BACKGROUND:While glucagon plays a role in hepatic lipid metabolism, alterations in circulating glucagon profiles and hepatic glucagon signaling in metabolic dysfunction-associated steatotic liver disease (MASLD) in humans remain unclear. We aimed to investigate the relationship between MASLD severity and plasma glucagon dynamics, and evaluate hepatic glucagon signaling using human liver tissue. METHODS:This retrospective cross-sectional study included 137 adults with prediabetes or type 2 diabetes who underwent a 75 g oral glucose tolerance test (OGTT) with fasting and 2-h plasma glucagon measurements. MASLD severity was assessed using noninvasive scores and transient liver elastography. To evaluate hepatic glucagon signaling across MASLD severity, human liver tissue transcriptome and single-nucleus RNA sequencing (snRNA-seq) were analyzed. RESULTS:Participants with moderate-to-severe hepatic steatosis or high-risk metabolic dysfunction-associated steatohepatitis exhibited a lower integrated glucagon response, assessed by glucagon AUC during the 2-h OGTT, than their respective control groups (46,500 vs. 60,480 pg·min/ml, P = 0.006; and 43,680 vs. 52,620 pg·min/ml, P = 0.014, respectively). In contrast, there was no significant association between plasma glucagon levels and fibrosis severity. Transcriptomic analyses revealed downregulation of the glucagon receptor (GCGR) and downstream signaling pathways in liver tissues from individuals with MASLD, particularly within hepatocytes from those with advanced disease. CONCLUSION:Among individuals with prediabetes or type 2 diabetes, greater hepatic steatosis and inflammation are associated with lower circulating glucagon levels and attenuated hepatic glucagon signaling. These findings may provide a basis for future investigation of glucagon-based therapeutic approaches.
AIMS:Pancreatic cancer disrupts islet cell function producing pancreatogenic diabetes, which may precipitate diabetic ketoacidosis (DKA). No national study has characterized DKA prevalence or outcomes among pancreatic cancer hospitalizations. We aimed to address this gap using the National Inpatient Sample (NIS). METHODS:We analyzed using NIS 2021-2023. Adult pancreatic cancer hospitalizations (ICD-10-CM C25) were stratified by concurrent DKA (E08.1-E13.1). The primary outcome was in-hospital mortality. Secondary outcomes included acute kidney injury (AKI), mechanical ventilation, septic shock, cardiac arrest, ICU, venous thromboembolism, palliative care consultation, length of stay, and total charges. Multivariable logistic regression adjusted for age, sex, race/ethnicity, income quartile, primary payer, Elixhauser comorbidity category, DM type, and hospital characteristics. RESULTS:Of 218,815 pancreatic cancer hospitalizations, 0.95% (n ≈ 2075) had concurrent DKA. 86.3% had Type 2 DM, while fewer than 2% had type 3c DM. DKA patients were younger, more likely Black (21.9%vs. 14.2%), and had higher comorbidity burden. After multivariable adjustment, DKA independently predicted mortality (aOR 1.76, 95% CI 1.30-2.38), AKI (aOR 3.09, 95% CI 2.49-3.83), mechanical ventilation (aOR 2.78, 95% CI 1.92-4.03), ICU (aOR 2.49, 95% CI 1.90-3.27), septic shock (aOR 2.53, 95% CI 1.86-3.43), and cardiac arrest (aOR 2.40, 95% CI 1.33-4.34). CONCLUSION:DKA complicates approximately 1% of US pancreatic cancer hospitalizations and independently predicts doubled mortality and markedly greater critical care utilization. Black patients and lower socioeconomic groups are disproportionately affected, identifying high-risk subgroups for targeted glycemic surveillance.
AIM:To compare all-cause mortality in adults with T2D initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP-4is) using a large multinational real-world dataset. METHODS:We conducted a retrospective, multinational, active-comparator, new-user cohort study using de-identified electronic health records from TriNetX (2015-2019). Adults aged >18 years with T2D who initiated a SGLT2i or DPP-4i after ≥12 months of continuous therapy were eligible. Propensity score matching (1:1 nearest neighbor) yielded 161,950 patients per group. All-cause mortality over 5 years was evaluated using a Cox proportional-hazards model to estimate hazard ratios and 95% confidence intervals. Kaplan-Meier curves were generated to compare cumulative mortality between groups. Sensitivity analyses and external validation in an independent Hong Kong/Singapore cohort were performed. RESULTS:Among 449,295 eligible patients, 161,950 initiated a SGLT2i and 161,950 initiated a DPP-4i after matching. Over 5 years, all-cause mortality was markedly lower in the SGLT2i group (9965 deaths; 6.2%) than in the DPP-4i group (27,330 deaths; 16.9%). Kaplan-Meier estimates showed cumulative mortality rates of 13.16% and 26.05% in the SGLT2i and DPP-4i groups, respectively. SGLT2i use was associated with a significantly reduced mortality risk (Hazard ratios 0.513; 95% confidence intervals 0.502-0.525; P < 0.001). Subgroup analyses revealed consistent reductions in mortality across sex, age categories, and baseline glycemic control levels. External validation confirmed improved survival associated with SGLT2i therapy. Collectively, these findings demonstrate a robust survival advantage of SGLT2is over DPP-4is. CONCLUSIONS:SGLT2is were consistently associated with significantly lower all-cause mortality than DPP-4is. These results underscore their clinical value and support SGLT2is as a preferred therapeutic option for patients with T2D.
OBJECTIVE:The Glycemic Risk Index (GRI) is a novel composite glycemic indicator, but its role in peripheral atherosclerotic lesions in type 2 diabetes (T2D) remains unclear. This study examined the association between GRI and the severity of peripheral atherosclerotic lesions in T2D patients and assessed its value in identifying high-risk individuals. METHODS:This retrospective study included 878 T2D patients hospitalized at the Second Hospital of Jilin University from October 2023 to October 2025. Patients were divided into no-lesion (n = 88), single-lesion (n = 287), and dual-lesion (n = 503) groups by carotid plus lower extremity arterial ultrasound examinations and stratified by GRI quartiles. The performance of GRI in identifying vascular lesion risk was compared with traditional indicators, including TIR and HbA1c. Multivariate ordinal logistic regression and subgroup analyses were conducted. RESULTS:Higher GRI quartiles were associated with poorer glycemic control, greater variability, and higher prevalence of peripheral atherosclerosis (86%-95% from Q1 to Q4), while TIR and HbA1c showed no similar trend. After full adjustment, the highest GRI quartile conferred a 76% higher risk of more severe atherosclerosis versus Q1 (OR = 1.76, 95%CI:1.15-2.70, P = 0.009; P for trend = 0.002). This association was stronger in overweight patients (BMI≥24 kg/m², P for interaction = 0.03). CONCLUSION:GRI is independently and positively associated with the severity of peripheral atherosclerotic lesions in T2D and outperforms traditional glycemic indicators, especially in overweight individuals, supporting its clinical use for atherosclerosis risk stratification.
AIM:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial metabolic benefits, but their association with pancreaticobiliary cancer risk remains unclear. We investigated the association between GLP-1RA use and pancreaticobiliary cancer incidence in patients with type 2 diabetes (T2D). METHODS:This population-based cohort study used Korean National Health Insurance Service data from 2011 to 2023. We identified 51,780 patients with T2D receiving metformin plus sulfonylurea who initiated either GLP-1RA (n=24,052) or dipeptidyl peptidase-4 inhibitor (DPP-4i, n=27,728). The primary outcomes were incident pancreatic cancer, bile duct cancer, gallbladder cancer, and composite pancreaticobiliary cancer. Hazard ratios (HRs) were estimated using Cox proportional hazards models adjusted for demographics, comorbidities, and previous diabetes medications. RESULTS:During 208,992 person-years of follow-up (mean 4.0 years), 321 pancreaticobiliary cancers occurred. GLP-1RA use was associated with a significantly lower risk of pancreatic cancer (adjusted HR 0.668, 95% CI 0.476-0.939). Similar trends were observed for bile duct cancer (adjusted HR 0.649, 95% CI 0.375-1.124), gallbladder cancer (adjusted HR 0.418, 95% CI 0.171-1.019), and composite pancreaticobiliary cancer (adjusted HR 0.681, 95% CI 0.515-0.901). These associations remained consistent in a propensity score-matched analysis and after excluding patients with baseline pancreaticobiliary disease. CONCLUSION:In this large cohort study, GLP-1RA use was associated with reduced pancreatic cancer risk compared with DPP-4i use among patients with T2D. Similar trends were observed for other pancreaticobiliary cancers. These findings suggest potential protective effects that warrant confirmation in longer-term studies.
