Intensive Glucose-lowering Therapy Research Articles

Longitudinal Trajectories of Biomarkers of Kidney Tubular Function in Type 1 Diabetes

Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage. We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia. At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m2 and 90% of participants had a urinary albumin excretion rate (AER)<30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF:-13.5% (-16.7 to-10.1), EGF-MCP1 ratio:-26.9% (-32.2 to-21.3), and tubular secretion score-0.9% (-1.8 to 0.0), versus-12.0% (CI:-12.9 to-11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]). Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.

Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial.

Non-surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short-term intensive glucose-lowering therapy. In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time-to-event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40-0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14-3.24) and 1.83 (1.03-3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00-3.53) at 48 weeks and 2.05 (0.98-4.29) at 64 weeks. A 12-week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.

Protective effect of intensive glucose lowering therapy on all-cause mortality, adjusted for treatment switching using G-estimation method, the ACCORD trial

Previous analysis of the action to control cardiovascular risk in diabetes showed an increased risk of mortality among patients receiving intensive glucose lowering therapy using conventional regression method with intention to treat approach. This method is biased when time-varying confounder is affected by the previous treatment. We used 15 follow-up visits of ACCORD trial to compare the effect of time-varying intensive vs. standard treatment of glucose lowering drugs on cardiovascular and mortality outcomes in diabetic patients. The treatment effect was estimated using G-estimation and compared with accelerated failure time model using two modeling strategies. The first model adjusted for baseline confounders and the second adjusted for both baseline and time-varying confounders. While the hazard ratio of all-cause mortality for intensive compared to standard therapy in AFT model adjusted for baseline confounders was 1.17 (95% CI 1.01–1.36), the result of time-dependent AFT model was compatible with both protective and risk effects. However, the hazard ratio estimated by G-estimation was 0.64 (95% CI 0.39–0.92). The results of this study revealed a protective effect of intensive therapy on all-cause mortality compared with standard therapy in ACCORD trial.

Risk Stratification of Cardiovascular Disease according to Age Groups in New Prevention Guidelines: A Review.

Age is a strong risk factor for cardiovascular disease. Accordingly, most cardiovascular risk prediction models have included age as an independent risk factor. There is much evidence that effective management of cardiovascular risk factors improves clinical outcomes even in older adults. However, there are concerns that intensive treatment for older adults increases the risk of adverse events. For hypertensive patients, intensive blood pressure reduction with combination therapy increases the risk of syncope, acute kidney injury, and falls. Intensive glucose-lowering therapy among older patients with diabetes increases the risk of hypoglycemia or cognitive impairment. These findings suggest that a balanced approach for older adults is required to increase the benefits and decrease the risk of side effects. In contrast to older people, the estimated 10-year cardiovascular risk in young and healthy individuals is low. However, the lifetime cardiovascular risk in these patients is actually high. The 2021 European Society of Cardiology guideline on cardiovascular disease prevention in clinical practice has been published. It proposed a different risk stratification and recommendation for treatment according to age group, based on the concept of avoiding undertreatment in young people and overtreatment in older persons. Although the guideline recommends age-dependent risk stratification, risk categories should not be applied to the mandatory initiation of drug treatment. In all age groups, other factors such as lifetime cardiovascular risk, treatment benefit and harm, comorbidities, frailty, and patient preferences should be considered when managing patients for primary prevention.

Remission as an Emerging Therapeutic Target in Type 2 Diabetes in the Era of New Glucose-Lowering Agents: Benefits, Challenges, and Treatment Approaches.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.

Influence of fasting plasma glucose-lowering rate on BNP levels in type 2 diabetes mellitus patients with coronary microcirculation dysfunction.

The aim was to analyze the influence of fasting plasma glucose-lowering rate (FPGLR) on plasma BNP levels in type 2 diabetes mellitus (T2DM) patients with coronary microcirculation dysfunction (CMD) and to determine the optimal FPGLR for these patients. A total of 170 T2DM patients who received intensive glucose-lowering therapy during hospitalization in the First Affiliated Hospital of Harbin Medical University were enrolled. Ninety-two patients with CMD and 78 patients without CMD were assigned to a study and a control group, respectively. The study group was stratified as S1 (4.1 ~ 6.0mmol·L-1·day-1), S2 (2.1 ~ 4.0mmol·L-1·day-1), and S3 (≤ 2.0mmol·L-1·day-1) by different FPGLR, and the same in the control group (C1, C2, and C3). The plasma BNP levels with the same FPGLR were compared between the study and the control group, and patients with a different FPGLR in the study group were also compared. In the study and the control group, the BNP level in S1 was significantly higher than that in C1 (87 vs. 12pg/ml, P < 0.001), although there was no significant difference between S2 and C2, S3 and C3. In the study group, the BNP level in S1 was significantly higher than that in S2 (87 vs. 22pg/ml, P < 0.001) and S3 (87 vs. 15pg/ml, P < 0.001), but there was no significant difference between S2 and S3. Rapid intensive glucose-lowering may lead to increased plasma BNP levels in T2DM patients with CMD. Optimal FPGLR for these patients was determined to be no more than 4.0mmol·L-1·day-1.

Severe Hypoglycemia Attributable to Intensive Glucose-Lowering Therapy Among US Adults With Diabetes: Population-Based Modeling Study, 2011-2014

ObjectiveTo estimate the contemporary prevalence of intensive glucose-lowering therapy among US adults with diabetes and model the number of hypoglycemia-related emergency department (ED) visits and hospitalizations that are attributable to such intensive treatment. Patients and MethodsUS adults with diabetes and glycated hemoglobin (HbA1c) levels less than 7.0% who were included in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Participants were categorized as clinically complex if 75 years or older or with 2 or more activities of daily living limitations, end-stage renal disease, or 3 or more chronic conditions. Intensive treatment was defined as any glucose-lowering medications with HbA1c levels of 5.6% or less or 2 or more with HbA1c levels of 5.7% to 6.4%. First, we quantified the proportion of clinically complex and intensively treated individuals in the NHANES population. Then, we modeled the attributable hypoglycemia-related ED visits/hospitalizations over a 2-year period based on published data for event risk. ResultsAlmost half (48.8% [10,719,057 of 21,980,034]) of US adults with diabetes (representing 10.7 million US adults) had HbA1c levels less than 7.0%. Among them, 32.3% (3,466,713 of 10,719,057) were clinically complex, and 21.6% (2,309,556 of 10,719,057) were intensively treated, with no difference by clinical complexity. Over a 2-year period, we estimated 31,511 hospitalizations and 30,954 ED visits for hypoglycemia in this population; of these, 4774 (95% CI, 954-9714) hospitalizations and 4804 (95% CI, 862-9851) ED visits were attributable to intensive treatment. ConclusionIntensive glucose-lowering therapy, particularly among vulnerable clinically complex adults, is strongly discouraged because it may lead to hypoglycemia. However, intensive treatment was equally prevalent among US adults, irrespective of clinical complexity. Over a 2-year period, an estimated 9578 hospitalizations and ED visits for hypoglycemia could be attributed to intensive diabetes treatment, particularly among clinically complex patients. Patients at risk for hypoglycemia may benefit from treatment deintensification to reduce hypoglycemia risk and treatment burden.

SAT-294 RANDOMISED EFFECTS OF INTENSIVE GLUCOSE-LOWERING THERAPY ON THE RISK OF MAJOR CLINICAL OUTCOMES IN TYPE 2 DIABETES ACCORDING TO eGFR AND UACR LEVELS

There is ongoing uncertainty regarding the risk-benefit ratio of intensive glucose-lowering therapy in the prevention of clinically important outcomes among people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We sought to assess the effects of intensive glycaemic control on the risk of major clinical outcomes in T2DM according to level of eGFR and UACR in the ADVANCE trial.

Abstract 17059: Re-Use of Clinical Trial Data From the NHLBI Data Repository (BioLINCC) for Patient-Level Meta-Analyses of Cardiovascular Outcomes: Challenges and Opportunities

Introduction: An objective of the Meta-AnalyTical Interagency Group (MATIG) is to conduct patient-level meta-analyses of cardiovascular outcomes using data from publicly available repositories. We describe challenges with data re-use from a seminal trial, provide a systematic approach to identify and curate data elements for hypothesis generation, and establish stackable trials to support these analyses. Methods: We used data from the ACCORD trial to assess risk factors and their gender specific differences for the event of hospitalization or death due to heart failure (hdHF), in patients with type 2 diabetes*. We identified the data elements needed to answer the research questions, reviewed the trial protocol to verify definitions, extracted patient-level data, performed quality assessment and statistical analysis. The results showed a gender difference in the effect of intensive vs. standard glucose-lowering therapy on hdHF. To validate the findings, we sought additional trials in BioLINCC to develop a compendium for meta-analysis, and repeated these steps for each trial. Results: Challenges for reusing the ACCORD trial included access to complete patient-level data and metadata. The compendium, developed to evaluate the stackability** of data across trials, identified differences in trial designs, patient populations, study interventions, and data elements that may impact the feasibility and interpretation of meta-analysis. An example of compendium components is shown in Table 1. Conclusion: High-quality metadata facilitate re-use of trial repository data. This compendium standardizes common data elements for gender, racial and age-group specific outcome assessment in major clinical trials. It provides the framework to assess the fitness of trials for patient-level meta-analyses. Efforts are underway by MATIG to expand the compendium to include risk factors and major cardiovascular outcomes across multiple large trials for meta-analysis.

Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose-lowering therapy.

Arginase is implicated in the pathogenesis behind endothelial dysfunction in type 2 diabetes mellitus (T2DM) by its inhibition of nitric oxide formation. Strict glycaemic control is not sufficient to improve endothelial function or cardiovascular outcomes in patients with T2DM, thus other treatment strategies are needed. We hypothesized that arginase inhibition improves endothelial function beyond glucose-lowering therapy following glucose optimization in patients with poorly controlled T2DM. Endothelial function was evaluated in 16 patients with poorly controlled T2DM (visit 1) and 16 age-matched controls using venous occlusion plethysmography. T2DM patients were re-evaluated (visit 2) after intensive glucose-lowering regimen. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatations were evaluated before and after 120 min intra-arterial infusion of the arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA). HbA1c was reduced from 87 ± 17 (visit 1) to 65 ± 11 mmol mol-1 (visit 2, P < 0.001). Basal EDV, but not EIDV, was significantly lower in patients with T2DM than in healthy subjects (P < 0.05). EDV and EIDV were unaffected by glucose-lowering regimen in patients with T2DM. Arginase inhibition enhanced EDV in T2DM patients both at visit 1 and visit 2 (P < 0.01). There was no difference in improvement in EDV between the two occasions. EIDV was unaltered by nor-NOHA in T2DM at visit 1, but was slightly improved at visit 2. Arginase inhibition improves endothelial function in patients with poorly controlled T2DM, which is maintained following glucose optimization. Thus, arginase inhibition is a promising therapeutic target beyond glucose lowering for improving endothelial function in T2DM patients.

P2619Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose lowering therapy

P2619Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose lowering therapy

Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials

BackgroundPrevious trials indicated that intensive glucose lowering in treatment of patients with type 2 diabetes mellitus (T2DM) was associated with a higher incidence of mortality. We therefore conducted a meta-analysis to evaluate the benefits and harms of intensive glucose lowering therapy in treatment of T2DM patients on major cardiovascular outcomes. MethodsRandomized controlled trials (RCTs) were obtained from searches of PubMed, EmBase, and the Cochrane Library electronic databases until Feb. 2016. Relative risk (RR) was used to measure the treatment effect by random-effect model. Meta-regression, sensitivity analyses, subgroup analyses, and publication biases were also conducted. ResultsThirteen RCTs were included with 58,160 T2DM patients and reported 5719 major cardiovascular events (MACEs), 6569 deaths, 2057 cardiac death cases, 3201 myocardial infarction (MI) cases, 1835 stroke cases, and 1778 congestive heart failure cases. Intensive glucose lowering therapy significantly reduced risk of MACEs (RR: 0.92; 95%CI: 0.85–1.00; P=0.042), and MI (RR: 0.90; 95%CI: 0.82–0.98; P=0.020) compared with conventional glucose control therapy. Furthermore, intensive glucose lowering therapy has no significant effect on the incidence of total mortality (RR: 0.98; 95%CI: 0.91–1.07; P=0.693), cardiac death (RR: 1.00; 95%CI: 0.87–1.04; P=0.999), stroke (RR: 0.94; 95%CI: 0.84–1.06; P=0.333), and congestive heart failure (RR: 1.19; 95%CI: 0.96–1.48; P=0.108). ConclusionT2DM patients who received intensive glucose lowering therapy are associated with a reduced risk of MACEs and MI, whereas it has no significant effect on the risk of total mortality, cardiac death, stroke, and congestive heart failure. These effects might differ when stratified by baseline characteristics in T2DM patients.

Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition.

Cardiovascular (CV) disease is the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial and involves direct and indirect injury to the vasculature and heart. The impact of intensive glucose-lowering therapy with antihyperglycemic agents on CV outcomes is not clear, and questions remain as to which glucose-lowering agents may be beneficial to CV health in patients with T2DM. This review discusses findings regarding the known mechanisms of CV injury in T2DM and current knowledge regarding the potential cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. Dipeptidyl peptidase-4 inhibitors are relatively new antihyperglycemic agents. Their main mechanism of action is to inhibit the degradation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide by DPP-4. By increasing levels of glucagon-like peptide-1, glucose-dependent insulin secretion is enhanced, glucagon secretion is suppressed, and the rate of gastric emptying is decreased. Dipeptidyl peptidase-4 also degrades other substances that are important in the regulation of CV function and inflammation. Animal studies, small observational studies in humans, and analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Recent prospectively designed CV outcomes trials with saxagliptin and alogliptin in patients with T2DM and high CV risk presented evidence that these DPP-4 inhibitors neither increased nor decreased adverse CV outcomes in this select patient population. Dipeptidyl peptidase-4 inhibitors are promising therapies for the treatment of T2DM. Able to improve glycemic control without the risk of weight gain or hypoglycemia, they provide a safe alternative to sulfonylureas and are an effective adjunct to metformin. To date, this class of drugs seems to be at least neutral in terms of CV effects. Time will tell if these findings translate into a benefit for our patients.

Free fatty acid availability is closely related to myocardial lipid storage and cardiac function in hypoglycemia counterregulation.

Hypoglycemia, a major side effect of intensive glucose-lowering therapy, was recently linked to increased cardiovascular risk in patients with diabetes. Whether increased circulating free fatty acids (FFA) owing to catecholamine-induced lipolysis affect myocardial energy metabolism and thus link hypoglycemia to cardiac vulnerability is unclear. Therefore, this study investigated the impact of hypoglycemia counterregulation (± inhibition of lipolysis) on myocardial lipid content (MYCL) and left ventricular function in healthy subjects. Nine healthy men were studied in randomized order: 1) insulin/hypoglycemia test (IHT; ins+/aci-), 2) IHT during inhibition of adipose tissue lipolysis by acipimox (ins+/aci+), 3) normoglycemia with acipimox (ins-/aci+), and 4) normoglycemia with placebo (ins-/aci-). MYCL and cardiac function were assessed by employing magnetic resonance spectroscopy/imaging at baseline and at 2 and 6 h. In response to acute hypoglycemia, plasma FFA (P<0.0001) and ejection fraction (EF; from 63.2±5.5 to 69.6±6.3%, P=0.0001) increased significantly and were tightly correlated with each other (r=0.68, P=0.0002); this response was completely blunted by inhibition of adipose tissue lipolysis. In the presence of normoglycemia, inhibition of lipolysis was associated with a drop in EF (from 59.2±5.5 to 53.9±6.9%,P=0.005) and a significant decrease in plasma FFA, triglycerides, and MYCL (by 48.5%, P=0.0001). The present data indicate that an intact interorgan cross-talk between adipose tissue and the heart is a prerequisite for catecholamine-mediated myocardial contractility and preservation of myocardial lipid stores in response to acute hypoglycemia.

Hypoglycemia and cardiovascular risk

Intensive glycemic control and aggressive glycated hemoglobin targets <7.0% have failed to show an improvement in cardiovascular mortality. Repetitive and severe hypoglycemic episodes with intensive glucose-lowering therapy may be a major factor in the failure to show cardiovascular benefit in diabetic patients. In this article, the cardiovascular effects of hypoglycemia, and the trials with an intensive glucose-lowering strategy that have studied microvascular and macrovascular complications are discussed. The current non-insulin drugs, which do not induce hypoglycemia, available for the treatment of diabetes and their cardiovascular impacts are clarified.

Glycemic variability and oxidative stress: a link between diabetes and cardiovascular disease?

Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials. HbA1c reflects average glucose level rather than glycemic variability. In in vivo and in vitro studies, glycemic variability has been shown to be associated with greater reactive oxygen species production and vascular damage, compared to chronic hyperglycemia. These findings suggest that management of glycemic variability may reduce cardiovascular disease in patients with diabetes; however, clinical studies have shown conflicting results. This review summarizes the current knowledge on glycemic variability and oxidative stress, and discusses the clinical implications.

Glycated hemoglobin variability and retinopathy progression in type1 diabetes: Is month-to-moth instability a better predictor?

Glucose instability has been proposed to be one of the risk factors for diabetic complications, in particular retinopathy, since the publication of the Diabetes Control and Complication Trial (DCCT) 20 years ago. In that study, as compared with conventional therapy, intensive therapy effectively delays the onset and slows the progression of diabetic complications in patients with type 1 diabetes1. The following analyses have found that in addition to mean glycated hemoglobin (HbA1c) level, high HbA1c variability, but not glucose variability, might be associated with increased risks of retinopathy, nephropathy and perhaps neuropathy, in type 1 diabetic patients (Table 1)2-8. Although many laboratory and clinical studies suggested that ‘short-term’ glucose fluctuation, mostly driven by high postprandial blood glucose levels, leading to increased oxidative stress and decreased endothelial function, is responsible for the higher risks of microvascular and cardiovascular outcomes in type 2 diabetic patients9, the role of ‘longer-term’ glucose stability in terms of HbA1c variability, and the occurrence and progression of diabetic complications among type 1 diabetic patients remains elusive. Retinopathy Nephropathy Retinopathy Nephropathy Retinopathy Nephropathy Neuropathy DCCT EDIC (first 4 years) Retinopathy Nephropathy ORPS NFS In a recently published study, Hietala et al.10 analyzed data from 2,019 type 1 diabetic patients who were enrolled in the Finnish Diabetic Nephropathy (FinnDiane) study. During the average follow up of 5.2 years, they have reconfirmed that high HbA1c variability was associated with an increased risk of incidence, as well as laser treatment for retinopathy. In the earlier report, they also showed that HbA1c variability was not only predictive of incident microalbuminuria and progression of renal disease, but also of incident cardiovascular events in type 1 diabetic patients7. Of note, patients with high mean HbA1c values also had high HbA1c variability. However, patients with low mean HbA1c value, but high HbA1c variability, had similar incidence for nephropathy progression as patients with high mean HbA1c value, but low HbA1c variability, suggesting an equally important effect of both absolute value and stability in the risk of progression in renal outcome. The significant association between HbA1c variability, and risks of retinopathy and nephropathy persisted even after taking the number of HbA1c measurements into consideration. Why was HbA1c instability independently associated with a higher chance of laser treatment for retinopathy? The authors emphasized that even short periods of higher HbA1c could have a sustained effect on worsening of retinopathy despite subsequent improvement in glycemic control10. However, because of the inherent limitations in the observational study design, there might be other explanations for the observed association (Figure 1). First, because there might be a lag time between worsening of visual symptoms and laser treatment, it is possible that diagnosis of retinopathy progression per se leads to attempts to improve glycemic control by physicians, and hence increasing HbA1c fluctuation (protopathic bias or reverse causation). Second, for poorly controlled patients with high and unstable HbA1c value, physicians were more likely to do fundoscopic or fundus photographic examinations, and were hence more likely to find retinopathy progression that might require laser treatment (detection bias). Third, from prior studies we knew that a variable HbA1c profile is associated with several factors, such as low socioeconomic status, physical inactivity and smoking7. Perhaps, it is these lifestyle and behavior factors (including medication non-adherence) that lead to poor outcomes. Again, we want to reassure our patients that long-term optimal glycemic control is crucial to reduce retinopathy occurrence and its complications. For healthcare professionals who are involved in the care of diabetic patients, the findings of the study by Hietala et al.10 highlight that patients with highly variable HbA1c warrant careful monitoring of retinopathy development and progression. Further research on the mechanism of the observed association and how to prevent early retinopathy worsening for those poorly controlled type 1 patients undergoing intensive glucose lowering therapy are required to fill the knowledge gap.

Abstract 368: Insulin Promotes Hypoxic Vascular Injury in Insulin Resistance

Clinical studies targeting aggressive lowering of blood glucose in type 2 diabetes (T2DM) by exogenous insulin failed to show cardiovascular protection, but paradoxically increased cardiovascular mortality. Previously, we demonstrated cerebrovascular insulin resistance (IR) and reduced mitochondria-mediated vasodilation in Zucker obese (ZO) rats with IR compared to lean (ZL) controls. Communication between endoplasmic reticula (ER) and mitochondria play a critical role in metabolic functioning and responses to hypoxia. Tethering of mitochondria to ER by mitofusin 2 (MFN2) creates Ca 2+ microdomains to aid inter-organelle communication. Overexpression of glucose regulated protein 78 kDa (GRP78), an ER chaperone and a marker of ER stress, is protective by preempting ER Ca 2+ leak. Our aim is to demonstrate the adverse impact of IR on ER-mitochondrial interactions. Levels of mitochondrial proteins (MFN2 and voltage dependent anionic channel or VDAC), ER stress marker (GRP78), and endothelial nitric oxide synthase (eNOS) were determined in cerebral arteries from ZO and ZL treated with vehicle or insulin under normoxic or hypoxia-reoxygenation (H-R) conditions. ZO arteries displayed decreased MFN2 and VDAC, elevated GRP78, and increased eNOS monomer/dimer ratio (eNOS uncoupling) at baseline. In ZL arteries, MFN2 and GRP78 proteins were increased under normoxic (1.2±0.1 and 0.97±0.27 respectively; p&lt;0.05 versus vehicle) and decreased under H-R conditions (1.43±0.4 and 0.43±0.02 respectively; p&lt;0.05 versus vehicle) by insulin. In contrast, in ZO arteries, MFN2 and GRP78 proteins were decreased under normoxic (0.69±0.1 and 0.71±0.01 respectively; p&lt;0.05 versus vehicle) and increased under H-R conditions (1.76±0.12 and 1.4±0.07 respectively; p&lt;0.05 versus vehicle) by insulin. Insulin decreased eNOS uncoupling under H-R versus normoxia in ZL, but increased it in ZO arteries. Thus, ZO arteries with IR display impaired mitochondria-ER communication at baseline which was further exacerbated by insulin under H-R leading to increased oxidative vascular injury. Our study provides a mechanistic basis for increased cardiovascular mortality following intensive glucose lowering therapy by high exogenous insulin in patients with IR and T2DM.

SIRT1, p66Shc, and Set7/9 in Vascular Hyperglycemic Memory

Diabetes represents a ramping public health issue in the Western world owing to overnutrition and reduced physical activity coupled with genetic susceptibility (1,2). Nowadays, obesity is a major determinant of insulin resistance, which results in compensatory hyperinsulinemia with subsequent impairment of insulin secretion and rise of blood glucose levels. Over the last 30 years, the detrimental effects of hyperglycemia on the vessel wall have promoted major research efforts leading to the understanding that high glucose decreases availability of endothelium-derived nitric oxide (NO) and triggers vascular inflammation via an array of mechanisms involving the overproduction of reactive oxygen species (ROS) (3,4). Although the identification of different signaling pathways has opened several windows of opportunity to prevent diabetic vascular disease, we are still far from having found a thorough and, most of all, effective approach against cardiovascular burden of diabetes. Indeed, recent clinical trials have shown that normalization of blood glucose failed to reduce cardiovascular outcomes in the diabetic population (5–7). It is noteworthy that intensive glucose-lowering therapy in these trials was started after a median duration of diabetes ranging from 8 to 11 years (8). By contrast, glucose-lowering treatment of patients with new-onset diabetes was shown to be beneficial (9–12). These findings hint that early preservation of physiological metabolic environment is crucial for interfering with the natural history of diabetic vasculopathy. In this Perspective, the landmark Diabetes Control and Complications Trial (DCCT) and the follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC), demonstrated not only that intensive glycemic control in subjects with type 1 diabetes reduced the risk of microvascular complications but also that episodes of poor glycemic control can lead many years later to the long-term complications of diabetes (9,12). More recently, the 10-year posttrial monitoring follow-up of the …

Targeting risk factors: a feasible way for prevention of vascular complications in type 2 diabetes mellitus

The article addresses challenges in the prevention of microvascular complications in type 2 diabetes mellitus (T2DM) and discusses necessity of multifactorial approach to management of these conditions. We present results of a large-scale ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial that elucidates the combined influence of antihypertensive and of intensive glucose-lowering therapy on the risk of development of micro- and macrovascular complications of T2DM