the connection between T2D and AF. In the interim, healthcare professionals can treat people with T2D, AF, or possibly both illnesses at the same time according to accepted guidelines.

Relationships of apolipoprotein E genotypes with a cluster of seven in persons with type 2 diabetes.

The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) for each member of the cluster of seven associated with type 2 diabetes (T2D). The cluster of seven includes abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDL-C) and increased plasma levels of triglycerides)), increased low-density lipoprotein (LDL) oxidation, and increased inflammation. Forty-six patients with well-controlled T2D participated in the study. Abdominal obesity (assessed by waist circumference), hypertension (measured by manual sphygmomanometry), platelet hyperaggregability (measured by bleeding time), hyperglycemia (by enzymatic kit and spectrophotometry), decreased plasma levels of HDL-C and increased plasma levels of triglycerides (by enzymatic kit and spectrophotometry), increased LDL oxidation (measured by LDL conjugated dienes using spectrophotometry) and increased inflammation measured by C-reactive protein (CRP) (by EIA kit) were determined. All genotypes, except 2/2 were found in the population studied. Abdominal obesity did not vary significantly across the five genotypes. However, glucose levels trended progressively higher going from 2/3 to 2/4 to 3/4 to 4/4. Systolic blood pressure was higher in 3/4 compared to 2/4 and trended higher in 3/4 compared to 3/3. Diastolic blood pressure trended higher in 3/3 vs 2/4 and significantly higher in 3/4 compared to 2/4. Triglycerides trended higher in 3/4 vs 3/3 while HDL-C came close to trending downward in 4/4 compared to 2/4. Bleeding time was unaffected by genotype. Plasma LDL conjugated dienes trended higher in 3/4 vs 2/4 and were significantly higher in 3/4 vs 3/3. CRP trended higher in 4/4 vs 2/3. We can conclude that those with at least one 4 allele in the presence of another allele being 2, 3 or 4 is potentially (in the case of trends) deleterious or is deleterious in terms of hyperglycemia, hypertension (systolic and diastolic blood pressure), dyslipidemia, LDL conjugated dienes and CRP levels.

The Impact of COVID-19 Lockdown on Patients with Type 2 Diabetes Mellitus: A Brief Report.

The Italian population's habits changed dramatically during the "COVID- 19 lockdown" due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. v Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed frombaseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

222-OR: Metformin Reduces Fasting Glycemia in Well-Controlled Type 2 Diabetes by Promoting Aerobic Glycolysis Independent of Decreasing Endogenous Glucose Production

It is well established that metformin improves glycemic control in individuals with poorly-controlled type 2 diabetes (T2D) by reducing rates of endogenous glucose production (EGP) mediated by inhibition of hepatic gluconeogenesis. However, the mechanism by which metformin reduces blood glucose levels in well-controlled individuals with T2D is still unknown. To address this question, we examined rates of EGP, lactate turnover and hepatic triglyceride (TAG), ATP and glycogen content in near-normoglycemic individuals with T2D (n=10, HbA1c 7±1%) with (M+; 1000 mg bid x 2 wks) and without (M-; 2 wks) metformin treatment using the PINTA method with [2H7]glucose and [3-13C]lactate tracer infusions in combination with 1H- /31P- /13C- magnetic resonance spectroscopy. Metformin treatment did not affect rates of EGP, but reduced fasting plasma glucose concentrations by 30% (p&amp;lt;0.01 vs. M-), which could be attributed to increased rates of glucose clearance (+18%, p&amp;lt;0.005 vs. M-) resulting in increased lactate production (+14%, p&amp;lt;0.01 vs. M-). These changes were associated with decreased hepatic ATP content (-20%, p&amp;lt;0.05 vs. M-), increased hepatic glycogen content (+40%, p&amp;lt;0.05 vs. M-) and no changes in hepatic TAG content. Conclusion: In contrast to the glucose-lowering effect of metformin in poorly-controlled T2D, which is due to reductions in gluconeogenesis, this study demonstrates that in well-controlled T2D metformin reduces fasting glycemia - independent of reductions in EGP - primarily by increasing rates of aerobic glycolysis as reflected by increased peripheral glucose clearance and lactate production as well as reduced hepatic ATP content, which is consistent with metformin-induced inhibition of mitochondrial electron transport chain activity. Disclosure T.Sarabhai: None. T.E.Lamoia: None. S.Friesl: None. M.Jonuscheit: None. K.Petersen: Advisory Panel; Novo Nordisk, Research Support; Merck Sharp &amp; Dohme Corp., Gilead Sciences, Inc. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck &amp; Co., Inc., Janssen Research &amp; Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi.

Well-controlled versus poorly controlled diabetes in patients with obesity: differences in MRI-evaluated pancreatic fat content.

Patients with obesity and poorly controlled type 2 diabetes (T2D) are at high risk of diabetic complications. This study aimed to determine the associations of visceral adipose tissue (VAT), hepatic proton-density fat fraction (PDFF), and pancreatic PDFF with poor glycemic control in patients with obesity and T2D and to evaluate the metabolic effect of bariatric surgery in patients with obesity and poorly controlled diabetes. In this retrospective cross-sectional study, from July 2019 to March 2021, 151 consecutive obese patients with new-onset T2D (n=28), well-controlled T2D (n=17), poorly controlled T2D (n=32), prediabetes (n=20), or normal glucose tolerance (NGT; n=54) were included. A total of 18 patients with poorly controlled T2D were evaluated before and 12 months after bariatric surgery, and 18 non-obese healthy individuals served as controls. VAT, hepatic PDFF, and pancreatic PDFF were quantified by magnetic resonance imaging (MRI) using a chemical shift-encoded sequence [iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ)]. Univariate analysis and multivariate regression analysis were performed. There were significant differences in VAT, hepatic PDFF, and all pancreatic PDFF between the new-onset T2D, prediabetes, and NGT groups (all P<0.05). Pancreatic tail PDFF was significantly higher in the poorly controlled T2D group than in the well-controlled T2D group (P=0.001). In the multivariate analysis, only pancreatic tail PDFF was significantly associated with increased odds of poor glycemic control [odds ratio (OR) =2.09; 95% confidence interval (CI): 1.11-3.94; P=0.022]. The glycated hemoglobin (HbA1c), hepatic PDFF, and pancreatic PDFF significantly decreased (all P<0.01) after bariatric surgery, and the values were statistically similar to those observed in the non-obese healthy controls. Increased fat in the pancreatic tail is strongly associated with poor glycemic control in patients with obesity and T2D. Bariatric surgery is an effective therapy for poorly controlled diabetes and obesity, which improves glycemic control and decreases ectopic fat deposits.

β-Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control.

Type 2 diabetes (T2D) is characterized by a progressive deterioration of β-cell function with a continuous decline in insulin secretion. Glucokinase (GCK) facilitates the rate-limiting step of glycolysis in pancreatic β-cells, to acquire the proper glucose-stimulated insulin secretion. Multiple glucokinase activators (GKAs) have been developed and clinically tested. However, the dynamic change of human pancreatic GCK expression during T2D progression has not been investigated. We evaluated GCK expression by measuring the average immunoreactivity of GCK in insulin+ or glucagon+ cells from pancreatic sections of 11 nondiabetic subjects (ND), 10 subjects with impaired fasting glucose (IFG), 9 with well-controlled T2D (wT2D), and 5 individuals with poorly controlled T2D (uT2D). We also assessed the relationship between GCK expression and adaptive unfolded protein response (UPR) in human diabetic β-cells. We did not detect changes of GCK expression in IFG islets. However, we found β-cell GCK levels were significantly increased in T2D with adequate glucose control (wT2D) but not in T2D with poor glucose control (uT2D). Furthermore, there was a strong positive correlation between GCK expression and adaptive UPR (spliced X-box binding protein 1 [XBP1s] and activating transcription factor 4 [ATF4]), as well as functional maturity marker (urocortin-3 [UCN3]) in human diabetic β-cells. Our study demonstrates that inductions of GCK enhanced adaptive UPR and UCN3 in human β-cells, which might be an adaptive mechanism during T2D progression. This finding provides a rationale for exploring novel molecules that activate β-cell GCK and thereby improve pharmacological treatment of T2D.

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to non-diabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

The ‘early’ postprandial glucagon response is related to the rate of gastric emptying in type 2 diabetes

Gastric emptying (GE) is a major determinant of the postprandial glycemic and insulinemic responses in health and type 2 diabetes (T2D). However, the effect of GE on the postprandial glucagon response, which is characteristically augmented in T2D, is unknown. This study examined the relationship between plasma glucagon and GE of a standardized mixed meal in individuals with well-controlled T2D. 89 individuals with T2D (HbA1c 6.6 ± 0.1%) consumed a mashed potato meal labeled with 100 µL 13C-octanoic acid between 0 and 5 min. Venous blood was sampled frequently over 4 h for measurements of blood glucose and plasma glucagon. The gastric half-emptying time (T50) was calculated by quantification of 13C in the breath. Blood glucose peaked at t = 90 min after the meal. Plasma glucagon increased to a peak at t = 30 min and then decreased to a nadir at t = 180 min. The T50 was 68.3 ± 1.6 min. The incremental area under the plasma glucagon curve between t = 0–30 min (glucagon iAUC0–30 min) was related inversely to the T50 (r = −0.23, P = 0.029), while the increase in blood glucose at t = 30 min was related directly to the plasma glucagon iAUC0–30 min (r = 0.25, P = 0.018). Accordingly, individuals with relatively faster GE exhibited higher postprandial glucagon and glucose levels (ANOVA: P<0.01 for each). In well-controlled T2D, the early postprandial glucagon response to a mixed meal is related to the rate of GE, and predictive of the initial glycemic response. These observations suggest that a reduction in plasma glucagon may contribute to the effect of dietary and pharmacological strategies which reduce postprandial glycemia in T2D by slowing GE.

Abstract A069: The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics

Abstract Although the association between type 2 diabetes (T2D) and breast cancer is well established, the relationship between glycemic control and breast cancer by hormone receptor subtype is poorly understood. We sought to investigate the relationship between glycemic control and the incidence of triple negative breast cancer (TNBC) among patients with T2D. Furthermore, we hoped to elucidate whether this hypothesized risk was further moderated by demographic factors, such as patient race. METHODS: A retrospective cohort study evaluating 1,679 patients with T2D diagnosed with breast cancer between 2010-2020 was conducted. Data including tumor hormone receptor status, Hgb A1c measured within 3 months of cancer diagnosis date, and patient race were ascertained via chart review. Tumor subtype was categorized as either hormone receptor-positive (ER+, PR+ or both) or triple-negative (ER/PR- and HER2/neu-). Based on Hgb A1c measurements, subjects were assigned to one of three categories of glycemic control: well-controlled (Hgb A1c less than 7.0), moderately controlled (Hgb A1c 7.0-9.4), or poorly controlled (Hgb A1c greater than or equal to 9.5) T2D. RESULTS: Accounting for all study subjects, the incidence of TNBC increased with worsening glycemic control (12.7% vs 15.2% vs 21.8%, P=0.040). Among non-Hispanic White patients, a significant increase in the incidence of TNBC with worsening glycemic control was also observed (9.2% vs 13.2% vs 21.9%, P=.010). Among Black patients, the incidence of TNBC did not significantly change across the three levels of glycemic control (17.6% vs 17.6% vs 22.7%, P=.700). Comparing the incidence rates of breast cancer by subtype between non-Hispanic White and Black patients across the three categories of glycemic control, a significant difference was only observed among patients with well-controlled T2D (17.6% of Black patients with TNBC versus 9.2% of non-Hispanic White patients, P&amp;lt;.001; 87.4% of non-Hispanic White patients with hormone receptor positive breast cancer versus 75.6% of Black patients, P&amp;lt;.001). CONCLUSION: Poor glycemic control is associated with a higher incidence of TNBC in patients with T2D overall. A significant increase in the incidence of TNBC with lesser degrees of glycemic control was only observed in the population of non-Hispanic white patients. Although previous studies have shown that Black patients are 2-3 times more likely to develop TNBC than their non-Hispanic White counterparts, a statistically significant racial difference in the rates of breast cancer by subtype was only noted among those with well-controlled T2D. Together our data not only suggests that T2D may serve as a modifiable risk factor for the development of TNBC, but also that the risk conferred by poor glycemic control may bear more significance for non-Hispanic White patients than Black patients. Citation Format: Madison E. Miller, Myah Bell, Priscella Holland, Vanessa Ibrahim, Gordon Jacobsen, Monique Swain. The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A069.

Erythrocyte osmotic fragility is not linked to vitamin C nutriture in adults with well-controlled type 2 diabetes.

Erythrocyte fragility is amplified by oxidative stress and linked to diabetes-specific microvascular disease. Vitamin C supplementation improves glycemic indices in adults with type 2 diabetes (T2D) by improving antioxidant status. This cross-sectional study examined the relationships between vitamin C status and erythrocyte osmotic fragility in adults with or without T2D. Participants provided a fasting blood sample for erythrocyte osmotic fragility testing as a function of hypotonic NaCl concentrations. Additionally, plasma was stabilized with metaphosphoric acid prior to vitamin C analysis using isocratic reverse-phase UV-HPLC separation. Participants were grouped as diagnosed T2D (n = 14; 36% female; 55.5 ± 8.2 y; 31.5 ± 9.0 kg/m2; HbA1c: 7.4 ± 1.9%; plasma vitamin C: 36.0 ± 12.2 μM) or no diabetes (n = 16; 69% female; 38.7 ± 13.5 y; 26.8 ± 6.6 kg/m2; HbA1c: 5.4 ± 0.3%; plasma vitamin C: 34.8 ± 10.9 μM). Participant characteristics differed between groups only for age and hemoglobin A1c (HbA1c; p < 0.05). All hemolysis parameters were in normal ranges for the participants with T2D, and no significant differences in hemolysis parameters were noted between those with or without T2D. However, among participants with T2D, the NaCl concentration eliciting 50% hemolysis was higher for those with low (<7%) vs. high (>7%) HbA1c values (p = 0.037) indicating a slightly higher erythrocyte fragility in the former group. Vitamin C status did not impact any of the hemolysis parameters in adults with or without T2D. Thus, erythrocyte fragility was not elevated in T2D, and vitamin C nutriture was not related to erythrocyte fragility in adults with well-controlled T2D.

A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes

Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40–75years, BMI of 25–38 kg/m², relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m²/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (ΔRd:13.2 ± 1.8 vs. 9.6 ± 1.8 µmol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.

Periodontal Clinicoradiographic Status and Whole Saliva Soluble Urokinase Plasminogen Activation Receptor and Tumor Necrosis Factor Alpha Levels in Type-2 Diabetic and Non-diabetic Individuals.

The authors hypothesise that whole saliva soluble-urokinase-type plasminogen-activator receptor (suPAR) and tumor necrosis factor-alpha (TNF-α) levels are higher in patients with poorly-controlled than well-controlled type-2 diabetes mellitus (DM) and non-diabetic controls. The aim was to assess the periodontal clinicoradiographic status and whole-salivary suPAR and TNF-α levels in type-2 diabetic and non-diabetic individuals. Patients with and without type-2 DM were included. In all patients, hemoglobin A1c (HbA1c) levels were measured. Participants were divided into 4 groups. Group 1: patients with poorly controlled type-2 DM; group 2: patients with well-controlled type-2 DM; group 3: non-diabetic patients with periodontitis; group 4: non-diabetic patients without periodontitis. Clinicoradiographic periodontal parameters (plaque index [PI], gingival index [GI], clinical attachment loss [AL], probing depth [PD] and mesial and distal marginal bone loss [MBL]) were measured. The whole saliva total protein concentration (TPC) and suPAR as well as TNF-α levels were measured. The level of statistical significance was set at p < 0.01. One hundred patients (25 patients per group) were included. Scores of PI (p < 0.01), GI (p < 0.01), clinical AL (p < 0.01), PD (p < 0.01), number of missing teeth and mesial (p < 0.01) and distal (p < 0.01) MBL were statistically significantly higher in group 1 than in groups 2-4. Scores of PI, GI, clinical AL, PD, mesial and distal MBL, and numbers of missing teeth were higher in group 3 (p < 0.01) than in groups 2 and 4. The whole saliva TPC, suPAR and TNF-α levels were statistically significantly higher among patients in group 1 (p < 0.01) than in groups 2-4. Patients with poorly-controlled type-2 DM presented with poorer clinicoradiographic periodontal status and increased whole saliva levels of suPAR, TNF-α and TPC compared with patients with well-controlled type-2 DM and non-diabetic individuals.

Platelet adhesion in type 2 diabetes: impact of plasma albumin and mean platelet volume

BackgroundAltered mean platelet volume (MPV) and plasma albumin has been reported in type 2 diabetes (T2D). MPV is suggested to predict cardiovascular risk but there is a lack of evidence for associations between MPV and platelet adhesion. Plasma albumin and magnesium are other factors reported to influence thrombotic risk. The objectives of this study were to assess the association between platelet adhesion and plasma factors with a potential role to affect platelet activation.MethodsBlood was collected from 60 T2D patients and 60 healthy controls. Platelet adhesion to different protein surfaces induced by various soluble activators were measured in microplates. MPV, albumin and magnesium were analysed together with additional routine tests.ResultsDespite normal levels, plasma albumin significantly correlated with adhesion of T2D platelets but not with controls. There was a significant association between MPV and platelet adhesion in both groups, but association was smaller in T2D. Levels of glucose, HbA1c or magnesium did not correlate with platelet adhesion.ConclusionsPlasma albumin was associated with platelet adhesion in T2D suggesting that albumin may be a factor to consider upon cardiovascular risk assessment. MPV was more associated with the level of platelet adhesion in healthy individuals than in well-controlled T2D patients.

Therapeutic Efficiency of Lowering Branched-Chain Amino Acid Levels in Patients with Type 2 Diabetes Using Sodium-Phenylbutyrate: &lt;i&gt;A Randomized Placebo Controlled Clinical Intervention Study&lt;/i&gt;

Background: Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models have suggested that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. In the present study, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as a tool to lower plasma BCAA levels in patients with T2D, and to evaluate its effect on patients’ metabolic health. Methods: This trial had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Netherlands. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C<8.5%) and treated with oral glucose-lowering medication. Participants were randomly assigned to receive either the NaPB 4.8g/m²/day or placebo three times a day for two weeks, separated by a washout period of six to eight weeks. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, whole-body substrate oxidation, ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA and their intermediates. The trial is registered with Netherlands Trial Register, NTR 7426. Findings: Between February 2019 and February 2020, sixteen patients were included. NaPB effectively led to a robust improvement in peripheral insulin sensitivity (ΔRd:13.2±1.8 vs. 9.6±1.8 µmol/kg/min, p=0.0155), carbohydrate-driven muscle mitochondrial oxidative capacity (O2-flux:74.0±4.1 vs. 67.1±4.3 pmol/(s*mg), p=0.0417), whole-body insulin-stimulated carbohydrate oxidation (10.9±0.6 vs. 9.6±0.7 µmol/kg/min, p=0.0246), and reduced plasma BCAA (549.2±4.5 vs. 598.4±5.0 µmol/L, p=0.0125) and oxidation-derived metabolites (KIV:13.4±0.1 vs. 15.2±0.1 µmol/L, p=0.0154; 3-HIB:36.94±0.7 vs. 43.5±0.6 µmol/L, p=0.0194:). No adverse events were reported. Interpretation: In patients with T2D, NaPB treatment significantly improved peripheral insulin sensitivity and glucose oxidation. These data establish the proof-of-concept in humans that targeting the BCAA pathway may represent a potential new treatment strategy for patients with T2D. Trial Registration: The trial has been registered with number NTR 7426, direct link to the trial: https://www.trialregister.nl/trial/7227. Funding: Dutch Diabetes Foundation Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: The study was conducted at the Maastricht University Medical Center (MUMC+), the Netherlands. The protocol was reviewed and approved by the Medical Review Ethics Committee of Maastricht University and Medical Centre.

Global survey investigating causes of treatment inertia in type 2 diabetes cardiorenal risk management.

To explore reasons behind treatment inertia in current approaches to early cardiorenal risk management in type 2 diabetes (T2D). A global, web-based, quantitative panel survey of primary care physicians (PCPs) and primary care diabetes specialists treating people living with T2D. The questions covered current management of T2D, particularly the use of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors as second-/third-line therapies. Of 1677 respondents from 18 countries who completed the survey, 73.4% were responsible for second-/third-line therapy initiation. Two thirds had modified treatment decisions based on recent cardiovascular outcomes trials (CVOTs). Respondents cited restricted access to therapies and limits on regular appointments as the greatest barriers to second-/third-line therapy prescription. Although 81.6% agreed that early intensification to second-/third-line therapies is associated with clinical benefits, 46.1% of respondents still reserve these for later lines of therapy, and 23.8% would not consider changing therapeutic approach in patients with well-controlled T2D but increasing cardiovascular risk. Substantial barriers still prevent optimization of primary setting T2D patient care. Education programs which enable PCPs to translate CVOT evidence into clinical benefits for patients with T2D could address many of the remaining knowledge gaps identified.

Diabetic retinopathy in well-controlled type 2 diabetes: Role of glycaemic memory

AimsAs diabetic retinopathy (DR) can occur even in well-controlled patients with type 2 diabetes (T2D), our study sought to determine whether it might be related to ‘glucose memory’ by evaluating patients’ HbA1c over previous years and their skin autofluorescence (SAF). MethodsIn 334 patients with T2D and HbA1c levels≤8%, their available values of HbA1c from previous years were collected, and their SAF measured by an advanced glycation end-product (AGE) reader. Binary logistic regression analysis was then used to correlate DR with previously recorded HbA1c levels and to SAF, with adjustment for DR risk factors [age, gender, BMI, duration of diabetes, arterial hypertension, diabetic kidney disease (DKD), blood lipid levels and statin treatment]. ResultsOur patients were mostly men (58.4%) aged 63±10years, with a duration of diabetes of 13±10years and HbA1c=7.1±0.7%. Of these patients, 84 (25.1%) had DR, which was associated with longer duration of diabetes and greater prevalence of DKD. A total of 605 HbA1c values from previous years were collected for time periods −4±3 months (n=255), −16±4months (n=152), −30±4months (n=93) and −62±26 months (n=105). After adjustment, the association between DR and having an HbA1c higher than the median was significant only for the oldest previous HbA1c values: OR=6.75, 95% CI: 1.90–23.90. Moreover, SAF values were higher in those with DR [2.95±0.67 arbitrary units (AU)] vs 2.65±0.65 AU with no DR (P<0.01) and were also associated with the oldest previous HbA1c values (P<0.01). ConclusionOur study found that 25.1% of our well-controlled T2D patients had DR, which was related to both their HbA1c levels from 5years prior to study admission and their SAF values, a marker of glucose memory.