Type 2 Diabetes Research Articles

Impaired neurogenic activity in the Zucker Diabetic Sprague Dawley (ZDSD) rat hippocampus

Diabetes prevalence is increasing worldwide, with type 2 diabetes (T2D), characterized by hyperglycemia and hyperinsulinemia being most common. Past studies associate diabetes with cognitive decline attributed to hippocampal neurodegeneration emanating from oxidative stress. However, findings from animal models are debatable as most involve a disturbance in the leptin signaling pathway. Therefore, we investigated hippocampal neurodegeneration associated with oxidative stress in the Zucker Diabetic-Sprague Dawley (ZDSD) as it maintains an intact leptin pathway. We used 15-week-old, male ZDSD rats (n=5) and Sprague Dawley rats (n=5) that served as controls. Adult hippocampal neurogenesis (AHN) was investigated by immunolabeling the hippocampal dentate gyrus for Ki 67 and doublecortin (DCX) for assessment of proliferating and differentiating neuroblasts, respectively. We quantified plasma malondialdehyde (MDA) concentration to evaluate oxidative stress. There were fewer proliferating and differentiating neuroblasts, respectively, in the ZDSD rat dentate gyrus. Additionally, the ZDSD rat dentate gyrus had fewer dendritic extensions to the molecular layer compared to that of the SD controls. Oxidative stress was greater in the ZDSD group. Our findings show that the ZDSD exhibits neurodegeneration similar to what is observed in other rodent models of diabetes and in humans. Decreased neuronal proliferation coupled with fewer dendritic extensions in the molecular layer of the dentate gyrus are characteristic of features exhibited in the ZDSD. These results complement the explanations given in scientific literature about the involvement of oxidative stress in the degeneration of hippocampal dentate gyrus neurons observed in type 2 diabetes.

An interventional study of digital therapy on blood glucose and weight management in Chinese patients with type 2 diabetes.

Our study aimed to evaluate the effectiveness of a 3-months digital therapy (DTx) intervention in the real world for the management of blood glucose in 3,902 Chinese patients with type 2 diabetes (T2D) in Lingshui, Hainan. Adults with T2D who were capable of using DTx application (app) were enrolled. Fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPBG), and body weight before and after the intervention were collected. Participants recorded blood glucose and body weight at least once weekly, and attended diabetes education program with the app during online follow-up once weekly. A total of, 3,902 patients with T2D were enrolled, including 46.3% of men, with an average age of 64.3 years. After 3-months of DTx, FBG decreased by 0.52 mmol/L (8.05-7.53, P < 0.001) from baseline, 2hPBG decreased by 1.18 mmol/L (11.95-10.77, P < 0.001), and body weight decreased by 1.50 kg (61.18-59.68, P < 0.001). The median number of glucose self-reports for each patient was three (0, 273) times. Defining participants who finished glucose or weight self-report for once within 7 days as the motivated group (n = 1,013), the motivated group showed significant weight loss after DTx intervention (motivated group vs inactive group, -3.01 kg vs -0.36 kg, P < 0.01). No significant difference was found in FBG and 2hPBG between the two groups. DTx reveals significant efficacy on glucose and weight control in patients with T2D, which can reduce FBG, PBG, and body weight. Better compliance and motivation with DTx and frequent weight monitoring help achieve better weight control.

Does remission of type 2 diabetes matter? A qualitative study of healthcare professionals' perspectives and views about supporting remission in primary care.

Trials conducted in highly selected populations have shown that type 2 diabetes (T2D) remission is possible, but the feasibility and acceptability of supporting remission in routine clinical practice remain uncertain. We explored primary care professionals' perceptions and understandings of T2D remission and their views about supporting remission within routine clinical care. Semi-structured interviews were conducted with 14 GPs and nine nurses working in Scottish general practices. Data were analysed thematically. Most participants considered remission to be a motivational tool but were unsure that it actually altered clinical management, due to patients still requiring follow-up and their expectations that remission is often temporary because of the constant effort required to sustain remission in an obesogenic environment. These perceptions, together with participants' concerns about loss to follow-up of patients who were likely to relapse and/or were still at high cardiovascular risk, appeared to underpin a reluctance to code remission in medical records. Most participants did not consider remission support to be a clinical priority. Moreover, they described being sensitive to the pitfalls of only encouraging some patients to pursue remission, because if resources were directed towards apparently more motivated, affluent individuals, there was a risk that this could widen health inequalities. For integration of remission support into mainstream T2D care to be successful, primary care professionals may need to be persuaded that remission matters more than encouraging well-managed T2D. They would also benefit from clear guidance on follow-up and optimal support for people in remission.

Comparing demographic/clinical characteristics, health care resource utilization, and costs among patients with type 2 diabetes and established atherosclerotic cardiovascular disease with and without the use of cardioprotective medications.

Type 2 diabetes (T2D) causes increased health care resource utilization (HCRU) and costs in the United States. People with T2D are more likely to have atherosclerotic cardiovascular disease (ASCVD), which is associated with significant morbidity and mortality. Medical associations recommend cardioprotective antidiabetic medications, including sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), to reduce the risk of cardiovascular events in patients with T2D with established, or a high risk of, ASCVD, but not all eligible patients receive these medications. To describe demographic/clinical characteristics and antidiabetic medication prescription patterns and compare HCRU and costs among patients with T2D and ASCVD with or without SGLT2i and/or GLP-1 RA use. We conducted a retrospective cohort study using the Merative MarketScan database of longitudinal US health care claims data with patients enrolled from July 1, 2014, to December 31, 2022. Patients with T2D and ASCVD receiving SGLT2is and/or GLP-1 RAs (case cohort) were compared with patients with T2D and ASCVD not receiving SGLT2is and/or GLP-1 RAs (control cohort) during a 12-month baseline period pre-index and a 12-month follow-up period post-index. The index date was SGLT2i/GLP-1 RA prescription for the case cohort and random health care visit for the control cohort. Baseline patient characteristics are reported before propensity score matching (PSM); HCRU and medical costs are reported after PSM. Before PSM, each cohort included 3,386 patients; after PSM, each cohort included 2,351 patients. Patients in the case cohort were significantly more likely to experience myocardial infarction (case, 26.2%; control, 21.5%; P < 0.001) or peripheral artery disease (case, 28.6%; control, 26.1%; P < 0.024) during the baseline period. Patients in the case cohort had significantly lower baseline Charlson Comorbidity Index scores than patients in the control cohort (case, 1.8; control, 2.1; P < 0.001). Patients in the case cohort had significantly fewer all-cause inpatient visits per patient (case, 0.4; control, 0.6; P < 0.001) and all-cause emergency department visits per patient (case, 0.9; control, 1.0; P = 0.024). Patients in the case cohort had significantly lower all-cause inpatient costs (case, $13,977; control, $22,056; P < 0.001), other all-cause outpatient costs (case, $16,504; control, $24,739; P < 0.001), and all-cause total medical costs including pharmacy costs (case, $51,143; control, $58,648; P = 0.01) in the 12-month follow-up period. Patients with T2D and ASCVD receiving SGLT2is and/or GLP-1 RAs within 12 months of ASCVD diagnosis may benefit from lower HCRU and costs.

Modeling of Disease Progression of Type 2 Diabetes Using Real-World Data: Quantifying Competing Risks of Morbidity and Mortality.

Type 2 diabetes (T2D) is a progressive metabolic disorder that could be an underlying cause of long-term complications that increase mortality. The assessment of the probability of such events could be essential for mortality risk management. This work aimed to establish a framework for risk predictions of macrovascular complications (MVC) and diabetic kidney disease (DKD) in patients with T2D, using real-world data from the Swedish National Diabetes Registry (NDR), in the presence of mortality as a competing risk. The study consisted of 41,517 patients with T2D registered in NDR between 2005 and 2013. At inclusion, patients were newly diagnosed (T2D < 1 year) and had no prior evidence of DKD or MVC. Using three-quarters of the data, a five-state multistate model was established to describe competing events of MVC, DKD, a combination thereof, and the terminal state, death. Two hypotheses were investigated: (1) the risk of MVC and DKD are mutually independent, and (2) mortality is independent of morbidities. At the end of the study, the majority of individuals remained in uncomplicated T2D; however, the probability of transition to complications and death increased over time. The mortality hazard depended on the presence of morbidities and was quantified as a life expectancy decreased by 5.0, 9.7, and 12.2 years for MVC, DKD, and the combined morbidity, respectively, compared to uncomplicated T2D. An established framework with a five-state model incorporating competing events was shown to be a useful tool for comorbidities risk assessment in newly diagnosed patients with T2D.

Weight stigma in pediatric type 1 diabetes: An associated risk for disordered eating?

Adolescents with type 1 diabetes (T1D) have elevated eating disorder risk. No studies have examined weight stigma as a potential factor associated with disordered eating. This study investigated cross-sectional associations among weight-based victimization, weight bias internalization, and disordered eating in adolescents with T1D. Adolescents (12-17 years; N = 166) self-reported experiences of weight-based victimization from peers, family members, and healthcare professionals. The Weight Bias Internalization Scale (WBIS) and Diabetes Eating Problems Survey (DEPS-R) assessed internalized weight bias and disordered eating, respectively. In a series of multiple hierarchical linear regression analyses (controlling for zBMI, diabetes duration, HbA1c, sex), weight bias internalization, weight-based victimization, and frequency of weight-based victimization by peers, family, and healthcare professionals were all positively associated with disordered eating. Weight stigma is an understudied but potentially important factor to address in adolescents with T1D. Reducing weight stigma may be a promising, novel target for eating disorder prevention in this population.

Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8+ T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8+ T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.

Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo controlled, randomised, crossover trial.

Type 2 diabetes (T2D) is a metabolic disease associated with cardiovascular dysfunction. The myocardium preferentially uses ketones over free fatty acids as a more energy efficient substrate. The primary aim was to assess the effects of ketone monoester (Kme) ingestion on cardiac output index (Q̇i). Secondary aims were to assess the effects of Kme ingestion on markers of cardiac haemodynamics, muscle oxygenation and vascular function at rest, during and following step-incremental cycling. We undertook a double-blind, randomised, crossover design study in 13 adults (age, 66±10 y; BMI, 31.3±7.0 kg·m-2) with T2D. Participants completed two conditions, where they ingested a Kme (0.115 g‧kg-1) or a placebo taste-mathced drink. Cardiac function was measured using thoracic impedance cardiography and muscle oxygenation of the calf was determined via near-infrared spectroscopy. Macrovascular endothelial function was measured by flow mediated dilation (FMD) and microvascular endothelial function was measured via transdermal delivery of acetylcholine (ACh) and insulin. Circulating β-hydroxybutyrate [β-Hb] was measured throughout. Kme ingestion raised circulating β-Hb throughout the protocol (peak 1.9 mM; P=0.001 vs. placebo). Kme ingestion increased Q̇i by 0.75±0.5 L∙min-1∙m-2 (P=0.003) stroke volume index by 7.2±4.5 mL∙m-2 (P=0.001), and peripheral muscle oxygenation by 9.9±7.1% (P=0.001) and reduced systemic vascular resistance index by-420±-225 dyn∙s-1∙cm-5∙m-2 (P=0.031) compared to placebo condition. There were no differences between Kme and placebo in heart rate (P=0.995), FMD (P=0.542), ACh max (P=0.800), insulin max (P=0.242). Ingestion of Kme improved Q̇i, stroke volume index and peripheral muscle oxygenation, but did not alter macro- or microvascular endothelial function in people with T2D.

Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.

Amyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies.

Therapeutic potential of stromal vascular fraction in early diabetic nephrotoxicity: a histomorphometric and immunohistochemical analysis in type 2 diabetes rat model.

Diabetic nephropathy (DN), a common complication of type 2 diabetes (T2D), significantly contributes to end-stage kidney disease (ESKD). Despite conventional treatments aimed at slowing disease progression, there is a pressing need for novel therapies. This study evaluates the potential therapeutic impact of adipose tissue derived stromal vascular fraction (SVF) on early diabetic nephrotoxicity in a rat model. Thirty-one male albino rats were divided into control and diabetic groups, with the latter further split into untreated (T2Da) and SVF-treated (T2Db) subgroups. Biochemical, histological, immunohistochemical, and morphometric analyses were conducted. We demonstrated that SVF treatment reduced oxidative stress, lowered serum creatinine, and improved renal architecture by mitigating fibrosis and cellular infiltration, suggesting enhanced tissue regeneration and reduced inflammation. SVF also facilitated cellular repair, indicated by increased endothelial cell proliferation and reduced glomerular damage. This study underscores SVF's potential as a promising regenerative approach for managing early-stage DN, warranting further research to elucidate its mechanisms.

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by diuretic use: A FIDELITY analysis.

This post hoc analysis aimed to assess the efficacy and safety of the non-steroidal mineralocorticoid receptor antagonist finerenone by baseline diuretic use in FIDELITY, a pre-specified pooled analysis of the phase III trials FIDELIO-DKD and FIGARO-DKD. Eligible patients with type 2 diabetes (T2D) and chronic kidney disease (CKD; urine albumin-to-creatinine ratio [UACR] ≥30-<300 mg/g and estimated glomerular filtration rate [eGFR] ≥25-≤90 ml/min/1.73 m2, or UACR ≥300-≤5000 mg/g and eGFR ≥25 ml/min/1.73 m2) were randomized 1:1 to finerenone or placebo. Patients were analysed by baseline diuretic use (yes/no) and type of diuretic (loop or thiazide). Key efficacy outcomes included a cardiovascular composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR, or kidney-related death). Out of 12 990 patients, 51.6% were taking diuretics at baseline (21.6% loop; 24.2% thiazide diuretics). Finerenone reduced the risk of cardiovascular and kidney composite outcomes versus placebo; diuretic use did not modify this effect on the cardiovascular (p-interaction = 0.94) or kidney outcomes (p-interaction = 0.55). Hyperkalaemia incidences were similar between finerenone subgroups irrespective of diuretic use and lower with placebo versus finerenone (with diuretics: finerenone 13.7% vs. placebo 5.7%; without diuretics: 14.3% vs. 8.3%). The incidence of hyperkalaemia leading to hospitalization or study drug discontinuation was low across treatment groups irrespective of diuretic use. This analysis showed that the efficacy and safety of finerenone in patients with CKD and T2D was not modified by baseline diuretic use.

Bcl-2 and Bcl-xL in Diabetes: Contributions to Endocrine Pancreas Viability and Function

Diabetes is a chronic metabolic disorder whose prevalence increases every year, affecting more than 530 million adults worldwide. Type 1 (T1D) and type 2 diabetes (T2D), the most common forms of diabetes, are characterized by the loss of functional pancreatic β-cells, mostly due to apoptosis. B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), two anti-apoptotic proteins belonging to the Bcl-2 family, are crucial for regulating the intrinsic pathway of apoptosis. However, over the years, they have been implicated in many other cellular processes, including intracellular Ca2+ homeostasis and the regulation of mitochondrial metabolism. Thus, understanding the biological processes in which these proteins are involved may be crucial to designing new therapeutic targets. This review summarizes the roles of Bcl-2 and Bcl-xL in apoptosis and metabolic homeostasis. It focuses on how the dysregulation of Bcl-2 and Bcl-xL affects pancreatic β-cell function and survival, and the consequences for diabetes development.

Automated insulin delivery in pregnant women with type 1 diabetes: a systematic review and meta-analysis.

The outcomes of automated insulin delivery (AID) systems in pregnant women with type 1 diabetes (T1D) have not been systematically evaluated. This study aims to evaluate the efficacy and safety of AID in pregnancy. Literature searches were conducted until July 5, 2024, on Embase, PubMed, Cochrane Library, and ClinicalTrials.gov website. We included clinical trials and observational studies evaluating AID systems in T1D pregnant individuals. Time in the target range (TIR, 3.5-7.8mmol/L) was the primary outcome. Secondary outcomes included time below range (TBR, < 3.5mmol/L), time above range (TAR, > 7.8mmol/L), and maternal and neonatal outcomes. Eighteen studies (550 participants) were included. Compared with standard care, AID did not improve 24-h TIR (mean differences [MD] 3.56%, 95% CI -0.60 to 7.72). However, the overnight TIR increased by 10.05% (95% CI 6.57 to 13.53). The association between AID and decreased TBR (MD -0.90%, 95% CI -1.60 to -0.20) was found, but not with deceased TAR. Only 7 of the 17 studies achieved the goal of a 24-h TIR above 70%. Additionally, the maternal and neonatal outcomes were comparable between AID and standard care, and AID might reduce maternal weight gain (MD -2.54kg, 95% CI -3.96 to -1.11). AID did not exhibit favourable TIR when compared to standard care. However, AID could increase overnight TIR and decrease TBR. Available evidence indicates that employing AID to meet the target of a 24-h TIR above 70% remains challenging.

Five-year outcomes of metabolic surgery in Chinese subjects with type 2diabetes.

Five-year outcomes of metabolic surgery in Chinese subjects with type 2diabetes.

Hepatic and Pancreatic Cellular Response to Early Life Nutritional Mismatch.

To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction associated steatotic liver disease (MASLD) and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric restricted rat with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate (RC), we investigated male and female IUGR-Hfhf and IUGR-RC, versus HFhf and CON offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islets insulin and humanin, and type1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype, by restoring functional β-islets and preventing MASLD and diabetes mellitus.

Investigation of the physicochemical factors affecting the in vitro digestion and glycemic indices of indigenous indica rice cultivars

Rice (Oryza sativa) is a vital food crop and staple diet for most of the world’s population. Poor dietary choices have had a significant role in the development of type-2 diabetes in the population that relies on rice and rice-starch-based foods. Hence, our study investigated the in vitro digestion and glycemic indices of certain indigenous rice cultivars and the factors influencing these indices. Cooking properties of rice cultivars were estimated. Further, biochemical investgations such as amylose content, resistant starch content were estimated using iodine-blue complex method and megazyme kit respectively. The in vitro glycemic index was estimated using GOPOD method. The rice cultivars considered in our study were classified into low-, intermediate-, and high-amylose rice varieties. The rice cultivars were subjected to physicochemical characterization by using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) techniques. FTIR spectral analysis revealed prominent bands at 3550-3200, 2927-2935, 1628-1650, 1420-1330, and 1300-1000 cm−1, which correspond to –OH groups, C=O, C=C, and C–OH stretches, and H–O–H and –CH bending vibrations, confirming the presence of starch, proteins, and lipids. Additionally, the FTIR ratio R(1047/1022) confirmed the ordered structure of the amylopectin. DSC analysis revealed variations in the gelatinization parameters, which signifies variations in the fine amylopectin structures and the degree of branching inside the starch granules. The percentage of resistant starch (RS) ranged from 0.50–2.6%. The swelling power (SP) of the rice flour ranged between 4.1 and 24.85 g/g. Furthermore, most of the rice cultivars are classified as having a high glycemic index (GI) based on the estimated in vitro GI (eGI), which varies from 73.74–90.88. The cooking properties of these materials were also investigated. Because the amylose content is one of the key factors for determining the cooking, eating, and digestibility properties of rice, we investigated the relationships between the amylose content and other biochemical characteristics of rice cultivars. The SP and GI were negatively correlated with the amylose content, whereas the RS had a positive relationship. The findings of our study can be beneficial in illustrating the nutritional profile and factors affecting the digestibility of traditional rice cultivars which will promote their consumption, cultivation, and contributes to future food security.

Amino acids and CART distinguish A-β+ Ketosis-Prone Diabetes from type 1 and type 2 diabetes during hyperglycemic crises.

When clinically stable, patients with A-β+ Ketosis-Prone Diabetes (KPD) manifest unique markers of amino acid metabolism. Biomarkers differentiating KPD from type 1 (T1D) and type 2 diabetes (T2D) during hyperglycemic crises would accelerate diagnosis and management. Compare serum metabolomics of KPD, T1D and T2D patients during hyperglycemic crises, and utilize Classification and Regression Tree (CART) modeling to distinguish these forms of diabetes. Urban hospital emergency center. Adults with KPD, T1D and T2D during hyperglycemic crises (with or without diabetic ketoacidosis (DKA), and healthy controls. Comparisons of serum metabolite and hormonal profiles, and CART analysis. Group differences in concentrations of amino acids, their metabolites and relationship to glucose counterregulatory hormones; C-peptide cutoffs and analytes to distinguish KPD, T1D and T2D. Concentrations of most amino acids were similar in KPD and T1D and lower compared to T2D (P<0.05). Glucagon and cortisol concentrations were correlated with 3-methylhistidine and blood urea nitrogen in KPD but not in T1D. A C-peptide cutoff of 0.496 ng/mL differentiated T1D from KPD during DKA. CART revealed that a regression model based on the concentrations of β-hydroxybutyrate, C-peptide, glucagon, alpha-keto-β-methylvalerate, cystine and myristoyl-L-carnitine distinguished KPD from T1D and T2D. During DKA, KPD and T1D patients have similarly altered amino acid profiles that differentiate them from T2D patients. Elevated protein catabolic hormones drive altered amino acid metabolism in KPD, rather than insulin deficiency as with T1D. A combination of 6 analytes differentiates KPD from T1D and T2D during hyperglycemic crises.

Strong Association of Autoantibodies Targeting Deamidated Extracellular Epitopes of Insulinoma Antigen-2 (IA-2) with Clinical Onset of Type 1 Diabetes.

Increasing evidence shows that pathogenic T cells in type 1 diabetes (T1D) that may have evaded negative selection recognize post-translational modified (PTM) epitopes of self-antigens. We have investigated the profiles of autoantibodies specifically targeting the deamidated epitopes of insulinoma antigen-2 extracellular domain (IA-2ec) to explore their relationship with T1D development. We compared the characteristics of autoantibodies targeting the IA-2ec Q>E epitopes (PTM IA-2ecA) as well as those targeting the IA-2ec unmodified epitopes (IA-2ecA) in participants across different stages of T1D development and in individuals with other types of diabetes and other kinds of autoimmunity. In patients with new-onset T1D, the prevalence of PTM IA-2ecA (26.1%) was significantly higher than that of IA-2ecA (19.5%, P<0.0001). In a longitudinal newborn cohort, both IA-2ecAs were present, but rare in preclinical stage 1 T1D, and with much lower positivity in individuals with stage 3 T1D who had been closely followed from birth in a clinical study compared to patients diagnosed in routine clinical settings with overt symptoms. In participants with latent autoimmune diabetes in adults, type 2 diabetes, and celiac disease autoimmunity, we did not observe significant positivity of either IA-2ecAs. These results indicate that PTM and unmodified IA-2ecA are predominantly present in clinical new-onset T1D patients, at late stages of T1D development.

Association of ABO Gene rs2073823 Polymorphism with Microvascular Complications, sP-Selectin Levels and Lipid Profile in Type 2 Diabetes.

Type 2 diabetes (T2D) is a prevalent metabolic disorder linked to chronic inflammation and endothelial dysfunction, which contributes to the development of microvascular complications (MVCs) such as diabetic retinopathy (DR) and diabetic neuropathy (DN). Genetic factors, including variations in the ABO gene, may influence these complications. This study aimed to investigate the association between the ABO rs2073823 polymorphism and the risk of MVCs in patients with T2D, as well as its impact on inflammatory biomarkers, endothelial markers, and lipid profiles. We conducted an exploratory study involving 96 T2D Iraqi patients (Asian Arabic), examining the distribution of the ABO rs2073823 polymorphism and its correlation with MVCs. We assessed levels of inflammatory markers (TNF-α, IL-6, sE-selectin, sP-selectin), glycemic markers, renal function biomarkers, and lipid profiles. Adjustment was made for confounding factors including age, gender, body mass index, duration of diabetes, and hypertension. Among the participants, 75% had MVCs, including DR (42%) and DN (65%). The ABO rs2073823 "A/A" genotype was associated with a reduced risk of MVCs under co-dominant (OR=0.16, p=0.045) and recessive models (OR=0.14, p=0.031). This protective effect remained significant after adjusting for confounding factors (OR=0.11, p=0.022). The "A/A" genotype was also linked to lower levels of total cholesterol, LDL-cholesterol, triglycerides, and sP-selectin. Patients with MVCs exhibited significantly higher levels of TNF-α, IL-6, and sP-selectin. The ABO rs2073823 polymorphism, particularly the "A/A" genotype, is associated with a decreased risk of MVCs in T2D patients and influences lipid metabolism and inflammatory markers. These findings suggest a genetic basis for the susceptibility to MVCs and highlight the role of the ABO gene in modulating inflammation and endothelial function in T2D. Further research is needed to validate these associations and explore potential therapeutic implications.

Novel T Cell reactivities to Hybrid Insulin Peptides in Islet Autoantibody-Positive At-Risk Subjects.

Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in T cell-mediated beta-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins. To identify T cell specificities contributing to T1D pathogenesis, we tested T cell reactivity from T1D patients or healthy control using an IFN-γ ELISPOT assay against a library of 240 C-peptide HIPs. We observed elevated T cell responses to peptide pools containing HIPs that form at the amino acid residues G15, A18 and L26 of C-peptide. In a second cohort of healthy controls, at-risk individuals, and T1D patients, T cell reactivity to HIPs forming at these three residues was monitored. Results indicate that, prior to clinical onset of T1D, there were significantly elevated responses to multiple pools of HIPs, and the magnitude of T cell reactivity to HIPs forming at residue A18 of the C-peptide was increased. Overall, our study identifies new T cell specificities in at-risk subjects and indicates that T cell reactivity to HIPs can be observed before T1D onset.