Optimizing treatment goals for long-term health outcomes among patients with type 2 diabetes mellitus

IntroductionConsiderable confusions on treatment target have resulted from recent changes in guidelines. Evidence in medical guidelines came from clinical trials with highly selected patients, whereas treatment goals may differ in some subgroups. This study aimed to assess optimal treatment goals (A1C, blood pressure, low-density lipoprotein cholesterol (LDL-C)) for patients with type 2 diabetes mellitus (T2DM), which lead to optimal health outcomes by different treatment strategies.Research design and methodsA retrospective longitudinal study was conducted for veterans with T2DM by using US Veterans Affairs Administrative Database (2005−2015). Medical records were prepared for repeated evaluation performed at 6-month intervals and multivariate longitudinal regression was used to estimate the risk of microvascular and macrovascular complication events. Second-degree polynomial and splines were applied to identify the optimal goals in their associations with lowest risk of clinical outcomes, controlling for demographic characteristics, medical history, and medications.ResultsA total of 124 651 patients with T2DM were selected, with mean of 6.72 follow-up years. In the general population, to achieve the lowest risk of microvascular and macrovascular complication, the optimal goals were A1C=6.81%, LDL-C=109.10 mg/dL; and A1C=6.76%, LDL-C=111.65 mg/dL, systolic blood pressure (SBP)=130.60 mmHg, respectively. The optimal goals differed between age and racial subgroups. Lower SBP for younger patients and lower LDL-C for black patients were associated with better health outcomes.ConclusionsOptimal treatment goals were identified and multi-faceted treatment strategies targeting hyperglycemia and hyperlipidemia and hypertension may improve health outcome in veterans with T2DM. In addition to guidelines’ recommended goals, health systems may examine their own large diverse patients with T2DM for better quality of care.

LncRNA LYPLAL1-DT in Type 2 Diabetes With Macrovascular Complication Contributes Protective Effects on Endothelial Cells via Regulating the miR-204-5p/SIRT1 Axis

Background: Long noncoding RNAs (lncRNAs) are involved in diabetes related diseases. However, the role of lncRNAs in the pathogenesis of type 2 diabetes with macrovascular complication (DMC) has seldomly been recognized. This study aimed to screen lncRNA profiles of leukocytes from DMC patients in order to explore the protective role of lncRNA LYPLAL1-DT in endothelial cells (EC) under high glucose (HG) and inflammatory conditions (IS).Methods: RNA sequencing was performed for critically pair-grouped blood samples of DMC patients and healthy control. Then the differentially expressed (DE) lncRNAs from circulating leukocytes were identified. Real-time PCR analyses were used to select the DE-lncRNAs within expanding cohorts. CCK8, transwell, Western blot, dual-luciferase system, and RIP were used to investigate the influence and molecular mechanisms of validated DE-lncRNAs in EC under HG and IS conditions. RNA sequencing was also used to identify DE-lncRNAs in exosomes isolated from the DMC serum and healthy control. Results: A total of 477 DE-lncRNAs were identified between DMC and healthy control. The enrichment and pathway analysis showed that most of them belonged to inflammatory, metabolic, and vascular diseases. A set of 12 of the 16 lncRNAs was validated as significant DE-lncRNAs in expanding cohorts. Furthermore, these DE-lncRNAs were shown to be significantly related to hypoxia, high glucose, and TNF-α stimulus (IS) in EC with an apparent metabolic memory of high glucose, especially novel lncRNA LYPLAL1-DT. LYPLAL1-DT overexpression results in the promotion of proliferation, migration of EC, as well as an elevation of autophagy under HG, and IS conditions. Overexpressed LYPLAL1-DT reduces the adhesion of monocytes to EC, boosts anti-inflammation, and suppresses inflammatory molecules secreted in the medium. Mechanistically, LYPLAL1-DT acts as ceRNA by downregulating miR-204-5p, therefore enhancing SIRT1 and protecting EC autophagy function; thus, alleviating apoptosis. Finally, exosome sequencing revealed LYPLAL1-DT expression was 4 times lower in DMC cells than in healthy samples. Conclusion: We identified 12 DE-lncRNAs related to DMC. Out of the 12 DE-lncRNAs lncRNA LYPLAL1-DT was identified to have protective effects on EC as ceRNA mediated through the miR-204-5p/SIRT1 pathway. Therefore, it inhibits the autophagy of EC as well as modulating systemic inflammation. This approach could be regarded as a new potential therapeutic target in DMC.

Haemoglobin A1c variability as an independent correlate of atherosclerosis and cardiovascular disease in Chinese type 2 diabetes

Objective: To examine the association between haemoglobin A1c variability and macrovascular complication in type 2 diabetes. Methods: We retrospectively enrolled 5278 diabetes patients with no history of cardiovascular disease and atherosclerosis by ultrasound at their first visit to the hospital from 1999 to 2010. Patients had a median of 4 haemoglobin A1c (range = 3–9) measurements during follow-up. Average haemoglobin A1c and haemoglobin A1c variability were calculated as intra-individual mean, standard deviation, coefficient of variation and adjusted standard deviation. Cardiovascular disease events and ultrasound results were re-evaluated from the medical history at the end of the study. Results: A total of 972 patients had macrovascular complication. Compared to those without atherosclerosis/cardiovascular disease (n = 4306), haemoglobin A1c intra-individual mean and haemoglobin A1c variability levels were significantly higher in patients with macrovascular complication ( p < 0.001). Multivariable logistic regression analysis showed that haemoglobin A1c variability was associated with macrovascular complication. Moreover, 488 patients with only atherosclerosis had significantly higher haemoglobin A1c intra-individual mean and haemoglobin A1c variability values than those without atherosclerosis/cardiovascular disease ( p < 0.001), but in 484 patients with cardiovascular disease incidents, only higher haemoglobin A1c intra-individual mean level was found ( p = 0.004). Conclusions: In Chinese type 2 diabetes, haemoglobin A1c variability was associated with macrovascular complication. Long-term stabilization of glucose is important in diabetes management, especially in the early stage of atherosclerosis.