Background: Obesity and type 2 diabetes (T2D) pose global health problems that continue to rise. A chronic low-grade inflammation and activation of the immune system are well established in both conditions. The presence of these factors can predict disease development and progression. Emerging evidence suggests that platelet-high density lipoprotein ratio (PHR) is a potential inflammatory marker. The purpose of this study was to investigate the relationship between PHR and T2D among obese patients. Methods: 203 patients with BMI ≥ 30 kg/m2 participated in the study. Patients were categorized into two groups: non-diabetic obese and diabetic obese. Comorbidities, baseline characteristics, laboratory data, as well as PHR levels of the study groups were analyzed. Medians, risk assessment, and the diagnostic performance of PHR values were examined in both groups. Results: In obese patients, the median PHR were significantly increased in obese patients with T2D compared to non-diabetic obese (p < 0.0001). Furthermore, T2D obese with high PHR had a significantly higher FBG and HbA1c (p < 0.05). Although PHR was weakly yet significantly correlated with glycemic markers, ROC curve analysis of the PHR indicated an AUC of 0.700 (p < 0.0001) in predicting T2D in obese patients, and the cutoff value was 6.96, with a sensitivity and specificity of 53.4% and 76.1%, respectively. Moreover, increased PHR (OR = 4.77, p < 0.0001) carried a significantly higher risk for developing T2D in obese individuals. Conclusions: The PHR is a convenient and cost-effective marker that can reliably predict the presence of T2D in high-risk obese population.

Type 2 diabetes (T2D) and prediabetes are classically defined by the level of fasting glucose or surrogates such as hemoglobin HbA1c. This classification does not take into account the heterogeneity in the pathophysiology of glucose dysregulation, the identification of which could inform targeted approaches to diabetes treatment and prevention and/or predict clinical outcomes. We performed gold-standard metabolic tests in a cohort of individuals with early glucose dysregulation and quantified four distinct metabolic subphenotypes known to contribute to glucose dysregulation and T2D: muscle insulin resistance, β-cell dysfunction, impaired incretin action, and hepatic insulin resistance. We revealed substantial inter-individual heterogeneity, with 34% of individuals exhibiting dominance or co-dominance in muscle and/or liver IR, and 40% exhibiting dominance or co-dominance in β-cell and/or incretin deficiency. Further, with a frequently-sampled oral glucose tolerance test (OGTT), we developed a novel machine learning framework to predict metabolic subphenotypes using features from the dynamic patterns of the glucose time-series (\"shape of the glucose curve\"). The glucose time-series features identified insulin resistance, β-cell deficiency, and incretin defect with auROCs of 95%, 89%, and 88%, respectively. These figures are superior to currently-used estimates. The prediction of muscle insulin resistance and β-cell deficiency were validated using an independent cohort. We then tested the ability of glucose curves generated by a continuous glucose monitor (CGM) worn during at-home OGTTs to predict insulin resistance and β-cell deficiency, yielding auROC of 88% and 84%, respectively. We thus demonstrate that the prediabetic state is characterized by metabolic heterogeneity, which can be defined by the shape of the glucose curve during standardized OGTT, performed in a clinical research unit or at-home setting using CGM. The use of at-home CGM to identify muscle insulin resistance and β-cell deficiency constitutes a practical and scalable method by which to risk stratify individuals with early glucose dysregulation and inform targeted treatment to prevent T2D.

Pancreas-derived islet amyloid polypeptide (IAPP) aggregates and deposits in the pancreas and periphery of Type 2 Diabetes (T2D) patients, contributing to diabetic complications. The excess IAPP can be removed by autoantibodies, and increased levels of immunoglobulin (Ig) G against IAPP have been reported in T2D patients. However, whether other Ig classes are also affected and if the levels can be managed is less known. This pre-post study examines IgA levels against IAPP oligomers (IAPPO-IgA) in T2D patients and assesses the impact of the Okinawa-based Nordic (O-BN) diet-a low-carbohydrate, high-fiber diet-on these levels after following the diet for 3 months. IAPP, IAPPO-IgA, and total IgA levels were measured in plasma and fecal samples from n = 30 T2D patients collected at baseline, after 3 months of diet, and after additional 4 months of unrestricted diets (a clinical follow-up). The IAPP and IAPPO-IgA levels were significantly lower after 3 months, with the latter also being significantly reduced at the clinical follow-up. The reduction in plasma IAPP and IAPPO-IgA levels correlated with reductions in plasma levels of metabolic and inflammatory markers. Hence, following the O-BN diet for at least 3 months is sufficient to reduce circulating IAPP and IAPPO-IgA levels, which may be principal in managing T2D.

Although prior studies have shown that adiponectin synthesis is genetically determined and that its levels influence susceptibility to T2D, the results in this regard have been inconsistent. This study aims, to investigate the relationship between adiponectin gene variants with the risk of developing T2D among Tunisian women and in relation to their BMI status. A cohort of 491 Tunisian T2D women and 373 non-diabetic subjects participated in the study. Nine ADIPOQ variants namely rs16861194, rs17300539, rs266729, rs822395, rs822396, rs2241766, rs1501299, rs2241767 and rs3774261 were selected and genotyped using the TaqMan® SNP genotyping assay. Fasting serum adiponectin levels were quantified using ELISA. The results showed that only the rs17300539 variant exhibited a significant association with the risk of T2D. However, upon considering T2D group stratification based on BMI (normal weight [18-24.99 Kg/m2], overweight [25-29.99 Kg/m2] and obese [30-34.99 Kg/m2]), the ADIPOQ rs2241766 variant emerged as a contributing risk factor for increased BMI in obese women with T2D. Linear regression analysis revealed that the minor allele (A), (GA) and (AA) genotypes of rs17300539 as well as the (G) allele and (GG) genotype of rs2241766 were significantly associated with hypoadiponectinemia in T2D subjects. Two haplotypes namely GGCAATGAA and AGCCGTGGA, were identified as conferring a higher risk of T2D with the GGCAATGAA haplotype also correlating with hypoadiponectinemia. Our study underscores the importance of the rs17300539 variant and the GGCAATGAA haplotype in the risk of T2D and hypoadiponectinemia. Additionally, the presence of the rs2241766 variant highlights its association with \'diabesity\' and hypoadiponectinemia among Tunisian T2D women.

Globally, type 2 diabetes (T2D) and Cancer are the major causes of morbidity and mortality worldwide and are considered to be two of the most significant public health concerns of the 21st century. Over the next two decades, the global burden is expected to increase by approximately 60%. Several observational studies as well as clinical trials have demonstrated the health benefits of consuming whole grains to lower the risk of several chronic non-communicable diseases including T2D and cancer. Cereals grains are the primary source of energy in the human diet. The most widely consumed pseudo cereals include (quinoa, amaranth, and buckwheat) and cereals (wheat, rice, and corn). From a nutritional perspective, both pseudo cereals and cereals are recognized for their complete protein, essential amino acids, dietary fibers, and phenolic acids. The bran layer of the seed contains the majority of these components. Greater intake of whole grains rather than refined grains has been consistently linked to a lower risk of T2D and cancer. Due to their superior nutritional compositions, whole grains make them a preferred choice over refined grains. The modulatory effects of whole grains on T2D and cancer are also likely to be influenced by several mechanisms; some of these effects may be direct while others involve altering the composition of gut microbiota, increasing the abundance of beneficial bacteria, and lowering harmful bacteria, increasing insulin sensitivity, lowering solubility of free bile acids, breaking protein down into peptides and amino acids, producing short-chain fatty acids (SCFAs), and other beneficial metabolites that promote the proliferation in the colon which modulate the antidiabetic and anticancer pathway. Thus, the present review had two aims. First, it summarized the recent knowledge about the nutritional composition and bioactive acids in pseudo cereals (quinoa, amaranth, and buckwheat) and cereals (wheat, rice, and corn); the second section summarized and discussed the progress in recent human studies, such as observational (cross-sectional studies, case-control studies, and cohort studies) and intervention studies to understand their role in T2D and cancer including the potential mechanism. Overall, according to the scientific data, whole grain consumption may reduce the incidence of T2D and cancer. Future studies should carry out randomized controlled trials to validate observational results and establish causality. In addition, the current manuscript encourages researchers to investigate the specific mechanisms by which whole grains exert their beneficial effects on health by examining the effects of different types of specific protein, dietary fibers, and phenolic acids that might help to prevent or treat T2D and cancer.

UNASSIGNED: Diabetic nephropathy (DN) represents a major chronic kidney disorder and a leading cause of end-stage renal disease (ESRD). Small RNAs have been showing great promise as diagnostic markers as well as drug targets. Identifying dysregulated micro RNAs (miRNAs) could help in identifying disease biomarkers and investigation of downstream interactions, shedding light on the molecular pathophysiology of DN. In this study, we analyzed small RNAs within human urinary extracellular vesicles (ECVs) from DN patients using small RNA next-generation sequencing.
UNASSIGNED: In this cross-sectional study, urine samples were collected from 88 participants who were divided into 3 groups: type 2 diabetes (T2D) with DN (T2D + DN, n = 20), T2D without DN (T2D - DN, n = 40), and healthy individuals (n = 28). The study focused on isolating urinary ECVs to extract and sequence small RNAs. Differentially expressed small RNAs were identified, and a functional enrichment analysis was conducted.
UNASSIGNED: The study revealed a distinct subset of 13 miRNAs and 10 Piwi-interacting RNAs that were significantly dysregulated in urinary ECVs of the DN group when compared to other groups. Notably, miR-151a-3p and miR-182-5p exhibited a unique expression pattern, being downregulated in the T2D - DN group, and upregulated in the T2D + DN group, thus demonstrating their effectiveness in distinguishing patients between the 2 groups. Eight driver genes were identified PTEN, SMAD2, SMAD4, VEGFA, CCND2, CDK6, LIN28B, and CHD1.
UNASSIGNED: Our findings contribute valuable insights into the pathogenesis of DN, uncovering novel biomarkers and identifying potential therapeutic targets that may aid in managing and potentially decelerating the progression of the disease.

BACKGROUND: Insulin efsitora alfa (efsitora) is a basal insulin with a flat pharmacokinetic profile and long half-life, enabling weekly dosing. These attributes may provide stable glucose levels. This exploratory phase 1 study aimed to assess the hypoglycemic risk during experimental conditions that mimic situations encountered in daily life.
METHODS: This was a single-site, open-label, two-period, fixed-sequence study in participants with type 2 diabetes (T2D) previously treated with basal insulin. The incidence, duration, and nadir glucose of hypoglycemia were assessed after treatment with efsitora versus insulin glargine (glargine) during three provocation conditions: 24-h prolonged fasting, prolonged fasting with exercise, and double dosing of study insulin.
RESULTS: The 54 enrolled adults (BMI 21.8-39.7 kg/m2, HbA1c 6.5-9.4%) achieved stable fasting glucose before undergoing provocation. Most hypoglycemic events were level 1 (≥ 54 to < 70 mg/dL) and resolved spontaneously or after oral glucose. The incidences of level 1 hypoglycemia for efsitora and glargine were not significantly different: for prolonged fasting, the incidences were 44.7 vs. 42.6% and the difference in proportion was 2.1% (95% CI: - 17.2, 21.4); for prolonged fasting with exercise, the corresponding values were 65.9 vs. 50.0% and 15.9% (- 3.0, 34.8); for double dosing, the corresponding values were 68.1 vs. 61.7% and 6.4% (- 12.8, 25.6). Level 2 hypoglycemia (< 54 mg/dL) was infrequent during both treatments and all provocations. No severe hypoglycemia was observed. Mean nadir glucose (range 62.8-66.3 mg/dL) and hypoglycemia duration (range 76.6-115.2 min) were also similar for the two treatments, depending on the provocation.
CONCLUSIONS: Overall, weekly efsitora did not increase the incidence, duration, or severity of hypoglycemia compared to daily glargine during provocation periods in patients with T2D.
BACKGROUND: ClinicalTrials.gov identifier NCT04957914.

OBJECTIVE: The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D).
METHODS: T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita-), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29, FOS, JUN, NF-AT2, NF-KB1, STAT1-2, IRF1, IRF3, IRF7, and IRF9 was assessed with real-time qPCR.
RESULTS: Increased protein and gene levels of IL-29 were observed in Sita- group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita- group (p < 0.001 and p = 0.008). Expression of FOS, NF-AT2 and NF-KB1 in Sita- patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS, NF-AT2, and NF-KB1 was found in Sita+ group versus Sita- parients (p = 0.027, p = 0.003, and p = 0.002). In Sita- patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all).
CONCLUSIONS: Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS, NF-AT2 and NF-KB1 in T2D.

BACKGROUND: This cross-sectional study aims to explore whether there exists an interaction between selenium and menopause concerning type 2 diabetes (T2D) prevalence and its related indicators such as fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR).
METHODS: 150 women aged 35-60 years old were finally analyzed in this study. Multivariate linear or logistic regression modeling was conducted to explore the association of selenium and the prevalence of T2D besides its related indicators. Subgroup analyses were conducted based on menopause status to assess the potential impact on the relationship.
RESULTS: In the fully adjusted model, serum selenium was positively associated with FBG (β: 0.03, CI: 0.01-0.05) and the prevalence of T2D (OR: 1.04, CI: 1.00-1.08). After stratifying the data by menopause status, compared with the postmenopausal women group, as the serum selenium concentrations increased, the FBG concentrations were significantly higher in the premenopausal women group (p for interaction = 0.0020).
CONCLUSIONS: The present study found serum selenium was positively associated with FBG and the prevalence of T2D. Furthermore, the relationship between serum selenium and FBG was different in the premenopausal and postmenopausal women. More studies are still needed in the future to verify the relationship as well as to explore the specific mechanisms.

Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders\' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.