Type 2 Diabetes Research Articles

Glycated hemoglobin as a prognostic factor for the progression of non-proliferative diabetic retinopathy in type 2 diabetes

Background. A promising direction of modern medicine is to increase the accuracy of predicting the possible outcomes of the disease, its complications or relapses. Several factors are important for the progression of diabetic retinopathy (DR) in type 2 diabetes (T2D), among which glycated hemoglobin, duration of T2D and others are discussed. The purpose was to determine the possibilities of predicting the progression of initial non-proliferative diabetic retinopathy (NPDR) based on the blood glucose, glycated hemoglobin and cholesterol indicators. Materials and methods. Three hundred and fifty-eight patients (358 eyes) with T2D and DR were examined and divided into groups: the first one — with NPDR (189 eyes), the second one — with pre-proliferative DR (96 eyes) and the third one — with proliferative DR (73 eyes). Patients were examined for 2 years using ophthalmological methods; serum fasting glucose, glycated hemoglobin and total cholesterol were determined by colorimetric method. The analysis of the research results was carried out in the EZR v. 1.54 package (Austria). Results. There was no significant difference between the groups at baseline in terms of age and T2D duration; these indicators were not associated with the DR progression (p = 0.512 and p = 0.339, respectively) as well. The independent risk factors for the NPDR progression in the univariate analysis were the content of blood glucose (p = 0.002; odds ratio (OR) = 1.08; 95% confidence interval (CI) 1.03–1.13) and total cholesterol (p < 0.001; OR = 2.02; 95% CI 1.53–2.6 %). Based on the glycated hemoglobin blood level, a logistic model of the NPDR progression was constructed. The area under the receiver operating characteristic curve was 0.84 (95% CI 0.80–0.88), which indicated a strong association with the NPDR progression. The threshold for predicting the glycated hemoglobin level was 8.9 % with a sensitivity of 75.6 % (95% CI 68.6–82 %) and a specificity of 79.9 % (95% CI 73.5–85.4 %). Conclusions. It was found that the content of glycated hemoglobin in the blood above 8.9 % is an independent factor for the NPDR progression, which allowed to build a prognostic model with a very good quality of prognosis.

Efficacy of Alogliptin/Metformin Fixed-Dose Combination Tablets and Vildagliptin/Metformin Fixed-Dose Combination Tablets on Glycemic Control in Real-World Clinical Practice for the Patients with Type 2 Diabetes: A Multicenter, Open-Label, Randomized, Parallel Group, Comparative Trial.

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Type I Diabetes Mellitus impairs cytotoxic immunity through CEACAM5 upregulation in colorectal cancer : Exploring the intersection of autoimmune dysfunction and cancer progression: the role of NF-κB p65 in colorectal cancer.

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.

Icodec: A Novel Once-Weekly Basal Insulin for Diabetes Management.

To evaluate the efficacy, safety, and clinical implications of insulin icodec, a novel once-weekly basal insulin for the treatment of type 1 diabetes (T1D) and type 2 diabetes (T2D), with an emphasis on its advantages and challenges in comparison with existing daily basal insulins. A literature search was performed using PubMed, Google Scholar, Embase, and ClinicalTrials.gov up to August 26, 2024, using the search terms icodec and ONWARDS trial. Studies involving patients living with T1D or T2D on once-weekly insulin icodec compared with once-daily insulins glargine U100, glargine U300, and degludec were considered for this review. Relevant English-language studies and those conducted in humans were considered. Insulin icodec offers reduced dosing frequency and potentially superior glycemic management with a safety profile comparable to existing basal insulins. Insulin icodec once-weekly dosing could significantly improve convenience and efficacy over daily basal insulins, representing a significant innovation in insulin therapy. Insulin icodec emerges as a promising option for diabetes management, potentially improving treatment adherence and quality of life.

Features of the development and progression of diabetic macular edema in patients with type 2 diabetes

Background. In the developed world, the prevalence of type 2 diabetes in the population aged 65 years and older is 33 %, and prediabetes is 50 %. Macular edema can be the first symptom of diabetic retinopathy or occur at any stage of its development. In developed countries, the most common cause of central vision loss in people under the age of 50 is diabetic macular edema (DME). Long-term studies have found that the risk of developing DME is higher in patients with type 2 diabetes. The purpose was to investigate the features of the development and progression of DME in patients with type 2 diabetes. Materials and methods. A total of 180 patients (360 eyes) with non-proliferative diabetic retinopathy and type 2 diabetes were examined. The nature, frequency, and features of the development and progression of DME were evaluated. All patients were examined for uncorrected visual acuity, best corrected visual acuity, intraocular pressure, static computed perimetry, optical coherence tomography and optical coherence tomography angiography. We used the Student’s t-test to determine the statistical significance of the mean differences in two independent groups. The null hypothesis was rejected and the differences between indicators were considered statistically significant at a significance level of p < 0.05. Results. In patients of the Ukrainian population with non-proliferative diabetic retinopathy and type 2 diabetes, the incidence of DME 0 averaged 55.56 %, DME 1 — 15.0 %, DME 2 — 15.56 %, DME 3 — 13.89 %. There was a statistically significant relationship between the frequency of DME of different stages and the duration of type 2 diabetes. At presentation, the frequency of DME 0 was on average 55.56 %; with the duration of type 2 diabetes of up to 10 years, it was 3 and 24 % statistically significantly higher (p < 0.05) than in patients with duration from 11 to 20 and above 20 years, respectively. The incidence of DME 1 was 15.0 %, DME 2 was 15.56 %; with the duration of type 2 diabetes of up to 10 years, it was 2 times lower (p < 0.05) than in patients with duration of 11 to 20 years and more than 20 years, respectively. The incidence of DME 3 was 13.89 %; with the duration of type 2 diabetes of up to 10 years, it was 3 times lower (p < 0.05) than in patients with duration of 11 to 20 years and above 20 years, respectively. A statistically significant dependence of the incidence of diabetic macular edema on treatment in patients with non-proliferative diabetic retinopathy and type 2 diabetes has been found. When taking hypoglycemic drugs, the incidence of DME 0 increases statistically significantly, and when insulin therapy is used, the incidence of DME 1–3 increases. Conclusions. A statistically significant relationship was found between the frequency of DME of different stages and the duration of type 2 diabetes. The longer the duration of type 2 diabetes, the higher the frequency of DME stages 1, 2 and 3. The incidence of DME 1–3 in patients on insulin therapy is 2 times higher compared to patients taking hypoglycemic drugs (p < 0.01).

Radical-directed dissociation mass spectrometry for differentiation and relative quantitation of isomeric ether-linked phosphatidylcholines

BackgroundEther-linked phosphatidylcholines (PCs) include both plasmanyl and plasmenyl PCs, which contain an ether or a vinyl ether bond at the sn-1 linkage position, respectively. Profiling and quantifying ether PCs with accurate structural information is challenging because of the common presence of isomeric and isobaric species in a lipidome. ResultsIn the present study, radical directed dissociation (RDD) from collision-induced dissociation (CID) of the bicarbonate anion adduct of ether PCs has been investigated to differentiate and relatively quantify ether PCs. Alkyl- and alkenyl- PCs give diagnostic characteristic fragment patterns that enable their confident identification and isomer differentiation. Additionally, the sn-position specific product ions have proven effective for relative quantitation among isomers in ether PCs and their isobaric PC species. Using this methodology, we successfully identified a total of 30 PC-O species, 21 PC-P species at the chain composition level, and 22 species of isobaric PC at the sn-position level in the human plasma lipid extract. The quantitative analysis revealed that ether PCs with a 20:4 fatty acyl chain are relatively more abundant in human plasma. Finally, the profile of ether PCs in type 2 diabetic (T2D) groups compared to normal control groups revealed a significant decrease in PC-O 18:1/20:5. We also found it is the PC species containing a 17-carbon fatty acyl chain, rather than their isobaric ether PCs, that shows a decreasing trend in the T2D groups. Significanceether-linked PCs are firstly investigated by RDD mass spectrometry.

Factors affecting time to recovery from diabetic ketoacidosis in adult diabetic patients in Alexandria Main University Hospital

BackgroundDiabetic ketoacidosis (DKA) is a life-threatening condition as a complication of diabetes and represents a significant healthcare global burden. The current study goal was to determine factors affecting time to recovery from DKA in Alexandria Main University Hospital.Patients and methodsOne hundred fifty patients who had been admitted with DKA were included in this study. All patients were managed with hospitalization for IV fluids, continuous intravenous insulin infusion, electrolyte correction, as well as detection and treatment of the predisposing factor until the full resolution of DKA.ResultsMales contributed to 58.7% of the total patients in this study with a mean age of 32.16 ± 15.06 years. DKA mean time of resolution was 18.76 ± 14.07 h. The majority of patients were with T1DM (86%), while T2DM were 14%. Missed insulin dose was the leading precipitating factor (60.7%) followed by infections (38.7%). There was a statistically significant relationship between DKA resolution time with age, time of presentation, type of diabetes, initial pH, initial serum K+ level, initial HCO3− level, initial anion gap, initial base excess, and initial RBS (p value < 0.001).ConclusionDelayed time of resolution from DKA was associated with initial lower pH, initial lower HCO3− level, initial lower base excess level, initial higher anion gap level, type 2 diabetes mellitus, patients on pre-mixed insulin regimen, old patients, delayed time for seeking medical care, and abnormal serum K+ level.

Prevalence and pattern of Mineral Bone Disorders in patients with end-stage renal disease and the impact of diabetic status and type of phosphate binders on these disorders

Prevalence and pattern of Mineral Bone Disorders in patients with end-stage renal disease and the impact of diabetic status and type of phosphate binders on these disorders

Identification of genetic risk variants for Type-2 Diabetes mellitus in Pakistani Pashtun population: A case-control association study

Background and Objective: Pakistan, a South Asian developing country, is experiencing a rapid increase in number of diabetes cases. High prevalence ratio of diabetes in Pakistani population and lack of genetic research studies prompted us to design this study. This present study investigated Pakistani Pashtun population for (known and novel SNPs) and its possible correlation with Type-2 Diabetes Mellitus (T2DM). Methods: This two stage (discovery &amp; validation stage), case-control association study included one thousand individuals (Patients with T2DM=500 &amp; controls=500) from eight districts of Khyber Pakhtunkhwa Pakistan. The study duration/period was from March 2018 to January 2020. In the first stage (the discovery stage) the target population was screened for known and novel T2DM-associated genetic markers. In the validation stage, identified variants were confirmed for T2DM association using MassARRAY genotyping and association analysis. Results: Exome sequencing detected eleven known and four novel/new genetic markers in the study population. Novel variants were preferred over the known for follow-up analysis/validation. Among the identified variants strong associations were confirmed for the following variants; rs1781133/ANKRD65 (OR=2.10, 95%Cl=1.06–3.08, P=0.003) rs2274791/TTLL10 (OR=1.97, 95%Cl=1.36-2.62, P=0.025), rs71628928/RNF223 (OR=1.82, 95%Cl=0.97-1.92, P=0.041), and rs609805/SCNN1D (OR=2.21, 95%Cl=1.92-3.09, P=0.001) with T2DM; other reported variants showed no noticeable association (having P&gt;0.05) with T2DM. Conclusion: This study reports new genetic risk variants for T2DM in Pashtun population providing valuable insights into the genetic basis of T2DM in this group. doi: https://doi.org/10.12669/pjms.40.10.10292 How to cite this: Jan A, Mothana RA, Kaimori JY, Muhammad T, Khan M, Ali SS, et al. Identification of genetic risk variants for Type-2 Diabetes mellitus in Pakistani Pashtun population: A case-control association study. Pak J Med Sci. 2024;40(10):2336-2343. doi: https://doi.org/10.12669/pjms.40.10.10292 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

A regulatory variant rs9379874 in T1D risk region 6p22.2 affects BTN3A1 expression regulating T cell function.

Genome-wide association studies (GWAS) have identified that 6p22.2 region is associated with type 1 diabetes (T1D) risk in the Chinese Han population. This study aims to reveal associations between this risk region and T1D subgroups and related clinical features, and further identify causal variant(s) and target gene(s) in this region. 2608 T1D and 4814 healthy controls were recruited from East, Central, and South China. Baseline data and genotyping for rs4320356 were collected. The most likely causal variant and gene were identified by bioinformatics analysis, dual-luciferase reporter assays, expression quantitative trait loci (eQTL), and functional annotation of the non-coding region within the 6p22.2 region. The leading variant rs4320356 in the 6p22.2 region was associated with T1D risk in the Chinese and Europeans. However, this variant was not significantly associated with islet function or autoimmunity. In silico analysis suggested rs9379874 was the most potential causal variant for T1D risk among thymus, spleen, and T cells, overlapping with the enhancer-related histone mark in multiple T cell subsets. Dual luciferase reporter assay and eQTL showed that the T allele of rs9379874 increased BTN3A1 expression by binding to FOXA1. Public single-cell RNA sequencing analysis indicated that BTN3A1 was related to T-cell activation, ATP metabolism, and cytokine metabolism pathways, which might contribute to T1D development. This study indicates that a functional variant rs9379874 regulates BTN3A1 expression, expanding the genomic landscape of T1D risk and offering a potential target for developing novel therapies.

Eighteen-Month Hybrid Closed-Loop Use in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Trial.

We aimed to evaluate the longer-term safety and efficacy of hybrid closed-loop (CL) therapy in very young children with type 1 diabetes (T1D). Following a 16-week multinational, randomized crossover trial comparing hybrid CL with sensor-augmented pump (SAP) therapy in 74 very young children aged 1-7 years with T1D, participants were invited to an extension phase using CL for a further 18 months. Outcomes were compared with the primary-phase SAP period and primary-phase CL period. After the primary study phase, 60 participants were eligible to enroll in the extension. Of these, 49 consented (mean ± SD age 6.6 ± 1.5 years) to continue use of CL for 18 months. Percentage time in range (TIR) 3.9-10.0 mmol/L was 8.4 percentage points (95% CI 6.7 to 10.1; P < 0.001) higher, while HbA1c was 0.4% ([5.0 mmol/mol], 95% CI 0.3 to 0.6 [3.7 to 6.2]; P < 0.001) lower during the CL extension phase compared with primary-phase SAP period. At 18 months, mean HbA1c was 6.7 ± 0.5% and TIR was 70 ± 7%, compared with 6.7 ± 0.5% and 71 ± 6% in the primary-phase CL period. Time in hypoglycemia (<3.9 mmol/L) was similar between CL extension phase and both primary-phase SAP (P = 0.31) and CL periods (P = 0.70). There were two severe hypoglycemia events and one other serious adverse event during the extension phase. One unexpected serious adverse device effect occurred. Use of the Cambridge hybrid CL system led to sustained improvements in glycemic control lasting more than 18 months in very young children with T1D.

GLP-1 Receptor Agonists and Risk of Paralytic Ileus: A drug-target Mendelian Randomization Study.

Paralytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management. To investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (n cases/controls =228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (n cases/controls =517/182,423) using GWAS data from the FinnGen project. Based on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally. Our study's findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.

GLP-1 Receptor Agonists in Overweight and Obese Individuals With Type 1 Diabetes Using an Automated Insulin Delivery Device: A Real-World Study.

Automated insulin delivery (AID) systems have improved glycemic control in individuals with type 1 diabetes (T1D) but overweight and increased cardiovascular risk remain a challenge. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improved cardiometabolic profile but are currently not approved for the treatment of T1D. Individuals with T1D at Steno Diabetes Center Copenhagen, Denmark, treated with AID and off-label GLP-1 RA for at least six months between January 2017 and May 2024 were included in a retrospective chart review study. Nineteen individuals with (median [range]) age 42 (24-60) years were included. At GLP-1 RA initiation, hemoglobin A1c (HbA1c) was 7.3% (6.1%-8.7%), HbA1c 56 (43-72) mmol/mol, body weight 91.5 (78.0-115.0) kg, and body mass index 35.4 (27.0-42.0) kg/m2. Time in range was 74% (29%-82%), time above range 25% (18%-71%) while time below range was 1% (0%-5%). After six months of treatment, body weight changed -11% (-22% to -3%; P = .001) and total daily insulin dose changed -15.1 (-32.5 to -8.2) IU (P = .004). There were no significant changes in HbA1c or other glucose measures. One person developed ketoacidosis caused by infusion set failure, but none reported severe hypoglycemia. Glucagon-like peptide-1 receptor agonist as add-on therapy for six months in individuals with obesity and AID-treated T1D led to considerable weight loss and a reduction in insulin dose.

Relationship Between C-Peptide Levels, Clinical Features, and Serum Data in a Brazilian Type 1 Diabetes Population with Large Variations in Genomic Ancestry.

Type 1 diabetes (T1D) is a chronic disease characterized by the immune-mediated destruction of the pancreatic beta cells responsible for insulin production. The secreted insulin and C-peptide are equimolar. Due to its longer half-life, C-peptide has become a safer means of assessing the pancreatic reserve. C-peptide levels were evaluated in a population of patients with T1D, focusing on the relationship between this variable and other factors. In addition, the influence of C-peptide on metabolic control and microvascular complications was investigated. This cross-sectional study included 95 patients who had been diagnosed with T1D at least five years earlier. These patients were evaluated using a clinical demographic survey, anthropometric data, laboratory tests, and fundoscopy. This study showed that 29.5% of patients had residual insulin secretion, which correlated directly with their age at diagnosis. No statistically significant differences in metabolic control or microvascular complications were observed between the C-peptide level groups. In addition, our results indicate that ancestry does not influence the persistence of residual C-peptide function in our highly mixed population. It is recommended that future research consider incorporating new variables, such as HLA and pancreatic autoimmunity, as factors that may influence residual β-cell function.

EXPRESS: Plasma from Type 1 Diabetes Patients Promotes Pro-atherogenic Cholesterol Transport in Human Macrophages.

Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of Advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits reverse cholesterol transport by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HC) and 20 patients with T1DM, 10 to 19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of CML-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized LDL. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.

Metabolic/Bariatric Surgery is Safe and Effective in People with Obesity, Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) are thought to increase surgical risks and reduce weight loss after metabolic/bariatric surgery (MBS). Electronic databases were searched between January 2013 and August 2023 for randomized controlled trials (RCT) of MBS reporting data on the safety, total weight loss (TWL), and metabolic control in patients with and without CKD. Forty-four out of 2904 articles were analyzed, representing 1470 patients. No significant differences were found in TWL after 1year (- 19%, CI - 0.19 to - 0.18 vs.: - 15%, CI - 0.20 to - 0.09, p = 0.13) or after 5years (- 20%, CI - 0.21 to - 0.18 vs. Group - 16%, CI - 0.28 to - 0.04, p = 0.50).Similarly, there were no significant differences in HbA1c at 1year (- 1.06, CI - 1.37 to - 0.76 vs. Group 2: - 1.52, CI - 2.25 to - 0.79, p = 0.26) or after 5years (- 0.97, CI - 1.53 to 0.41 vs. Group 2: - 1.09, CI - 2.21 to 0.03, p = 0.85). For fasting plasma glucose, no differences were seen at 2years (- 30.43, CI - 60.47 to 0.39 vs. - 35.11, CI - 48.76 to - 21.46, p = 0.78) or after 5years (- 11.24, CI - 53.38 to 30.89 vs. - 5.4, CI 20.22 to 9.42, p = 0.80). In terms of total cholesterol, no significant differences were found after 1year (- 10.36, CI - 32.94 to 12.22 vs. - 19.80, CI - 39.46 to - 0.14, p = 0.54) or after 5years (- 7.43, CI - 25.09 to 5.23 vs. - 21.30, CI - 43.08 to 0.49, p = 0.15). For triglycerides, both showed similar reductions after 1year (- 76.21, CI - 112.84 to - 39.59 vs. - 78.00, CI - 100.47 to - 55.53, p = 0.94) and after 5years (- 79.65, CI - 121.09 to - 38.21 vs. - 53.15, CI - 71.14 to - 35.16, p = 0.25). The presence of CKD in patients with obesity and T2D does not reduce the safety and efficacy of MBS.

Effectiveness and safety of insulin glargine 300 U/mL in insulin-naïve individuals according to diabetes duration: Results from the REALI European pooled data analysis.

To evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiation according to diabetes duration (DD). We analysed patient-level data from 2381 insulin-naïve individuals with type 2 diabetes (T2D), of whom 2349 (98.7%) were treated with Gla-300 for 24 weeks. Of the 2381 participants, 1048 (44.0%) had a DD of less than 8 years and 1333 (56.0%) had a DD of 8 years or longer. We further analysed the subgroups of participants having a DD of less than 4 years (N = 450), 4-8 years (N = 598), 8-12 years (N = 627) and 12 years or longer (N = 706). Mean ± standard deviation age was 60.2 ± 9.0 years in participants with a DD less than 8 years and 64.2 ± 8.8 years in those with a DD of 8 years or longer. At 24 weeks of Gla-300 therapy, HbA1c improved with a least-squares (LS) mean change from baseline of -1.88% (95% confidence interval [CI], -1.95 to -1.80) and -1.71% (95% CI, -1.77 to -1.65), respectively, resulting in a LS mean difference between groups of 0.17% (95% CI, 0.07 to 0.26; P = .0005). In the subgroup analysis, LS mean HbA1c reduction from baseline to week 24 was highest in participants with a DD of less than 4 years and lowest in participants with a DD of 12 years or longer. Overall, incidences of symptomatic and severe hypoglycaemia were low, irrespective of DD, without body weight changes. Gla-300 was effective and safe in insulin-naïve individuals with T2D, regardless of DD. Improvement in HbA1c was greater when Gla-300 was initiated in participants with a DD of less than 4 years, although the difference between the groups was modest.

Exome Sequence Data of Eight SLC Transporters Reveal That SLC22A1 and SLC22A3 Variants Alter Metformin Pharmacokinetics and Glycemic Control.

Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans.

A study to determine a capillary alternative to the gold standard oral glucose tolerance test - Protocol

Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.