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Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Long-lived PFKFB3-expressing β-cells are dysfunctional partly because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type 2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition that maintains islet function by favoring constant selection of healthy winner cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional loser β-cells, we analyzed the overlap between human β-cells with bona fide loser signature across diabetes pathologies using the HPAP scRNA-seq and spatial transcriptomics of PFKFB3-positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of loser β-cells was represented by down-regulated ribosomal biosynthesis and genes encoding for mitochondrial respiration. PFKFB3-positive loser β-cells had the reduced expression of HLA class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 rs1983890 can interact with the anti-apoptotic gene MAIP1 implicating positive epistasis as a mechanism for prolonged survival of loser β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional loser β-cells leading to restored glucose tolerance in the mouse model of T2D.

BACKGROUND: Type 2 diabetes is a major public health concern in the United States and worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease. OBJECTIVE: The aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Womens Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes. DESIGN: Participants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the United States. DII/E-DII scores were calculated from a self-administered food frequency questionnaire at baseline that included 122 food items, of which 12 are representative of Hispanic eating patterns. PARTICIPANTS/SETTINGS: Participants included 3,849 postmenopausal women who self-identified as Hispanic that were recruited for the WHI from 1993 to 1998 at 40 US clinical centers. MAIN OUTCOME MEASURES: The outcome was incident diabetes. STATISTICAL ANALYSIS PERFORMED: Cox regression models were used to assess the association between DII/E-DII and incident diabetes. Models were adjusted for age at baseline, lifestyle-related risk factors, known type 2 diabetes mellitus (T2DM) risk factors, and neighborhood socioeconomic status. Interaction was tested between the DII/E-DII scores and obesity. RESULTS: The incidence of diabetes was 13.1% after a median follow-up of 13 years. Higher E-DII scores were associated with a higher risk of incident diabetes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04-1.14). There was no interaction between E-DII scores and obesity (P = 0.73). CONCLUSIONS: Pro-inflammatory diets, as measured by higher E-DII scores, were associated with a higher risk of incident diabetes. Future research is needed for understanding how the inflammatory potential of diets can be decreased.

BACKGROUND: The University of Californias Diabetes Prevention Program (UC DPP) Initiative was implemented systemwide to address diabetes and obesity risk on all 10 campuses. As little is known about implementing lifestyle change programs in university settings, we examined implementation partners (i.e., UC DPP leaders and campus leads) perceptions of factors influencing program success on UC campuses. METHODS: We conducted qualitative interviews with UC DPP leaders and campus leads to examine challenges and opportunities with university-based DPP delivery models. Interviews were recorded, professionally transcribed, and reviewed in detail by the research team. Transcripts were analyzed using rapid qualitative analysis (RQA). The study was approved by the UCLA Institutional Review Board. All implementation partners provided verbal informed consent. RESULTS: Twenty-six implementation partners (8 UC DPP leaders and 18 campus leads) completed interviews in 2021. Seven themes were identified as critical for implementation, including (1) marketing and recruitment (i.e., market and recruit broadly through established channels as well as target at-risk populations); (2) enrollment (i.e., offer the program during convenient times and let participants know what to expect); (3) use an adaptable, evidence-based program; (4) secure funding for the program, participants, lifestyle coaches, and space; (5) hire experienced and dedicated staff and lifestyle coaches; (6) ensure leadership support; and (7) utilize campus linkages and resources. Perceptions of challenges faced with respect to these themes are also described. CONCLUSIONS: This is one of the first studies to examine the challenges and opportunities of delivering an intensive lifestyle change program across 10 university sites. Understanding factors that enhance success of university-based diabetes prevention programs can facilitate UC DPP efforts and help inform delivery strategies of health and wellness programs across other university settings more broadly.

Plant-based dietary patterns, including vegetarian and vegan dietary patterns, may help to manage type 2 diabetes (T2DM) by contributing to maintenance of a healthy body weight, improved glycemic control, and reduced risk of diabetes complications. Several diabetes clinical practice guidelines support the use of vegetarian dietary patterns, but there has not been a recently updated systematic review (SR) of evidence from randomized controlled trials (RCTs) to examine efficacy. The primary objective of this SR was to examine the effect of vegetarian dietary patterns compared with nonvegetarian dietary patterns in adults with T2DM. MEDLINE, CINAHL, Cochrane CENTRAL Database of Controlled Trials, Food Science Source, and SportsDiscus databases were searched for RCTs published from 1998 to May 2023. Two independent reviewers extracted data and assessed risk of bias using the Cochrane RoB 2 tool. Data were pooled using a DerSimonian-Laird random-effects model and expressed as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the I2 statistic, and certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Full texts of 66 articles were reviewed, and 7 RCTs (n = 770 participants) were included in this SR. Vegetarian dietary patterns likely reduce hemoglobin A1c [MD (95% CI): -0.40% (-0.59, -0.21)] and body mass index [MD (95% CI): -0.96 kg/m2 (-1.58, -0.34)] (moderate certainty evidence); may allow for reduced diabetes medication (in 2 of 3 included studies) (low certainty); and may improve metabolic clearance of glucose (insulin sensitivity) [MD (95% CI): 10% (1.86, 18.14)] (very low certainty), compared with nonvegetarian dietary patterns. There were no effects of vegetarian dietary patterns on fasting blood glucose, fasting insulin, or low-density lipoprotein cholesterol concentrations. These findings support the inclusion of vegetarian or vegan dietary patterns as options in nutrition care plans for adults with T2DM. PROSPERO REGISTRATION: CRD42023396453.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Understanding chronic kidney disease (CKD) through the lens of evolutionary biology highlights the mismatch between our Paleolithic-optimized genes and modern diets, which led to the dramatically increased prevalence of CKD in modern societies. In particular, the Standard American Diet (SAD), high in carbohydrates and ultra-processed foods, causes conditions like type 2 diabetes (T2D), chronic inflammation, and hypertension, leading to CKD. Autosomal dominant polycystic kidney disease (ADPKD), a genetic form of CKD, is characterized by progressive renal cystogenesis that leads to renal failure. This review challenges the fatalistic view of ADPKD as solely a genetic disease. We argue that, just like non-genetic CKD, modern dietary practices, lifestyle, and environmental exposures initiate and accelerate ADPKD progression. Evidence shows that carbohydrate overconsumption, hyperglycemia, and insulin resistance significantly impact renal health. Additionally, factors like dehydration, electrolyte imbalances, nephrotoxin exposure, gastrointestinal dysbiosis, and renal microcrystal formation exacerbate ADPKD. Conversely, carbohydrate restriction, ketogenic metabolic therapy (KMT), and antagonizing the lithogenic risk show promise in slowing ADPKD progression. Addressing disease triggers through dietary modifications and lifestyle changes offers a conservative, non-pharmacological strategy for disease modification in ADPKD. This comprehensive review underscores the urgency of integrating diet and lifestyle factors into the clinical management of ADPKD to mitigate disease progression, improve patient outcomes, and offer therapeutic choices that can be implemented worldwide at low or no cost to healthcare payers and patients.

BACKGROUND: This study aimed to test the efficacy of patient-centered self-management intervention (PACE-SMI) to improve HbA1c, self-efficacy, and self-care behaviors in adults with type 2 diabetes mellitus (T2DM). METHODS: In this multicenter, parallel two-arm randomized controlled trial, 612 adults with T2DM and HbA1c ≥ 7% were enrolled and assigned to the control group (n = 310) and the intervention group (n = 302) using stratified permuted block randomization. The control group received usual care, whereas the intervention group received usual care plus nurse-led, theory-driven, culturally tailored PACE-SMI, comprising eight weekly sessions of individualized education, counseling, behavioral training, and home visit. Outcomes were assessed at baseline, postintervention, and 3 months follow-up. RESULTS: Data at 3 months were provided by 583 participants (control: n = 295, intervention: n = 288). Per-protocol analysis showed that the intervention group had a lower mean HbA1c (8.49% [standard deviation (SD), 1.58]) than the control group (8.74% [SD, 1.62]), with small yet statistically significant mean difference of 0.25% (95% confidence interval [CI], -0.01 to 0.51; Cohens d = 0.16; p = 0.03). Self-efficacy and self-care behaviors significantly improved in the intervention group (116.89 [SD, 25.50] and 70.01 [SD, 17.97]) compared to the control group (75.43 [SD, 18.99] and 51.54 [SD, 12.04]), with mean differences of 41.48 (95% CI, 37.83-45.13; Cohens d = 1.84; p

This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

PURPOSE: In addition to the existing biomarkers HER2 and PD-L1, FGFR2b has become an area of interest for the development of new targeted-based treatment. Given that clinical evaluation of FGFR2 targeted therapy is underway, we sought to elucidate the genomic landscape of FGFR2amp in gastroesophageal cancer (GEC) using a circulating tumor DNA (ctDNA) platform. MATERIALS AND METHODS: We retrospectively evaluated the Guardant Health database from 2017 to 2022 for patients with GECs with Guardant360 ctDNA next-generation sequencing (NGS) performed. We assessed co-occurring genetic alterations for patients who harbored FGFR2amp versus FGFR2null. We also explored real-world evidence database with Guardant Health, publicly available genomic databases (MSK cohort using cBioPortal), and pooled clinical data from large-volume cancer centers for FGFR2amp GECs. RESULTS: Less than 4% of patients with GEC in the Guardant Health database were identified to be FGFR2amp. The most commonly co-occurring gene mutations were TP53, CTNNB1, CDH1, and RHOA. Upon interrogation of the MSK cohort, these same genes were not significant on tissue NGS in the FGFR2amp cohort of GEC. In the pooled institutional cohort, we noted that FGFR2amp tumors were most commonly involving the gastroesophageal junction (GEJ). The overall survival of these patients was noted at 13.1 months. CONCLUSION: FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important in defining patient subgroups with responses to FGFR2-directed therapy. Using ctDNA to provide a more detailed genomic landscape in patients with GECs will allow the advancement of targeted therapy in the near future for these aggressive cancers.

BACKGROUND: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). METHODS: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). FINDINGS: Sixteen genes showed an association with PDAC risk (FDR

The association of gut microbial features with type 2 diabetes (T2D) has been inconsistent due in part to the complexity of this disease and variation in study design. Even in cases in which individual microbial species have been associated with T2D, mechanisms have been unable to be attributed to these associations based on specific microbial strains. We conducted a comprehensive study of the T2D microbiome, analyzing 8,117 shotgun metagenomes from 10 cohorts of individuals with T2D, prediabetes, and normoglycemic status in the United States, Europe, Israel and China. Dysbiosis in 19 phylogenetically diverse species was associated with T2D (false discovery rate < 0.10), for example, enriched Clostridium bolteae and depleted Butyrivibrio crossotus. These microorganisms also contributed to community-level functional changes potentially underlying T2D pathogenesis, for example, perturbations in glucose metabolism. Our study identifies within-species phylogenetic diversity for strains of 27 species that explain inter-individual differences in T2D risk, such as Eubacterium rectale. In some cases, these were explained by strain-specific gene carriage, including loci involved in various mechanisms of horizontal gene transfer and novel biological processes underlying metabolic risk, for example, quorum sensing. In summary, our study provides robust cross-cohort microbial signatures in a strain-resolved manner and offers new mechanistic insights into T2D.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c

OBJECTIVE: Real-time continuous glucose monitoring (CGM) is effective for diabetes management in cases of type 1 diabetes and adults with type 2 diabetes (T2D) but has not been assessed in adolescents and young adults (AYAs) with T2D. The objective of this pilot interventional study was to assess the feasibility and acceptability of real-time CGM use in AYAs with T2D. METHODS: Adolescents and young adults (13-21 years old) with T2D for six months or more and hemoglobin A1c (A1c) greater than 7%, on any Food and Drug Administration-approved treatment regimen, were included. After a blinded run-in period, participants were given access to a real-time CGM system for 12 weeks. The use and acceptability of the real-time CGM were evaluated by sensor usage, surveys, and focus group qualitative data. RESULTS: Participants (n = 9) median age was 19.1 (interquartile range [IQR] 16.8-20.5) years, 78% were female, 100% were people of color, and 67% were publicly insured. Baseline A1c was 11.9% (standard deviation ±2.8%), with median diabetes duration of 2.5 (IQR 1.4-6) years, and 67% were using insulin. Seven participants completed the study and demonstrated statistically significant improvement in diabetes-related quality of life, with the mean Pediatric Quality of Life inventory (PedsQL) diabetes score increasing from 70 to 75 after using CGM (P = .026). Focus group results supported survey results that CGM use among AYAs with T2D is feasible, can improve quality of life, and has the potential to modify behavior. CONCLUSION: Real-time CGM is feasible and acceptable for AYAs with T2D and may improve the quality of life of patients with diabetes. Larger randomized controlled trials are needed to assess the effects on glycemic control and healthy lifestyle changes.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Introduction: The purpose of this study was to characterize how family influences diabetes self-management in Mexican American adults. Methods: Data were analyzed from previously collected data that included 34 semi-structured interviews with Hispanic adults with diabetes and six focus groups with 37 adults with diabetes and family members. Themes related to family and diabetes management were identified and analyzed using a modified template approach. Results: Family-related facilitators to T2DM self-management were (1) provides support, (2) provides motivation, and (3) desire to protect family from diabetes. Family-related challenges were (1) lack of support, (2) family responsibilities, and (3) stress related to family. Diabetes education was shared with family members. Family member perspectives on T2DM included (1) not knowing how to help, (2) effect on emotional wellbeing, (3) diabetes affects the whole family, and (4) family provides support. Conclusion: Most participants with T2DM felt supported by family, but many desired more social support and support surrounding dietary changes from family. Many felt family did not understand what living with diabetes meant for them. Most family members wished to learn more about how to help. Future interventions should include family members and teach them supportive strategies to support beneficial diabetes self-management behaviors.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. METHODS: Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined pure DbCM when SBHF is associated solely with T2D and mixed SBHF when other medical conditions can contribute to SBHF. Pure DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m2, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. RESULTS: Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with mixed SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of pure DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. CONCLUSIONS: Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus (T2DM) subjects. Eighteen animals were allocated to three groups: (i) control, (ii) MS (diet for obesity induction), and (iii) T2DM (diet plus streptozotocin for T2DM induction). Maxillary and mandible premolars and first molar were extracted. After 3 months of healing, four implants per side were placed in both jaws of each animal. After 2 months, peri-implantitis was induced by plaque formation using silk ligatures. SAPAE polymer was mixed with mineral oil (3.75 mg/μL) and topically applied biweekly for up to 60 days to halt peri-implantitis progression. Periodontal probing was used to assess pocket depth over time, followed by histomorphologic analysis of harvested samples. The adopted protocol resulted in the onset of peri-implantitis, with healthy minipigs taking twice as long to reach the same level of probing depth relative to MS and T2DM subjects (∼3.0 mm), irrespective of jaw. In a qualitative analysis, SAPAE therapy revealed decreased levels of inflammation in the normoglycemic, MS, and T2DM groups. SAPAE application around implants significantly reduced the progression of peri-implantitis after ∼15 days of therapy, with ∼30% lower probing depth for all systemic conditions and similar rates of probing depth increase per week between the control and SAPAE groups. MS and T2DM conditions presented a faster progression of the peri-implant pocket depth. SAPAE treatment reduced peri-implantitis progression in healthy, MS, and T2DM groups.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

BACKGROUND: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). METHODS: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. CONCLUSIONS: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). CLINICAL TRIAL REGISTRATION: NCT03694522.

BackgroundSouth Asians are at higher risk for type 2 diabetes (T2D) than many other race/ethnic groups. Ectopic adiposity, specifically hepatic steatosis and visceral fat may partially explain this. Our objective was to derive metabolite risk scores for ectopic adiposity and assess associations with incident T2D in South Asians.MethodsWe examined 550 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort study aged 40-84 years without known cardiovascular disease or T2D and with metabolomic data. Computed tomography scans at baseline assessed hepatic attenuation and visceral fat area, and fasting serum specimens at baseline and after 5 years assessed T2D. LC-MS-based untargeted metabolomic analysis was performed followed by targeted integration and reporting of known signals. Elastic net regularized linear regression analyses was used to derive risk scores for hepatic steatosis and visceral fat using weighted coefficients. Logistic regression models associated metabolite risk score and incident T2D, adjusting for age, gender, study site, BMI, physical activity, diet quality, energy intake and use of cholesterol-lowering medication.ResultsAverage age of participants was 55 years, 36% women with an average body mass index (BMI) of 25 kg/m2 and 6% prevalence of hepatic steatosis, with 47 cases of incident T2D at 5 years. There were 445 metabolites of known identity. Of these, 313 metabolites were included in the MET-Visc score and 267 in the MET-Liver score. In most fully adjusted models, MET-Liver (OR 2.04 [95% CI 1.38, 3.03]) and MET-Visc (OR 2.80 [1.75, 4.46]) were associated with higher odds of T2D. These associations remained significant after adjustment for measured adiposity.ConclusionsMetabolite risk scores for intrahepatic fat and visceral fat were strongly related to incident T2D independent of measured adiposity. Use of these biomarkers to target risk stratification may help capture pre-clinical metabolic abnormalities.

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.

Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m-2 in the European subpopulation and 24.2 (22.9-25.5) kg m-2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m-2 in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.

Multiomics has shown promise in noninvasive risk profiling and early detection of various common diseases. In the present study, in a prospective population-based cohort with ~18 years of e-health record follow-up, we investigated the incremental and combined value of genomic and gut metagenomic risk assessment compared with conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer disease and prostate cancer. We found that polygenic risk scores (PRSs) improved prediction over conventional risk factors for all diseases. Gut microbiome scores improved predictive capacity over baseline age for CAD, T2D and prostate cancer. Integrated risk models of PRSs, gut microbiome scores and conventional risk factors achieved the highest predictive performance for all diseases studied compared with models based on conventional risk factors alone. The present study demonstrates that integrated PRSs and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases.

PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Chronic use of nicotine is known to dysregulate metabolic signaling through altering circulating levels of feeding-related hormones, contributing to the onset of disorders like type 2 diabetes. However, little is known about the acute effects of nicotine on hormonal signaling. We previously identified an acute increase in food intake following acute nicotine, and we sought to determine whether this behavior was due to a change in hormone levels. We first identified that acute nicotine injection produces an increase in feeding behavior in dependent rats, but not nondependent rats. We confirmed that chronic nicotine use increases circulating levels of insulin, leptin, and ghrelin, and these correlate with rats' body weight and food intake. Acute nicotine injection in dependent animals decreased circulating GLP-1 and glucagon levels, and administration of glucagon prior to acute nicotine injection prevented the acute increase in feeding behavior. Thus, acute nicotine injection increases feeding behavior in dependent rats by decreasing glucagon signaling.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

Compared to a Western diet, the Mediterranean diet moves away from red meat and processed foods. Universally regarded as a healthier dietary alternative, the Mediterranean diet has garnered scientific endorsement for its ability to confer an array of compelling benefits. These health benefits encompass not only a lowered incidence of Type 2 diabetes with a reduction in obesity, but also a robust protective effect on cardiovascular health. Extensive literature exists to corroborate these health benefits; however, the impact of a Mediterranean diet on urologic diseases, specifically sexual dysfunction, lower urinary tract symptoms, stone disease, and urologic cancers are not well studied. Understanding how dietary habits may impact these urologic conditions can contribute to improved prevention and treatment strategies.A total of 955 papers from PubMed and Embase were systematically reviewed and screened. After exclusion of disqualified and duplicated studies, 58 studies consisting of randomized controlled trials, cohort studies, cross sectional studies, reviews and other meta-analyses were included in this review. 11 primary studies were related to the impact of a Mediterranean diet on sexual dysfunction, 9 primary studies regarding urinary symptoms, 8 primary studies regarding stone disease, and 9 primary studies regarding urologic cancers. All primary studies included were considered of good quality based on a New-Castle Ottawa scale. The results demonstrate a Mediterranean diet as an effective means to prevent as well as improve erectile dysfunction, nephrolithiasis, lower urinary tract symptoms, and urinary incontinence. The review highlights the need for additional research to study the impact of diet on urologic cancers and other urologic conditions such as premature ejaculation, loss of libido, female sexual dysfunction, and overactive bladder.

BACKGROUND: Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction. METHODS: A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network. RESULTS: Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets. CONCLUSIONS: This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.

BACKGROUND: To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds. METHODS AND RESULTS: This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. CONCLUSIONS: The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.

INTRODUCTION: The University of California (UC) implemented the Diabetes Prevention Program (DPP) to address diabetes and obesity risk. This project examined the reach and effectiveness of this university-based DPP delivery approach. METHODS: This project compared 12-month weight change among three groups of UC beneficiaries with overweight/obesity: (1) those who received invitation letters and enrolled in UC DPP, (2) those mailed invitation letters but did not enroll, and (3) those who were not mailed letters and did not enroll (controls). Using 2012-2022 EHR, administrative and DPP cohort data, an interrupted time series was conducted in 2022-2023 to compare group differences in rate of weight change. RESULTS: Among 6,231 beneficiaries (132 UC DPP aware enrollees, 1,750 DPP aware non-enrollees, 4,349 controls), UC DPP enrollees were older (mean age 49), mostly women (76%), and more diverse (33% Asian, 8% Black, 20% Hispanic, 4% Multi/Other). Over 12 months of follow-up, UC DPP enrollee postenrollment rate of weight loss was -0.68 lbs./month. UC DPP enrollees had significantly greater weight change from pre- to post-enrollment than DPP aware non-enrollees (adjusted Δ-1.02 vs. Δ-0.07 lbs./month, difference= -0.95, p

Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimers disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.

Objective: Examine the impact of a primary care-embedded clinical pharmacist-led intervention (UCMyRx) on hemoglobin A1C and blood pressure control, relative to usual care, among patients with Type 2 diabetes (TD2) and Medicaid, in a large healthcare system. Methods: We used data extracted from the Electronic Health Records system and a Difference-In-Differences study design with a 2:1 propensity-matched comparison group to evaluate the impact of UCMyRx on HbA1c and systolic blood pressure among patients with TD2 and Medicaid, relative to usual care. Results: Having at least one UCMyRx clinical pharmacist visit was associated with a significant reduction in HbA1c; (-.27%, P-value= .03) but no impact on SBP. We do not find differential UCMyRx effects on HbA1c or SBP among the subpopulations with baseline HbA1C ≥9% or SBP ≥150 mmHg, respectively. In Charlson Comorbidity Index (CCI)-stratified analyses we found stronger UCMyRx effects on HbA1C (-.47%, P-value< .02) among the CCI tercile with the lowest comorbidity score (CC1 ≤ 5). Significant UCMyRx effects are only observed among the subpopulation of Medicaid beneficiaries without Medicare (-.35%, P-value= .02). Conclusions: The UCMyRx intervention is a useful strategy for improving HbA1c control among patients with TD2 and Medicaid.

BACKGROUND: Dyslipidemia is treated effectively with statins, but treatment has the potential to induce new-onset type-2 diabetes. Gut microbiota may contribute to this outcome variability. We assessed the associations of gut microbiota diversity and composition with statins. Bacterial associations with statin-associated new-onset type-2 diabetes (T2D) risk were also prospectively evaluated. METHODS: We examined shallow-shotgun-sequenced fecal samples from 5755 individuals in the FINRISK-2002 population cohort with a 17+-year-long register-based follow-up. Alpha-diversity was quantified using Shannon index and beta-diversity with Aitchison distance. Species-specific differential abundances were analyzed using general multivariate regression. Prospective associations were assessed with Cox regression. Applicable results were validated using gradient boosting. RESULTS: Statin use associated with differing taxonomic composition (R2, 0.02%; q=0.02) and 13 differentially abundant species in fully adjusted models (MaAsLin; q

Background/Objectives: Lowering low-density lipoprotein cholesterol (LDL-C) to <70 mg/dL is recommended for most patients with diabetes. However, clinical trials investigating subjects with diabetes who are not at high cardiovascular risk are inconclusive regarding the all-cause mortality benefit of the current target, and real-world studies suggest greater mortality. We aimed to assess the all-cause mortality at different LDL-C levels among subjects with diabetes not at high risk and to examine the potential roles of early deaths and frailty for this greater mortality. Methods: We followed 2098 such participants of the ELSA-Brasil cohort between 2008 and 2019. Results: Over 10.3 (1.4) years of follow-up, 204 (9.7%) individuals died. In the proportional hazards models, participants with LDL-C values < 100 mg/dL and <70 mg/dL had greater adjusted mortality compared to those with LDL-C 100–129 mg/dL (HR = 1.67; 95%CI 1.21–2.30 and HR = 2.27; 95%CI 1.51–3.41, respectively). Increased risk when LDL-C was <100 mg/dL was higher in those >60 years (HR = 2.12; 95%CI 1.35–3.34) and greatest for deaths due to cancer (HR = 2.55; 95%CI 1.10–5.91). Further analyses for those with LDL-C < 100 mg/dL that excluded early deaths and adjusted for the frailty phenotype (HR = 2.01; 1.19–3.41) or frailty index (HR = 1.92; 1.17–3.16) did not materially alter the results. The risk of death across the spectrum of LDL-C was U-shaped, with a nadir at 112.2 mg/dL. Conclusions: The higher risk of all-cause mortality in these subjects with LDL-C within currently recommended levels was not explained by early deaths or frailty. Given the recent decline in cardiovascular mortality and the increased risk of cancer and infections in persons with diabetes, the clinical significance of low LDL-C in diabetes requires reconsideration and the definition of LDL-C treatment targets in diabetes warrants further trial evaluation. [ABSTRACT FROM AUTHOR]

Introduction: Streptococcus suis (SS) is one of the most important pathogens causing major economic losses in the global pig farming industry and is a serious threat to public health safety. It has multiple serotypes, with poor cross-protection between serotypes, and effective typing methods are lacking. Methods: In this study, a quadruplex TaqMan fluorescence quantitative PCR assay that can differentiate between Streptococcus suis types 2, 7 and 9 was developed using the gdh gene, a generic gene for Streptococcus suis , and cps2J , cps7H and cps9J , genes encoding podocarp-associated genes for types 2, 7 and 9, respectively, as targets. Results: The method is specific enough to accurately type Streptococcus suis pigmentosus without detecting non-target pathogens (Escherichia coli , Pasteurella multocida , Staphylococcus aureus , Streptococcus agalactiae, Streptococcus pneumoniae and et al). The sensitivity was high, with a minimum lower detection line of 10 copies for P-SS and P-SS9, and 100 copies for P-SS2 and P-SS7. The standard curves generated showed good linearity with R2 of 0.999, 0.999, 0.997 and 0.998 respectively. The repeatability was good, with coefficients of variation between batch to batch and batch to batch tests ranging from 0.21% to 1.10%. Testing of 156 samples yielded 68 positive and 88 negative samples, of which the positive rate of SS was 5.77% (9/156), SS2 was 20.51% (32/156), SS7 was 8.33% (13/156) and SS9 was 9.6% (15/156), which was in line with the existing fluorescent quantitative PCR assay of 93.75%~100%, which was higher than the detection rate of conventional PCR. Discussion: The quadruplex TaqMan fluorescence quantitative PCR method of Streptococcus suis generic, type 2, 7 and 9 established in this study can accurately differentiate the three serotypes of Streptococcus suis that currently have high prevalence and pathogenicity, which is of great importance for accurate clinical prevention and treatment, epidemiological investigation and vaccine development. [ABSTRACT FROM AUTHOR]

Background/Aim. Diabetes mellitus (DM) represents a significant and enduring health concern and, due to various complications arising from inadequate management, leads to disability and mortality. The aim of this study was to examine the impact of the family-engaged multidisciplinary collaborative care (FEC) model on the management of type 2 DM (T2DM) in young and middle-aged patients, considering the presence of DM distress. Methods. The study included 98 patients aged 18 to 59 diagnosed with T2DM and experiencing DM distress. The patients were admitted to the Department of Endocrinology of The First People's Hospital of Jingzhou, in Hubei province, China, between February and December 2023. Using the random number table method, the patients were randomly assigned to either the intervention group (IG) or control group (CG), each consisting of 49 patients. While both groups received standard care, IG additionally received FEC. We assessed and compared glycated hemoglobin (HbA1c) levels, Diabetes Distress Scale (DDS) scores, Summary of Diabetes Self-care Activities (SDSCA) scores, and body mass index (BMI) between the two groups before the intervention and three months after. Results. Three months post-intervention, IG exhibited lower HbA1c levels (6.02 ± 0.63 vs. 6.81 ± 0.85) and DDS scores (25.27 ± 2.70 vs. 34.24 ± 4.46) while demonstrating higher SDSCA scores (30.69 ± 1.91 vs. 25.03 ± 2.13) compared to CG. Additionally, the BMI of patients in IG measured 23.83 ± 2.51 kg/m2, which, compared to the BMI of CG (25.64 ± 3.68 kg/m2), was statistically significant (p < 0.05). Conclusion. The FEC model demonstrated efficacy in lowering HbA1c levels and BMI, mitigating DM distress, and enhancing self-care capabilities among young and middle-aged patients with T2DM experiencing DM-related distress. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) increases the risk of interstitial lung disease (ILD). SLE is also linked to an elevated risk of type 2 diabetes mellitus (T2DM). However, the impact of T2DM on ILD risk in patients with SLE is still unclear. This study aimed to compare the prevalence of ILD in patients with SLE based on the presence of T2DM (SLE + T2DM+) or its absence (SLE + T2DM−). Methods: This was a retrospective cohort study using the 2019–2020 National Inpatient Sample database. Adult SLE patients were identified and stratified by T2DM status. Comparable cohorts were created using propensity score matching, resulting in 10,532 patients in each cohort. Multivariate logistic regression assessed the association between T2DM and ILD. Results: T2DM was associated with a lower prevalence of ILD in patients with SLE (OR 0.798, 95% CI: 0.695–0.918, p =.002), occurring in 371 (3.5%) patients with T2DM compared to 463 (4.4%) patients without T2DM. Specifically, this difference was mainly driven by pulmonary fibrosis, which was significantly less frequent in the T2DM group (1.3% vs 1.8%, OR 0.7, 95% CI: 0.560–0.875, p =.002). No differences were found in secondary outcomes, including death rates, length of hospital stay, ARDS, pneumothorax, pleural effusion, or pulmonary arterial hypertension. Conclusion: Our study suggests that T2DM significantly reduced ILD risk in patients with SLE, specifically diminishing pulmonary fibrosis prevalence. Further research should explore mechanisms for this protective association between T2DM and ILD development in SLE. These findings may guide management strategies for this vulnerable population. [ABSTRACT FROM AUTHOR]

Our goal was to determine the prevalence of anxiety and depression in a sample of U.S. military veterans with type 2 diabetes and elevated diabetes distress (DD). Cross-sectional analyses were conducted. The association between DD and anxiety and depression was assessed with logistic regression. Almost 80% of persons with elevated DD had clinically significant anxiety or depression symptoms. The odds of depression and anxiety increased with DD severity. Given the large overlap of depression and anxiety with elevated DD, we recommend providers screen for all three conditions and, if positive, connect to resources for diabetes self-management and/or clinical treatment. [ABSTRACT FROM AUTHOR]

Diabetes distress (DD) is a negative psychosocial response to living with type 2 diabetes mellitus (T2DM). We sought insight into Veterans' experiences with DD in the context of T2DM self-management. The four domains in the Diabetes Distress Scale (i.e. regimen, emotional, interpersonal, healthcare provider) informed the interview guide and analysis (structural coding using thematic analysis). The mean age of the cohort (n = 36) was 59.1 years (SD 10.4); 8.3% of patients were female and 63.9% were Black or Mixed Race; mean A1C was 8.8% (SD 2.0); and mean DDS score was 2.4 (SD 1.1), indicating moderate distress. Veterans described DD and challenges to T2DM self-management across the four domains in the Diabetes Distress Scale. We found that (1) Veterans' challenges with their T2DM self-management routines influenced DD and (2) Veterans experienced DD across a wide range of domains, indicating that clinical interventions should take a "whole-person" approach. Trial Registration: NCT04587336 [ABSTRACT FROM AUTHOR]

Pancreatic β cell damage is the primary contributor to type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains nebulous. This study explored the role of ferroptosis in pancreatic β cell damage and the protective effects of grape seed proanthocyanidin extract (GSPE). In T2DM model rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of the T2DM model. MIN6 mouse insulinoma β cells were cultured in high glucose and sodium palmitate conditions to obtain a glycolipid damage model, which was administered with GSPE, ferrostatin-1 (Fer-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. GSPE and Fer-1 treatment significantly improved pancreatic β-cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved iron metabolism. Furthermore, the treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing β-cell damage and dysfunction in T2DM. Therefore, GSPE is a potential treatment strategy against T2DM. [ABSTRACT FROM AUTHOR]

Background: The global burden of type 2 diabetes (T2D) and colorectal cancer (CRC) continues to rise. Observational studies have suggested a link between T2D and an elevated risk of CRC. However, these studies are often susceptible to confounding factors and reverse causation, leading to inconsistent findings. There is a specific gap in knowledge regarding the causal nature of the relationship between T2D and CRC, which this study aims to address using a more robust approach. To fill this gap, we employed Mendelian randomization (MR), a method that uses genetic variants as instrumental variables (IVs) to infer causality, providing clearer insight into the genetic links between T2D and CRC. Methods: A bidirectional MR study was conducted to investigate the causal links between T2D and CRC. Genetic instruments for T2D were derived from two large genome-wide association studies (GWAS) with a total sample size of X individuals, and CRC genetic instruments were obtained from a GWAS with Y individuals. The MR analysis utilized the inverse-variance weighted (IVW) method as the primary analysis, alongside sensitivity analyses such as heterogeneity and pleiotropy analysis to account for potential pleiotropy and bias. Additionally, to enhance the robustness of the findings and minimize the influence of data from different GWAS sources, we performed a meta-analysis of the IVW results. Results: The MR analysis and meta-analysis revealed that genetically predicted T2D is associated with an increased risk of CRC (Pooled ORIVW = 1.07, 95% CI 1.02–1.12, P = 0.003). However, the reverse analysis did not indicate a causal effect of genetically predicted CRC on T2D risk (Pooled ORIVW = 1.02, 95% CI 0.96–1.09, P = 0.469). Sensitivity analyses supported the robustness of these findings, indicating no evidence of heterogeneity or pleiotropic effects that could bias the results (all P > 0.05). Conclusion: Our bidirectional MR study and meta-analysis provide evidence that T2D increases the risk of colorectal cancer. However, there is no evidence to support a reverse causal relationship. These findings highlight the importance of monitoring and managing T2D as part of CRC prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus is a metabolic disease categorized by hyperglycemia, resistance to insulin, and ß-cell dysfunction. Around the globe, approximately 422 million people have diabetes, out of which 1.5 million die annually. In spite of innovative advancements in the treatment of diabetes, no biological drug has been known to successfully cure and avert its progression. Thereupon, natural drugs derived from plants are emerging as a novel therapeutic strategy to combat diseases like diabetes. Objective: The current study aims to investigate the antidiabetic potential of natural compounds of Oryza sativa L. indica (black rice) in disease treatment. Methods: Antioxidant activity and alpha amylase assays were performed to evaluate the therapeutic potential of the extract of Oryza sativa L. indica. Gas chromatography–mass spectrometry (GC–MS) was used for identification of constituents from the ethanol extract. ADMET profiling (absorption, distribution, metabolism, excretion, and toxicity), network pharmacology, and molecular dynamics simulation were employed in order to uncover the active ingredients and their therapeutic targets in O. sativa L. indica against type 2 diabetes mellitus. Results: GC–MS of the plant extract provided a list of 184 compounds. Lipinski filter and toxicity parameters screened out 18 compounds. The topological parameters of the protein–protein interaction (PPI) were used to shortlist the nine key proteins (STAT3, HSP90AA1, AKT1, SRC, ESR1, MAPK1, NFKB1, EP300, and CREBBP) in the type 2 diabetes mellitus pathways. Later, molecular docking analysis and simulations showed that C14 (1H-purine-8-propanoic acid,.alpha.-amino-2, 3, 6, 7-tetrahydro-1,3,7-trimethyl-2,6-dioxo-) and C18 (cyclohexane-carboxamide, N-furfuryl) bind with AKT1 and ESR1 with a binding energy of 8.1, 6.9, 7.3, and 7.2 kcal/mol, respectively. RMSD (root-mean-square deviation) and RMSF (root-mean-square fluctuation) values for AKT1 and ESR1 have shown very little fluctuation, indicating that proteins were stabilized after ligand docking. Conclusion: This study suggests therapeutic drug candidates against AKT1 and ESR1 to treat type 2 diabetes mellitus. However, further wet-lab analysis is required to discover the best remedy for type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background The application of clinical practice guidelines (CPGs) across the spectrum of individuals living with diabetes can be challenging, particularly in older adults, where factors such as frailty and multimorbidity exacerbate the complexity of management. Objective This systematic review aimed to explore the guidance provided within diabetes CPGs for management of individuals who are older and/or frail, including recommendations for haemoglobin A1C (HbA1c) target and pharmacotherapeutic management. Methods A systematic search was completed in Medline and Embase to identify national or international type 2 diabetes CPGs published in the last 10 years. Data extracted included recommendations for HbA1c targets and pharmacotherapy in older and frail adults, frailty screening and deprescribing. Quality of included CPGs was appraised with the AGREE II tool. Results Twenty-three CPGs were included, within which older adults and frailty were discussed in 21 and 14 CPGs, respectively. Specific HbA1c targets for older and/or frail adults were provided by 15 CPGs, the majority of which suggested a strict target (<7.0%–7.5%) in healthier older adults and a more relaxed target (<8.0%–8.5%) in those who are frail or medically complex. Ten CPGs provided recommendations for insulin therapy and 16 provided recommendations for non-insulin antihyperglycaemic agents that were specific to older and/or frail populations, which primarily focused on minimising risk of hypoglycaemia. Conclusion Most diabetes CPGs recommend strict HbA1c targets in healthier older adults, with more relaxed targets in those living with frailty or medical complexity. However, significant variability exists in pharmacotherapy recommendations and there were proportionately less recommendations for individuals who are frail. [ABSTRACT FROM AUTHOR]

Background Type 2 diabetes mellitus (T2DM) intricately involves disrupted lipid metabolism. Exosomes emerge as carriers of biomarkers for early diagnosis and monitoring. This study aims to identify lipid metabolites in serum exosomes for T2DM diagnosis. Methods Serum samples were collected from newly diagnosed T2DM patients and age and body mass index−matched healthy controls. Exosomes were isolated using exosome isolation reagent, and untargeted/targeted liquid chromatography−tandem mass spectrometry (LC-MS/MS) was used to identify and validate altered lipid metabolites. Receiver operating characteristic curve analysis was used to evaluate the diagnostic value of candidate lipid metabolites. Results Serum exosomes were successfully isolated from both groups, with untargeted LC-MS/MS revealing distinct lipid metabolite alterations. Notably, phosphatidylethanolamine (PE) (22:2(13Z,16Z)/14:0) showed stable elevation in T2DM-serum exosomes. Targeted LC-MS/MS confirmed significant increase of PE (22:2(13Z,16Z)/14:0) in T2DM exosomes but not in serum. PE (22:2(13Z,16Z)/14:0) levels not only positively correlated with hemoglobin A1C levels and blood glucose levels, but also effectively distinguished T2DM patients from healthy individuals (area under the curve = 0.9141). Conclusion Our research sheds light on the importance of serum exosome lipid metabolites in diagnosing T2DM, providing valuable insights into the complex lipid metabolism of diabetes. [ABSTRACT FROM AUTHOR]