Dapagliflozin Impairs the Suppression of Endogenous Glucose Production in T2D Following Oral Glucose
Findings provide novel evidence that the increase in EGP induced by SGLT2i is present during an oral glucose load.
KEY FINDINGS: These findings provide novel evidence that the increase in EGP induced by SGLT2i is present during an oral glucose load. The fact that stimulation of EGP occurs despite elevated plasma insulin and glucagon suggests that additional factors must be involved.
BACKGROUND: Purpose of this trial is to examine the effect of SGLT2 inhibitors (SGLT2i) on endogenous glucose production (EGP) in patients with type 2 diabetes after an oral glucose load.
DETAILS: Forty-eight patients with type 2 diabetes received an 8-h [3-3H]-glucose infusion (protocol I) to assess EGP response to: 1) dapagliflozin (DAPA), 10 mg; 2) exenatide (EXE), 5 μg s.c.; 3) DAPA/EXE; and 4) placebo (PCB). After 2 weeks (protocol II), patients were restudied with a 5-h double-tracer (i.v. [3-3H]-glucose and oral [1-14C]-glucose) oral glucose tolerance test (OGTT) preceded by PCB, DAPA, EXE, or DAPA/EXE. Protocol I: EGP decreased (P < 0.01) with PCB (2.16 ± 0.15 to 1.57 ± 0.08 mg/kg/min) and EXE (2.13 ± 0.16 to 1.58 ± 0.03) and remained unchanged (P = NS) with DAPA (2.04 ± 0.17 vs. 1.94 ± 0.18) and DAPA/EXE (2.13 ± 0.10 vs. 2.09 ± 0.03). During OGTT, EGP decreased (P < 0.01) with PCB (2.30 ± 0.05 to. 1.45 ± 0.06 mg/kg/min) and EXE (2.53 ± 0.08 to 1.36 ± 0.06); with DAPA (2.20 ± 0.04 vs. 1.71 ± 0.07) and DAPA/EXE (2.48 ± 0.05 vs. 1.64 ± 0.07), the decrease in EGP was attenuated (both P < 0.05). During OGTT, the insulin/glucagon (INS/GCN) ratio increased in PCB (0.26 ± 0.03 vs. 0.71 ± 0.06 μU/mL per pg/mL), whereas in DAPA (0.26 ± 0.02 to 0.50 ± 0.04), the increase was blunted (P < 0.05). In EXE, INS/GCN increased significantly (0.32 ± 0.03 to 1.31 ± 0.08) and was attenuated in DAPA/EXE (0.32 ± 0.03 vs. 0.78 ± 0.08) (P < 0.01).
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Copyright © American Diabetes Association. All rights reserved.
Source: Alatrach, M., Agyin, C., Solis-Herrera, C., et al. (2022). Dapagliflozin Impairs the Suppression of Endogenous Glucose Production in Type 2 Diabetes Following Oral Glucose. Diabetes Care . 2022; 45(6): 1372-1380. Published: June 6, 2022. DOI: 10.2337/dc21-1798.
Re-envisioning the Lifespan Approach to Cardiovascular Disease Prevention and Treatment in Women
The anticipated life course of women supports a broadening focus on CVD toward that of lifelong care and emphasize key transitional stages for women - early risk factor onset, pregnancy, menopausal transition, and so on. This review is a call to action to re-envision a health system approach for lifespan prevention, detection, and treatment pathways to reduce CVD risk in women.
KEY FINDINGS:
- Mortality: CVD deaths in women exceed combined deaths from breast and lung diseases.
- Gap in Care: Insufficient sex-specific evidence continues to hinder lifesaving care.
- Call to Action: Transition from episodic care to a lifelong cardiovascular health system for women.
BACKGROUND: Despite the common misconception that respiratory or oncological diseases pose the greatest threat to women, Cardiovascular Disease (CVD) accounts for more female deaths than breast cancer, lung cancer, and chronic lung disease combined, with a comparable mortality to that of men. Historically, both the public and the medical community have underestimated CVD risks in women, leading to diagnostic delays and a scarcity of sex-specific evidence to guide clinical interventions. While advances have been made in the diagnosis, treatment and outcomes of CVD in women, there often remains insufficient evidence to guide effective, lifesaving care of women.
DETAILS: This review of sex-specific and traditional CVD risk and risk-enhancing factors in women identifies areas of knowledge gaps to consider for investigation. A focus on the coronary vasculature reveals physiological differences of clinical relevance which can be interrogated. Inspection of and addressing disadvantage and gender bias in both the medical and lay communities should continue to be addressed. As CVD results from traditional risk factors and emerging risk-enhancing factors, a focus on the detection of preclinical cardiovascular disease may be of particular importance for women. Unique risk markers originate early in pre-menopausal women, as this is considered a healthy period of life. Awareness and implementation of the existing knowledge of sex-specific risk factors and sex-specific thresholds to educate women and physicians are needed. The anticipated life course of women supports a broadening focus on CVD toward that of lifelong care and emphasize key transitional stages for women-early risk factor onset, pregnancy, menopausal transition, and so on. This review is a call to action to re-envision a health system approach for lifespan prevention, detection, and treatment pathways to reduce CVD risk in women.
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Kidney Juxtaglomerular Cells' Renin Shutdown Mechanism in Blood Pressure Regulation
Juxtaglomerular cells monitor calcium levels to toggle renin release. Studying live tissue outperforms isolated cell models for understanding renin regulation. Targeting renin suppression could yield novel hypertension therapies and reduce related complications.
KEY FINDINGS: The findings demonstrate that juxtaglomerular cells shut down renin production through calcium-mediated mechanisms observed directly in kidney tissue. This approach highlights the brakes on hormone systems, differing from traditional focus on activation pathways.
BACKGROUND: Juxtaglomerular cells in the kidney serve as key sensors for blood pressure homeostasis. These cells release renin, a hormone that elevates blood pressure when levels drop too low. They rely on intracellular calcium as an on-off switch to control renin production, preventing hypotension.
DETAILS: Juxtaglomerular cells function as the body's primary baroreceptors, constantly assessing systemic blood pressure through mechanosensory mechanisms in the afferent arterioles. When pressure falls, these cells detect reduced stretch and rising intracellular calcium, triggering renin release to activate the renin-angiotensin-aldosterone system (RAAS). This study shifts focus to the inhibitory phase: how elevated calcium levels or other signals in intact kidney tissue suppress renin synthesis, acting as a regulatory "brake" to prevent overactivation. Traditional research emphasized renin induction using isolated cell cultures, which overlooked tissue-specific interactions like interstitial signaling and vascular coupling. By contrast, this work analyzed living kidney slices, revealing precise calcium-dependent shutdown pathways that halt transcription and secretion in real-time. This tissue-level insight explains why excessive renin persists in hypertension, potentially due to faulty off-switches, and opens avenues for therapies targeting suppression rather than blockade alone—such as modulating calcium channels or downstream inhibitors.
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Telomere Dysfunction in Renal Tubular Epithelial Cells Leads to Kidney Fibrosis
Trf1 deletion in renal tubular epithelial cells led to renal tubulointerstitial fibrosis, contributing to CKD pathogenesis and progression. Loss of Trf1 induced cellular senescence, DNA damage, and telomere shortening and activated regenerative repair. Trf1 deletion triggered kirsten rat sarcoma viral oncogene homolog and TNF-alpha signaling through NF-KB pathway in renal tubules, suggesting a key molecular mechanism in CKD progression.
KEY FINDINGS: The study underlies a role of renal tubular epithelial cells in the development and progression of kidney fibrosis and CKD induced by telomere dysfunction.
BACKGROUND: Renal tubular epithelial cells are the critical mediators of kidney fibrogenesis. Telomere dysfunction has been associated with kidney injury and fibrosis. However, the role of telomere dysfunction specifically in renal tubular epithelial cells in the onset and progression of kidney fibrosis remains poorly understood. TRF1 is a critical component of the telomeric protective complex known as shelterin, and its deficiency results in telomere dysfunction.
DETAILS: To investigate the impact of telomere dysfunction on kidney injury and fibrosis, authors generated mice depleted for the shelterin component TRF1 specifically in renal tubular epithelial cells.vGenetic ablation of Trf1 caused decline in kidney function accompanied by increased tubular injury and tubulointerstitial fibrosis 8 weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix, cell cycle arrest at G2/M phase, and telomeric damage. Trf1Δ/Δ mice activated regenerative repair mechanisms, supporting proliferation-mediated telomere shortening in renal tubular epithelial cells. At humane end point, Trf1Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (UACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. At the mechanistic level, authors reported the unprecedented finding that Trf1 deletion upregulates the Ras–Raf–Mek–Erk, PI3k/Akt/mammalian target of rapamycin, and p38 pathways.
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Copyright © American Society of Nephrology. All rights reserved.
Source: Saraswati, S., Martínez, P., Serrano, R., et al. Telomere Dysfunction in Renal Tubular Epithelial Cells Leads to Kidney Fibrosis. Journal of the American Society of Nephrology. 2025; 36(12): 2348-2363. Published: December, 2025. DOI: 10.1681/ASN.0000000771.
Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria
Within the studied participants, there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR.
KEY FINDINGS: Within the studied participants, there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR.
BACKGROUND: There is uncertainty about the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in participants with chronic kidney disease, with guidelines offering different strengths of recommendation based on diabetes status and urine albumin to creatinine ratio (UACR). Study was conducted to assess the relative and absolute effects of SGLT2 inhibitor use across efficacy and serious safety outcomes in participants stratified by diabetes status and UACR (>=200 mg/g or <200 mg/g). Included 8 randomized clinical trials that studied an SGLT2 inhibitor with a label indication for use in kidney disease and recorded longitudinal kidney outcomes and baseline data on albuminuria. Assessed the effects of SGLT2 inhibitor use on clinical efficacy and safety outcomes. Heterogeneity by baseline level of UACR was assessed separately by diabetes status.
DETAILS: A total of 58,816 participants (mean age, 64 [SD, 10] years; 35% were female; 48,946 with diabetes and 9870 without diabetes) were included from trials comparing an SGLT2 inhibitor vs placebo. Allocation to an SGLT2 inhibitor produced a lower rate of kidney disease progression (33 vs 48 for placebo per 1000 patient-years; hazard ratio [HR], 0.65 [95% CI, 0.60-0.70] in those with diabetes and 32 vs 46 per 1000; HR, 0.74 [95% CI, 0.63-0.85] in those without diabetes), a lower rate of acute kidney injury (14 vs 18 per 1000 [HR, 0.77; 95% CI, 0.69-0.87] with diabetes and 13 vs 18 per 1000 [HR, 0.72; 95% CI, 0.56-0.92] without diabetes), a lower rate of any hospitalization (202 vs 231 per 1000 [HR, 0.90; 95% CI, 0.87-0.92] with diabetes and 203 vs 237 per 1000 [HR, 0.89; 95% CI, 0.83-0.95] without diabetes), and a lower rate of any death (42 vs 47 per 1000 [HR, 0.86; 95% CI, 0.80-0.91] with diabetes and 42 vs 48 per 1000 [HR, 0.91; 95% CI, 0.78-1.05] without diabetes). Diabetes-specific HRs were similar in participants (with a UACR >=200 mg/g vs with a UACR <200 mg/g) considered separately. Higher absolute risk at a UACR of 200 mg/g or greater meant larger estimated absolute benefits on kidney disease progression were evident in this subgroup. Clear absolute benefits were evident for other efficacy outcomes, and particularly hospitalization, in participants with a UACR less than 200 mg/g. Net absolute benefits remained in the analyses of non–heart failure populations and when estimated glomerular filtration rate was less than 60 mL/min/1.73 m2.
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Copyright © American Medical Association. All Rights Reserved.
Source: Staplin, N., Roddick, A. J., Neuen, B. L., et al. Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis. JAMA. . 2025; Published online: November 7, 2025. DOI: 10.1001/jama.2025.20835.
Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis
In this trial involving participants receiving hemodialysis, fish oil (n-3 fatty acids) was compared with corn-oil placebo. The rate of serious cardiovascular events was lower with daily fish-oil supplementation.
KEY FINDINGS: The rate of serious cardiovascular events among participants receiving maintenance hemodialysis was lower with daily supplementation with n-3 fatty acids than with placebo.
BACKGROUND: Cardiovascular disease is the leading cause of death in patients receiving hemodialysis, yet effective preventive therapies remain limited. Supplementation with n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have cardiovascular benefits in the general population, but efficacy among patients receiving hemodialysis is uncertain.
DETAILS: In a double-blind, randomized, placebo-controlled trial conducted at 26 sites in Canada and Australia, we assigned adult patients receiving maintenance hemodialysis to daily supplementation with fish oil (4 g of n-3 polyunsaturated fatty acids [1.6 g of EPA and 0.8 g of DHA]) or corn-oil placebo. The primary end point was a composite of all serious cardiovascular events including sudden and nonsudden cardiac death, fatal and nonfatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and nonfatal stroke. Secondary end points included extension of the primary end point to include noncardiac causes of death, the individual components of the primary end point, and a first cardiovascular event or death from any cause. In a double-blind, randomized, placebo-controlled trial conducted at 26 sites in Canada and Australia, we assigned adult patients receiving maintenance hemodialysis to daily supplementation with fish oil (4 g of n-3 polyunsaturated fatty acids [1.6 g of EPA and 0.8 g of DHA]) or corn-oil placebo. The primary end point was a composite of all serious cardiovascular events including sudden and nonsudden cardiac death, fatal and nonfatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and nonfatal stroke. Secondary end points included extension of the primary end point to include noncardiac causes of death, the individual components of the primary end point, and a first cardiovascular event or death from any cause.
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Copyright © Massachusetts Medical Society. All rights reserved.
Source: Lok, C. E., Farkouh, M., Hemmelgam, B. R., et al. Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis. NEJM. 2025; Published: November 7, 2025. DOI: 10.1056/NEJMoa2513032.
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