Risk Of Microvascular Complications Research Articles

Exploring potential correlations between HLA class II and the risk of microvascular complications in Japanese patients with type 1 diabetes

Managing complications in Type 1 diabetes (T1D) remains challenging. HLA genes, particularly DR and DQ, are linked to T1D susceptibility. We studied 48 Japanese T1D inpatients and revealed associations between DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotypes and complications, offering a new perspective for future research.

Relationship Between Triglyceride-Glucose Index and Microvascular Complications in Hospitalized Patients with Type 2 Diabetes Mellitus

Aim: The increasing prevalence of diabetes mellitus (DM) brings about a rise in nephropathy, retinopathy, and neuropathy, which are microvascular complications of diabetes. The triglyceride-glucose (TyG) index is a convenient indicator of insulin resistance. It is related to microvascular and macrovascular complications among nonhospitalized patients with diabetes. However, it is unclear if the TyG index poses risks for vascular complications of type 2 DM in hospitalized patients. This study aims to investigate possible relations between this index and the risk of microvascular complications in hospitalized patients with type 2 DM. Material and Methods: The present study included 420 type 2 DM patients who were hospitalized in our clinic between February 2019 and May 2022. The TyG index was measured as fasting triglycerides mg/dL × fasting glucose mg/dL/2. The presence of microalbuminuria (MAU), diabetic neuropathy, chronic kidney disease (CKD), and retinopathy (DR) were evaluated. The data were analzed using IBM SPSS 22.0 statistical software. The level of statistical significance was taken as p

Associations Between Beverage Consumption and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes.

The relationship between the consumption of different beverages and the risk of microvascular complications in individuals with type 2 diabetes (T2D) is unclear. To investigate the association of individual beverage consumption, including artificially sweetened beverages (ASBs), sugar-sweetened beverages (SSBs), tea, coffee, natural juice, and yogurt, with the risk of microvascular complications in adults with T2D. This cohort study included 6676 participants with T2D who were free of macrovascular and microvascular complications at baseline in the UK Biobank. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 11.7 years, 1116 cases of composite microvascular complications were documented. After multivariable adjustment, a linear dose-response relationship was demonstrated between the consumption of ASBs and SSBs and the risk of microvascular complications. Compared with nonconsumers, those who consumed ≥2.0 units/day of ASBs and SSBs had an HR (95% CI) of 1.44 (1.18-1.75) and 1.32 (1.00-1.76) for composite microvascular complications, respectively. In addition, higher tea consumption was associated with a lower risk of diabetic retinopathy, with an HR (95% CI) of 0.72 (0.57-0.92) for whom consuming ≥4.0 units/day. There was no significant association between individual beverage consumption and the risk of diabetic neuropathy. No significant association was observed between the consumption of coffee, natural juice, or yogurt and the risks of microvascular complications. Moreover, substituting half units/day of ASBs or SSBs with tea or coffee was associated with a 16% to 28% lower risk of microvascular complications. Higher consumption of ASBs and SSBs was linearly associated with an increased risk of microvascular complications in adults with T2D.

Long-term exposure to ambient air pollution and risk of microvascular complications among patients with type 2 diabetes: a prospective study.

Patients with type 2 diabetes (T2D) may disproportionately suffer the adverse cardiovascular effects of air pollution, but relevant evidence on microvascular outcome is lacking. We aimed to examine the association between air pollution exposure and the risk of microvascular complications among patients with T2D. This prospective study included 17 995 participants with T2D who were free of macro- and micro-vascular complications at baseline from the UK Biobank. Annual average concentrations of particulate matter (PM) with diameters <2.5 μm (PM2.5), <10 μm (PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx) were assessed using land use regression models. Cox proportional hazards regression was used to estimate the associations of air pollution exposure with incident diabetic microvascular complications. The joint effects of the air pollutant mixture were examined using quantile-based g-computation in a survival setting. In single-pollutant models, the adjusted hazard ratios (95% confidence intervals) for composite diabetic microvascular complications per interquartile range increase in PM2.5, PM10, NO2 and NOx were 1.09 (1.04-1.14), 1.06 (1.01-1.11), 1.07 (1.02-1.12) and 1.04 (1.00-1.08), respectively. Similar significant results were found for diabetic nephropathy and diabetic neuropathy, but not for diabetic retinopathy. The associations of certain air pollutants with composite microvascular complications and diabetic nephropathy were present even at concentrations below the World Health Organization limit values. Multi-pollutant analyses demonstrated that PM2.5 contributed most to the elevated risk associated with the air pollutant mixture. In addition, we found no interactions between air pollution and metabolic risk factor control on the risk of diabetic microvascular complications. Long-term individual and joint exposure to PM2.5, PM10, NO2 and NOx, even at low levels, was associated with an increased risk of diabetic microvascular complications, with PM2.5 potentially being the main contributor.

Knowledge, attitudes and practices towards glycemic control among persons with diabetes mellitus at two tertiary hospitals in Uganda

Background: Intensive glycaemic control reduces the risk of microvascular complications in persons with diabetes mellitus(DM). Owing to limited data available, we aimed to determine the knowledge, attitude, and practices (KAPs) toward glycaemiccontrol among Ugandans with DM at two large tertiary healthcare facilities. Methods: A cross-sectional study was conducted among persons with DM attending outpatient clinics at Kiruddu NationalReferral Hospital (KNRH) and Mulago National Specialized Hospital (MNSH) between March and April 2022. Eligible participantsprovided written informed consent and were recruited through a systematic sampling technique and relevant data wascollected using a pretested, interviewer-administered, semi-structured questionnaire. Results: Of the 452 participants, 318 (70.4%) were females. The median age was 52 years (IQR: 45-60 years), with more thantwo-thirds diagnosed with DM at ≥36 years (69.8%, n=310). Overall, 274 participants (60.6%) had good knowledge on glycemiccontrol. At multivariable logistic regression analysis, good knowledge about glycaemic control was significantly associated withhaving received training on glycaemic control (aOR: 2.3, 95% CI: 1.4 – 3.7, p=0.002), level of education: diploma (aOR: 4.3, 95%CI: 1.1 – 17.8, p=0.042), degree aOR: 4.9, 95% CI: 1.0 – 23.1, p=0.046) compared to informal education, and nearest distancefrom the health facility (aOR: 3.1, 95% CI: 1.0 – 9.6, p=0.047) Conclusions: More than half of the patients had good knowledge about glycaemic control and this was associated with levelof education, distance from the health facility and having received training. Further studies assessing the correlations betweenactual level of glycaemic control and patient related KAPs are recommended. Keywords: Diabetes mellitus; glycemic control; HbA1C; KAPs.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.

Management of Early-Onset Type 2 Diabetes

Early-onset type 2 diabetes is experiencing a rapid global increase, coinciding with the escalating rates of obesity. In contrast to diagnoses later in life, an earlier diagnosis is associated with unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and premature mortality. Patients with early-onset type 2 diabetes appear to undergo a more aggressive clinical course, which can be exacerbated by the limited availability of treatments. The heightened burden of complications places individuals with early-onset type 2 diabetes at a substantial risk of multimorbidity, underscoring the urgency for interventions to reverse these concerning trends. While the pathophysiology and interventions for adolescent-onset (&lt; 19 years) type 2 diabetes within the early-onset cohort have received considerable attention in research, young adults aged 19~39 years (a larger proportion numerically) remain insufficiently characterized and are notably absent in the current evidence guiding management. Current management approaches derived from trials in later-onset type 2 diabetes may not be suited for this specific demographic. This review provides a comprehensive summary of recent findings related to early-onset type 2 diabetes, aiming to contribute valuable insights that could shape future strategies for prevention, diagnosis, and treatment.

Abstract P423: Individual and Combined Effects of Diet, Exercise, and Metformin on Risk of Microvascular Complications in Older Type 2 Diabetes Patients: Post-Hoc Analysis of Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Data

Introduction: Microvascular complications are a major burden on the health of type 2 diabetes (T2D) patients. The literature has yielded mixed results regarding synergistic effects of common diabetes treatments (i.e., metformin, exercise, and diet) on microvascular complication risk. Some trials demonstrated that the combination of metformin and exercise diminished beneficial effects. We aimed to explore this ambiguity in findings by examining the effects of metformin, exercise, and diet on microvascular complication risk over time among T2D patients in the U.S. and Canada. Hypothesis: We hypothesize that the combined effects of metformin, exercise, and diet would be better than their individual effects on microvascular complication risk. Methods: We analyzed data from 923 participants [mean age: 62.6; 39.2% female; mean years with diabetes: 10.7] of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (2003-2009) trial. Adequate exercise was defined as &gt; 150 mins of moderate-intensity physical activity per week. Metformin use was defined as yes vs. no. An adequate diet score was ≤ 2.4 of the summary fat intake score (range: 0 - 5). We defined composite outcomes for microvascular complications (i.e., nephropathy, retinopathy, and neuropathy) based on several measurements including serum creatinine doubling, decrease in estimated glomerular filtration ratio (≥ 20 ml/min/1.73 m2 decrease), vision loss, Michigan Neuropathy Screening Instrument. We performed longitudinal analysis with synergy factor (SF) approach using multinomial logistic regression models adjusted for sex, diabetes years, education, alcohol, treatment arm, and baseline outcome. Results: Among individuals with poor diet score, those taking metformin but not adequate exercise had an odds ratio of 1.12 (95% CI: 0.65 - 1.94, p = 0.68) for microvascular complication. Those not taking metformin but had adequate exercise had an odds ratio of 2.71 (95% CI: 1.12 - 6.59, p &lt; 0.05). However, taking metformin and having adequate exercise produced an odds ratio of 0.90 (95% CI: 0.49 - 1.67, p = 0.75), which was 0.30 times less than the predicted odds of the joint effect (SF = 0·30, 95% CI: 0 - 0.59, p = 0·05). Individuals with an adequate diet, adequate exercise, and taking metformin had an odds ratio of 0.85 (95% CI: 0.48 - 1.49, p = 0.57). However, we did not find these associations to be statistically significant. A similar pattern holds for individual microvascular complication outcomes. Conclusion: Additional randomized controlled trials are needed to confirm the potential additive beneficial effect of metformin, adequate exercise, and adequate diet combination over their individual effects on odds of microvascular complications.

Trajectories of Body Mass Index and Risk for Diabetes Complications and All-Cause Mortality in Finnish Type 2 Diabetes Patients.

We aimed to assess how longitudinal body mass index (BMI) trajectories are associated with diabetes complications and all-cause mortality in Finnish patients with type 2 diabetes (T2D). In this cohort study, electronic health records from public primary and specialized healthcare services in all 13 municipalities of North Karelia, Finland, were utilized. This study included a total of 889 adults with newly diagnosed T2D in 2011 or 2012 (mean age at baseline 62.0 years). Individual BMI trajectories from the T2D diagnosis until 2014 were estimated and grouped by growth mixture modeling (GMM). Hazard ratios (HRs) with 95% confidence intervals (CIs) for microvascular complications, macrovascular complications, any diabetes complications, and all-cause mortality from 2015 to 2022 across BMI trajectory groups were estimated using Cox regression models. Three distinct BMI trajectory groups were identified using GMM and labeled as follows: "stable" (n = 774, 87.1%), "decreasing" (n = 87, 9.8%), and "increasing" (n = 28, 3.1%). During a median follow-up of 8 years, there were 119 (13.3%) patients with microvascular complications, 187 (21.0%) with macrovascular complications, 258 (29.0%) with any diabetes complications, and 180 (20.2%) deaths. Compared with the "stable" BMI, the "increasing" BMI was associated with an increased risk of microvascular complications (HR = 2.88, 95% CI: 1.32 to 6.28), macrovascular complications (HR = 2.52, 95% CI: 1.17 to 5.43), and any diabetes complications (HR = 2.21, 95% CI: 1.16 to 4.20). The "decreasing" BMI was associated with an increased risk of all-cause mortality (HR = 1.90, 95% CI: 1.14 to 3.15), compared to the "stable" BMI. Our findings underscore the significance of continuous BMI monitoring and weight management in patients with T2D. Tailored treatments are crucial for efficiently preventing weight gain and reducing the risk of diabetes complications.

Lipid variability and risk of microvascular complications in patients with diabetes: a systematic review and meta-analysis

Background and aimsThe current systematic review aimed to elucidate the effects of lipid variability on microvascular complication risk in diabetic patients. The lipid components studied were as follows: High-density lipoprotein (HDL), High-density lipoprotein (LDL), Triglyceride (TG), Total Cholesterol (TC), and Remnant Cholesterol (RC).MethodWe carried out a systematic search in multiple databases, including PubMed, Web of Science, and SCOPUS, up to October 2nd, 2023. After omitting the duplicates, we screened the title and abstract of the studies. Next, we retrieved and reviewed the full text of the remaining articles and included the ones that met our inclusion criteria in the study.ResultIn this research, we examined seven studies, comprising six cohort studies and one cross-sectional study. This research was conducted in Hong Kong, China, Japan, Taiwan, Finland, and Italy. The publication years of these articles ranged from 2012 to 2022, and the duration of each study ranged from 5 to 14.3 years. The study group consisted of patients with type 2 diabetes aged between 45 and 84 years, with a diabetes history of 7 to 12 years. These studies have demonstrated that higher levels of LDL, HDL, and TG variability can have adverse effects on microvascular complications, especially nephropathy and neuropathic complications. TG and LDL variability were associated with the development of albuminuria and GFR decline.Additionally, reducing HDL levels showed a protective effect against microalbuminuria. However, other studies did not reveal an apparent relationship between lipid variations and microvascular complications, such as retinopathy. Current research lacks geographic and demographic diversity. Increased HDL, TG, and RC variability have been associated with several microvascular difficulties. Still, the pathogenic mechanism is not entirely known, and understanding how lipid variability affects microvascular disorders may lead to novel treatments. Furthermore, the current body of this research is restricted in its coverage. This field's lack of thorough investigations required a more extensive study and comprehensive effort.ConclusionThe relationship between lipid variation (LDL, HDL, and TG) (adverse effects) on microvascular complications, especially nephropathy and neuropathic (and maybe not retinopathy), is proven. Physicians and health policymakers should be highly vigilant to lipid variation in a general population.

Body composition and sexual hormones for the glucose control of autoimmune diabetes in males: are they necessary to predict diabetes-related complications?

Glucose control in diabetes is essential for avoiding diabetes-related complications. To determine the impact of body composition and sexual hormones in glucose control and diabetes-related complications, in males with autoimmune diabetes. Thirty-nine patients with autoimmune diabetes and flash glucose monitoring were included. A morphofunctional nutritional evaluation with bioelectrical impedance vector analysis (BIVA), abdominal adipose tissue ultrasound, rectus femoris ultrasound and biochemical parameters, was performed. Strong, positive correlations were observed between body composition parameters, biochemical variables and sexual hormones (p<0.05). Adipose tissue measured by BIVA and ultrasound was more significantly associated with glucose control (including time in range >70%, glucose variability <36% determined by flash glucose monitoring; p<0.05) and the presence of microvascular/macrovascular complications (p<0.05) than lean mass. After adjusting by the duration of diabetes, BMI, abdominal circumference, fat mass and phase angle increased the risk for microvascular complications (OR 1.32(1.00 - 1.73), OR 1.06(1.00 - 1.12), OR 1.14(1.01 - 1.20), 0R 0.3(0.10 - 0.91) respectively; for macrovascular complications: BMI OR 1.38(1.04 - 1.84) and fat mass OR 1.26(1.00 - 1.58)]. Sexual hormone levels did not influence on glucose control or the development of diabetes-related complications. Anthrpometric parameters, especially adipose tissue, were associated with glucose control and variability determined by flash glucose monitoring. Furthermore, changes in fat and lean mass were associated with the presence of microvascular and macrovascular complications. Thus, a comprehensive nutritional evaluation might be useful for the evaluation of males with autoimmune diabetes, in order to identify patients with increased risk of complications.

Влияние сахарного диабета на когнитивные функции в детском и подростковом возрасте

Type 1 diabetes mellitus (DM1) is widespread among children and adolescents in Russia. In addition to the pretty well-studied microvascular complications of the disease, scientific sources also describe the brain damage that is manifested by cognitive impairment. Despite the problem being studied actively by researchers Worldwide, they have reported mixed and sometimes contractionary results. Thus, as of now there are disputes about the etiology, pathogenesis, clinical manifestations and factors affecting the development of the abovementioned complications. Changes in the brain are registered at all age periods with special attention being fairly paid in childhood and adolescence because such disorders of carbohydrate metabolism during active growth can lead not only to functional, but also to structural changes in the brain. This is manifested by memory impairment and decreased attention concentration, which in its turn negatively affects the academic performance of schoolchildren and therefore reduces the quality of life of patients. Further study of this problem would help developing an algorithm for early diagnosis of cognitive impairment among children and adolescents with DM1 in order to increase compliance among patients, reduce the risk of microvascular complications and possible disability in older age. A promising direction in the diagnosis of cognitive disorders are neuroimaging methods, which, as opposed to neuropsychological tests, are helping to identify morphofunctional changes in the brain. This bibliographical review describes the etiology of cognitive disorders in children and adolescents with DM1, the main variants of cognitive dysfunction, the effect of the disease on schooling performance and neuroimaging disorders of the brain.

Cost Utility Analysis Vildagliptin dan Glimepiride dalam Mencegah Komplikasi Mikrovaskuler menggunakan Model Markov

Microvascular complications can occur due to type 2 diabetes mellitus (DM). The cost of therapy increases due to the use of various antidiabetic drugs over a long period. This research is a pharmacoeconomic study that uses the Markov Model to compare costs and utilities in type 2 DM patients who receive metformin+glimepiride and metformin+vildagliptin therapy. Primary data was collected through the EQ5D questionnaire at Cirebon Harbor Hospital and secondary data (transition probability) was collected through a literature study. Characteristics of type 2 DM patients show that the majority of people suffering from this condition are aged between 55 and 59 years. Primary data from the hospital shows that the cost of therapy for controlled type 2 DM patients who receive combination therapy of metformin + glimepiride, and metformin + vildagliptin is Rp. 1,699,400, Rp. 5,807,786, and Rp. 10,100,426, respectively. Secondary data from articles treating type 2 DM shows that the 55-59 year age group is the largest. With an ICER of 61,493,943/QALYS, microvascular prevention in T2DM patients receiving the metformin+vildagliptin combination in Indonesia is considered effective and able to reduce the number of microvascular cases. This is based on the ICER value compared to the Indonesian Government's GDP, namely Rp. 71,030,183.3. This study shows that replacing glimepiride with vildagliptin for the prevention of microvascular complications is cost-effective and has better utility and effectiveness in reducing the incidence of microvascular complications. The use of vildagliptin can be recommended to reduce costs and the risk of microvascular complications.

APOEe4*TREM2 and sickle cell trait in a late onset Alzheimer’s disease mouse model

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease associated with neuroinflammation, dysregulated neurovascular coupling, abnormal neuroplasticity, and neuropathological makers, including tau and β‐amyloid deposition. Advancing age is the greatest risk factor, and apolipoprotein E (APOE) e4 and triggering receptor expressed on myeloid cells 2 (TREM2) are genetic risk factors for late‐onset AD, which comprises &gt;95% of all AD cases. Sickle cell trait (SCT) refers to the heterozygous inheritance of the sickle cell hemoglobin mutation. Studies from our laboratory and others show that SCT is associated with increased risk of microvascular complications and peripheral inflammation. Given the role of cerebral small vessel disease and inflammation in the pathogenesis of AD, we hypothesized that SCT may interact with late‐onset AD gene variants, resulting in earlier development of cognitive impairments, possibly via promoting neuroinflammation.MethodTo test our hypothesis, 10‐12 weeks old mice carrying APOE e4*TREM2 combined late‐onset AD genes were transplanted with bone marrow from humanized Townes mice with SCT (AS) or normal (AA) hemoglobin, following irradiation. Using a longitudinal cross‐sectional design, 3 cohorts were evaluated at 8, 12, and 18 months for presence of cognitive deficits using rodent behavioral testing. Mice were sacrificed immediately following behavioral testing, and brain tissue was evaluated using immunohistochemistry and Golgi‐Cox impregnation histology.ResultBehavioral testing suggested only age‐related cognitive impairments. There were no significant differences in neuroinflammation at any age between AS and AA mice in the hippocampus or corpus callosum and external capsule. Within genotypes, there was an age dependent increase in neuroinflammation, between 8 and 12 months in the hippocampus (p &lt; 0.0001, p = 0.0002) and 12 versus 18 months in white matter tracts (p &lt; 0.0001, p &lt; 0.0001). There were no significant differences in the dendritic spine density or the proportion of immature spines between AS and AA mice. However, within genotypes there was significant differences between 12 and 18 months (p &lt; 0.0001, p &lt; 0.0001), with 18 months having lower spine density and higher proportion of immature spines.ConclusionAddition of SCT to a background of APOE e4*TREM2 did not result in earlier onset of cognitive impairment or more severe neuroinflammation.

Diabetes Modulates Iodothyronine Deiodinase 2 Expression in the Mouse Retina: A Role for Thyroid Hormone in the Pathogenesis of Diabetic Retinopathy.

Clinical investigations associate hypothyroidism with an increased risk for microvascular complications, yet the mechanism by which thyroid hormone regulates the development of diabetic retinopathy is not clearly understood. We investigated the role of iodothyronine deiodinase 2 (DIO2) in the pathogenesis of diabetic retinopathy. Retinas from streptozotocin-induced diabetic and nondiabetic mice were evaluated by RNA sequencing, RT-PCR, and immunostaining. Media and cell lysates from mouse retinal microvascular endothelial cells and retinal astrocytes exposed to physiologic (5mM) and high glucose (25 mM) containing media were assessed by liquid chromatography-tandem mass spectrometry to measure tetraiodothyronine (T4) and tri-iodothyronine (T3) concentrations and by Western blot analysis to determine the relationship of T4/T3 to oxidative stress and inflammatory mediators. Cell death was determined by Trypan Blue exclusion assay. At 12 weeks of diabetes duration, retinas from diabetic mice compared with nondiabetic mice demonstrated a significant decrease in Dio2 transcripts and Dio2 gene and protein (P < 0.05) expression. When cultured in the presence of high glucose, both mouse retinal astrocytes and microvascular endothelial cells demonstrated a significant reduction of DIO2 protein compared with cells cultured in physiologic glucose. High glucose inhibited generation of T3, leading to a significantly increased T4/T3 (P < 0.0079). Supplementation of cells with T3, but not T4, prevented the high glucose-induced rise in endothelial nitric oxide synthase, intercellular cell adhesion molecule 1, and endothelial cell death (P < 0.0079). Decreased intraretinal T3 owing to diabetes-induced loss of DIO2 may lead to dysfunction and death of cells in the retina, thereby contributing to the pathogenesis of early diabetic retinopathy.

The impact of glycated hemoglobin A1c on cardiovascular risk in patients with and without coronary artery disease

Abstract Background Diabetes is defined according to the level of glycated hemoglobin (HbA1c) based on the risk of microvascular complications. However, HbA1c has been associated with increased risk of macrovascular complications at lower HbA1c levels than the conventional cut-off for "microvascular" diabetes. In patients without known diabetes, it is unsettled when HbA1c becomes a marker of macrovascular complications in non-diabetes patients with and without coronary artery disease (CAD). Purpose We tested the hypothesis that the HbA1c cut-off for macrovascular complications differ for patients with versus without CAD. Methods We included every patient undergoing coronary angiography in Western Denmark from 2011-2021 without known diabetes prior to examination. Follow-up was censored if it exceeded 10 years. We examined the risk of atherosclerotic cardiovascular disease (ASCVD, a composite of myocardial infarction and ischemic stroke) and HbA1c using Cox regression. We modeled the relation between ASCVD and HbA1c using restricted cubic splines with 38 mmol/mol as reference. In a separate analysis, we stratified patients by HbA1c levels (&amp;lt;30 mmol/mol, 31-38 mmol/mol (reference), 39-47 mmol/mol, and ≥48 mmol/mol) and CAD. Results We included 56,927 patients without known diabetes at the time of angiography, of whom 1,225 (2.2%) had undiagnosed, untreated diabetes, i.e. HbA1c ≥48 mmol/mol. Mean HbA1c was 38 mmol/mol. In patients without CAD we did not observe any association between HbA1c and ASCVD (Figure 1). In contrast, we observed a U-shaped relationship between HbA1c and ASCVD in patients with CAD. The lowest risk of ASCVD was observed at HbA1c 35 mmol/mol, which was followed by a steady incline with higher HbA1c levels. When categorizing HbA1c, the adjusted ASCVD risk was significantly increased in patients with CAD and HbA1c 39-47 mmol/mol (aHR 1.09, 95% CI 1.01-1.19), with HbA1c ≥48 mmol/mol (aHR 1.60, 95% CI 1.32-1.94) having the highest ASCVD risk (Figure 2). Conclusions The current study provides two novel findings. Firstly, HbA1c provides no prognostic information concerning risk of ASCVD when CAD is absent. Secondly, a U-shaped relationship between HbA1c and ASCVD was found in patients where CAD is present. The lowest risk of ASCVD was observed at HbA1c 35 mmol/mol and the risk steadily increased with higher (and lower) HbA1c levels. Thus, the risk of ASCVD associated with HbA1c starts much earlier than the conventional 48 mmol/mol HbA1c cut-off for diabetes, but the relationship exists only when CAD is present.Figure 1Figure 2

Expression and clinical association of MFG-E8 and TAM receptors in diabetic patients with different stages of microvascular complication: An experimental study.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus that leads to end-stage renal disease. Hyperglycemia triggers apoptosis and kidney damage. Milk fat globule-epidermal growth factor 8 (MFG-E8) and TAM receptor tyrosine kinases, Tyro3, Axl, and Mer, are phagocytic receptors that mediate the clearance of apoptotic cells. This study aimed to identify the role of MFG-E8 and TAM receptors in the development of DN. A total of 146 patients with type 2 diabetes mellitus (T2DM), early stage DN, clinical DN and 48 healthy controls were employed to analyze the serum levels of MFG-E8, soluble Tyro3, Axl, Mer, and RAGE by enzyme-linked immunosorbent assay. The serum levels of CREA, hsCRP, CysC, and β2-microglobulin were measured by spectrophotometric analysis using a biochemical analyzer (AU5800). Our results showed that the serum levels of MFG-E8 were elevated in patients with T2DM compared with healthy controls; however, it decreased gradually in patients with DN with the severity of kidney injury, especially in the clinical DN group. Moreover, the levels of sTyro3, sAxl, and sMer were reduced in patients with T2DM and DN compared to healthy controls, particularly in patients with DN. The levels of MFG-E8, sTyro3, sAxl, and sMer were negatively correlated with UAER at 24 hours, CREA, hsCRP, CysC, β2-microglobulin, and RAGE, respectively. In addition, TAM receptors had significantly higher predictive and diagnostic values for early stage DN from T2DM than hsCRP, β2-microglobulin, and CysC, which are also predictive biomarkers of early stage DN from clinical DN. Decreased MFG-E8 and TAM receptor expression is associated with an increased risk of microvascular complications in patients with T2DM, which plays a critical role in the diagnosis of diabetic patients with microvascular complications, especially early stage DN, and in monitoring the development of DN.

The evolution of type 2 diabetes management: glycemic control and beyond with SGLT-2 inhibitors and GLP-1 receptor agonists.

Diabetes mellitus (DM) is one of the most prevalent diseases encountered by the primary care physician on a daily basis. Complications associated with DM can include nephropathy, neuropathy, and retinopathy ("microvascular complications"), along with cardiovascular disease (CVD), which can include myocardial infarction (MI) and strokes ("macrovascular complications"). In the 1990s, landmark clinical trials demonstrated that intensive glycemic control can reduce the risk of developing microvascular complications, but reduction in macrovascular complications with intensive glycemic control was not clearly demonstrated. At this point, intensive glycemic control became the standard of care (SOC). In the 2000s, additional trials evaluating the effect of intensive glycemic control in patients with type 2 diabetes mellitus (T2D) and established CVD, or risk factors for CVD, subsequently failed to identify a macrovascular benefit from intensive glycemic control, and one of the trials was terminated early because of an increase in the risk of mortality observed among patients assigned to receive intensive glycemic control. These results led to less strict glycemic targets being recommended in older patients, particularly those with established CVD. In 2007, everything changed after a report surfaced suggesting that rosiglitazone was associated with a significant increase in the risk of MI, as well as an increase in the risk of cardiovascular death that was of borderline significance. As a result, in 2008, the FDA mandated that all new diabetes medications must exclude an unacceptable level of risk for atherosclerotic cardiovascular disease (ASCVD) prior to drug approval, and thus undergo additional cardiovascular safety trials. Accordingly, through these trials, some of the newer agents, particularly sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), were demonstrated to reduce the risk of major adverse cardiovascular events (MACEs), independent of their effect on glycemic control. These findings subsequently led to further trials to evaluate the effects of some of these therapies on the risk of chronic kidney disease (CKD) progression, as well as adverse heart failure-related outcomes. SGLT-2 inhibitors have been demonstrated to reduce the risk of CKD progression, as well as a reduction in the risk of cardiovascular death or hospitalization secondary to heart failure in patients with both reduced ejection and preserved ejection fractions. A trial evaluating the effects of GLP-1RA on CKD outcomes is ongoing. The aim of this narrative review article, compiled by identifying relevant studies via the utilization of PubMed, is to provide a broad overview over the various clinical trials and analyses that have led to current diabetes management guidelines, and ultimately, help guide primary care physicians in selecting therapies that will not only improve glycemic control and reduce the risk of microvascular complications, but also reduce the risk of macrovascular disease in their patients with T2D.

Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery.

Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.

SAT087 Maternally Inherited Diabetes And Deafness: Support For SGLT2 Inhibitor Use

Abstract Disclosure: S. Pandya: None. K. Selk: None. Introduction: Maternally inherited diabetes and deafness (MIDD) is a rare genetic disease resulting from a mitochondrial mutation. There is a wide phenotypic expression secondary to heteroplasmy. The clinical manifestations of MIDD are hyperglycemia, sensorineural hearing loss, maculopathy, cardiac conduction defects, myopathy/poor exercise tolerance, and neuropathy. Diabetes mellitus generally occurs during the third decade of life, and there tends to be rapid progression to insulin therapy with reported earlier onset of microvascular complications. Here we present a case of MIDD successfully treated long-term with empagliflozin and linagliptin. Clinical Case: A 36-year-old male with sensorineural hearing loss presented with a 20-pound unintentional weight loss, polyphagia, and polydipsia. His blood glucose level was 300 mg/dL and HbA1c was 14.3%. His mother carried a diagnosis of type 2 diabetes mellitus and his grandmother had latent autoimmune diabetes of adulthood. Prior to presenting to endocrinology, he had been started on metformin, glipizide, and linagliptin with ongoing poor glycemic control. Given his presentation, family history, and lean habitus with BMI of 20, he was assessed for possible autoimmune diabetes. Testing for glutamic acid decarboxylase 65-kilodalton isoform antibody (GAD65), islet cell antibody, tyrosine phosphatase-related islet antigen 2 (IA2), and zinc transporter 8 antibody (ZNT8) was unrevealing. A C-peptide level was detectable but &amp;lt;1 ng/mL. His sulfonylurea was discontinued, and he was started on basal insulin with a dramatic improvement in his glycemic control. He was later able to discontinue insulin therapy. However, given poor exercise tolerance and his known hearing loss, he was seen by genetics where he underwent testing and was found to have a m.3243 A&amp;gt;G mutation in MT-TL1 gene making the diagnosis of MIDD. Metformin was discontinued due to a possible risk of lactic acidosis and sitagliptin was initiated. Due to hyperglycemia, empagliflozin was added and he was later transitioned to empagliflozin-linagliptin to reduce his pill burden. He has continued to have a1c levels of 6.5% or less for the last 3 years and periodic C-peptide measurements have been &amp;gt;1 ng/mL. Conclusion: Given MIDD is a rare form of monogenic diabetes, treatment tends to be individualized with many transitioning to insulin early in their disease course. Given the reported increased risk for microvascular complications, sodium-glucose cotransporter-2 (SGLT2) inhibitors are an attractive therapeutic agent. However, there is little literature on the use of these agents in MIDD and there is concern about the risk for diabetic ketoacidosis given insulin use is required by many afflicted individuals. This case highlights the safety of long-term empagliflozin in a patient with MIDD. Presentation: Saturday, June 17, 2023