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Adenylyl cyclase 5 knockout (AC5 KO) is a healthful longevity model; not only do the AC5 KO mice live a third longer than wild-type (WT) mice, but they are also protected against obesity, diabetes, heart failure, and exercise intolerance, mediated by anti-apoptosis, cell survival, myocardial biogenesis, and anti-oxidative stress mechanisms. To translate these salutary effects to the clinics, we developed a drug, C90, which recapitulates the AC5 KO model of healthful longevity. We then examined its effects on glucose tolerance and exercise capacity. C90 (30 mg/kg/day) or vehicle was chronically administered to age-matched C57BL/6 mice via an osmotic pump. The WT mice receiving C90 exhibited improved glucose tolerance, following glucose i.v. injection, when compared to the vehicle. Furthermore, the C90-treated mice had a lower fasting glucose level when compared to the vehicle-treated mice (113 ± 6.5 mg/dL vs. 129 ± 4.2 mg/dL, p < 0.05). Additionally, the WT group that received C90 exhibited greater exercise capacity, reflected by longer running distance (384 ± 27 m vs. 253 ± 16 m, p < 0.05) and greater work to exhaustion (18.1 ± 1.5 J vs. 12.4 ± 0.7 J, p < 0.05) than mice receiving vehicle. In view of these findings, C90 is an excellent candidate for clinical development as an effective pharmacological treatment for glucose intolerance and enhancing exercise performance.
Adenylyl cyclase 5 knockout (AC5 KO) is a healthful longevity model; not only do the AC5 KO mice live a third longer than wild-type (WT) mice, but they are also protected against obesity, diabetes, heart failure, and exercise intolerance, mediated by anti-apoptosis, cell survival, myocardial biogenesis, and anti-oxidative stress mechanisms. To translate these salutary effects to the clinics, we developed a drug, C90, which recapitulates the AC5 KO model of healthful longevity. We then examined its effects on glucose tolerance and exercise capacity. C90 (30 mg/kg/day) or vehicle was chronically administered to age-matched C57BL/6 mice via an osmotic pump. The WT mice receiving C90 exhibited improved glucose tolerance, following glucose i.v. injection, when compared to the vehicle. Furthermore, the C90-treated mice had a lower fasting glucose level when compared to the vehicle-treated mice (113 ± 6.5 mg/dL vs. 129 ± 4.2 mg/dL, p < 0.05). Additionally, the WT group that received C90 exhibited greater exercise capacity, reflected by longer running distance (384 ± 27 m vs. 253 ± 16 m, p < 0.05) and greater work to exhaustion (18.1 ± 1.5 J vs. 12.4 ± 0.7 J, p < 0.05) than mice receiving vehicle. In view of these findings, C90 is an excellent candidate for clinical development as an effective pharmacological treatment for glucose intolerance and enhancing exercise performance.
DOI: https://doi.org/10.37349/eemd.2025.101445
This article belongs to the special issue Innovative Strategies for Diabetes and Metabolic Disorders: Current and Future Directions
Type 2 diabetes mellitus (T2DM), expected to exceed 700 million cases by 2045, is usually attributed to obesity and peripheral resistance but neglects insulin’s structural integrity. This review introduces the Sulfur-Insulin Deformation Hypothesis, positing T2DM as a sulfur metabolism disorder where mitochondrial suffocation disrupts the transsulfuration pathway [methionine to cysteine via cystathionine β-synthase (CBS) and γ-lyase (CGL)], depleting cysteine and glutathione (GSH), impairing protein disulfide isomerase (PDI) activity, and deforming insulin’s disulfide bonds (A6–A11, A7–B7, A20–B19) as a primary trigger of insulin resistance. A literature synthesis was conducted (1995–2025) across PubMed, Scopus, Web of Science, and Google Scholar, using Medical Subject Headings (MeSH) terms like “sulfur metabolism”, “insulin misfolding”, and “mitochondrial dysfunction”. From 1,202 articles, 113 studies were selected, including in vitro insulin folding models, animal metabolic stress data, human sulfur biomarker analyses, and trials of sulfur donors (e.g., N-acetylcysteine). Mitochondrial dysfunction reduces adenosine triphosphate (ATP), depleting cysteine and GSH by 30–73.8% (red blood cell GSH: 1.78 ± 0.28 µmol/g vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001), elevating reactive oxygen species (ROS). This impairs PDI isoforms (PDIA1, PDIA3, PDIA4), disrupting insulin bonds; the A6–A11 bond loses 50–70% affinity [r = –0.65, P < 0.05 for homeostatic model assessment of insulin resistance (HOMA-IR)], hindering phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling and glucose transporter type 4 (GLUT4) translocation. In 225 T2DM patients, PDIA4 elevation correlated with glucose (r = 0.62, P < 0.01) and reduced sensitivity (r = –0.67, P < 0.01). PDIA4 inhibition [presenilin 1 (PS1), IC50 = 4 μM] cuts ROS by 50% (P < 0.01), lowers hemoglobin A1c (HbA1c) by 1.2% (P < 0.05), and boosts β-cell survival by 30% (P < 0.05). Redox-mediated chain splitting degrades 20% of insulin (0.40 nmol/kg/min) at –137 mV, modulated by GSH. The hypothesis redefines T2DM as a sulfur-driven structural disorder, unveiling the gut-mitochondria-sulfur-insulin axis and advocating sulfur-centric therapies (e.g., N-acetylcysteine, methylsulfonylmethane).
Type 2 diabetes mellitus (T2DM), expected to exceed 700 million cases by 2045, is usually attributed to obesity and peripheral resistance but neglects insulin’s structural integrity. This review introduces the Sulfur-Insulin Deformation Hypothesis, positing T2DM as a sulfur metabolism disorder where mitochondrial suffocation disrupts the transsulfuration pathway [methionine to cysteine via cystathionine β-synthase (CBS) and γ-lyase (CGL)], depleting cysteine and glutathione (GSH), impairing protein disulfide isomerase (PDI) activity, and deforming insulin’s disulfide bonds (A6–A11, A7–B7, A20–B19) as a primary trigger of insulin resistance. A literature synthesis was conducted (1995–2025) across PubMed, Scopus, Web of Science, and Google Scholar, using Medical Subject Headings (MeSH) terms like “sulfur metabolism”, “insulin misfolding”, and “mitochondrial dysfunction”. From 1,202 articles, 113 studies were selected, including in vitro insulin folding models, animal metabolic stress data, human sulfur biomarker analyses, and trials of sulfur donors (e.g., N-acetylcysteine). Mitochondrial dysfunction reduces adenosine triphosphate (ATP), depleting cysteine and GSH by 30–73.8% (red blood cell GSH: 1.78 ± 0.28 µmol/g vs. 6.75 ± 0.47 µmol/g Hb, P < 0.001), elevating reactive oxygen species (ROS). This impairs PDI isoforms (PDIA1, PDIA3, PDIA4), disrupting insulin bonds; the A6–A11 bond loses 50–70% affinity [r = –0.65, P < 0.05 for homeostatic model assessment of insulin resistance (HOMA-IR)], hindering phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling and glucose transporter type 4 (GLUT4) translocation. In 225 T2DM patients, PDIA4 elevation correlated with glucose (r = 0.62, P < 0.01) and reduced sensitivity (r = –0.67, P < 0.01). PDIA4 inhibition [presenilin 1 (PS1), IC50 = 4 μM] cuts ROS by 50% (P < 0.01), lowers hemoglobin A1c (HbA1c) by 1.2% (P < 0.05), and boosts β-cell survival by 30% (P < 0.05). Redox-mediated chain splitting degrades 20% of insulin (0.40 nmol/kg/min) at –137 mV, modulated by GSH. The hypothesis redefines T2DM as a sulfur-driven structural disorder, unveiling the gut-mitochondria-sulfur-insulin axis and advocating sulfur-centric therapies (e.g., N-acetylcysteine, methylsulfonylmethane).
DOI: https://doi.org/10.37349/eemd.2025.101444
This article belongs to the special issue Current Views on Pathogenesis, Diagnosis and Management of Type 2 Diabetes Mellitus and Its Complications and Related Conditions
Background:
Metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist, showing a bidirectional relationship. MAFLD increases the risk of T2DM, while T2DM independently raises the likelihood of MAFLD.
Methods:
A comprehensive review was carried out on recent systematic reviews and meta-analyses by searching databases including PubMed, Embase, Web of Science, and the Cochrane database of systematic reviews, covering studies from inception to February 2025. Additionally, manual searches of reference lists were conducted. Inclusion criteria involved systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating treatment effects on health outcomes in individuals with T2DM and MAFLD.
Results:
The search yielded 19 meta-analyses and 112 health outcomes from 622 unique articles. Most analyses focused on treatment effects on endocrine metabolic outcomes (n = 28), lipid metabolic indicators (n = 26), liver health indicators (n = 34), and body composition indicators (n = 24). High-quality evidence indicates that high-intensity interval training improves insulin resistance and low-density lipoprotein cholesterol levels. High-quality evidence also indicates sodium-glucose cotransporter-2 (SGLT-2) inhibitors improved liver proton density fat fraction and fatty liver index, while glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly liraglutide, enhanced subcutaneous adipose tissue (SAT). Moderate-quality evidence shows that dipeptidyl peptidase-4 (DPP-4) inhibitors enhanced insulin resistance and GLP-1RAs benefited triglycerides, aspartate transaminase, liver fat, and visceral adipose tissue. SGLT-2 inhibitors improved controlled attenuation parameter, body mass index (BMI), SAT, visceral fat mass, and moderate-intensity continuous training improved triglycerides and high-density lipoprotein cholesterol. Fifty-six outcomes were rated as low-quality evidence, and five as very low-quality.
Discussion:
GLP-1RAs, SGLT-2 inhibitors, DPP-4 inhibitors, exercise, and Chinese Herbal Medicines benefited liver health, glycemic control in T2DM with MAFLD, and impacted body composition and lipid metabolism.
Background:
Metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist, showing a bidirectional relationship. MAFLD increases the risk of T2DM, while T2DM independently raises the likelihood of MAFLD.
Methods:
A comprehensive review was carried out on recent systematic reviews and meta-analyses by searching databases including PubMed, Embase, Web of Science, and the Cochrane database of systematic reviews, covering studies from inception to February 2025. Additionally, manual searches of reference lists were conducted. Inclusion criteria involved systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating treatment effects on health outcomes in individuals with T2DM and MAFLD.
Results:
The search yielded 19 meta-analyses and 112 health outcomes from 622 unique articles. Most analyses focused on treatment effects on endocrine metabolic outcomes (n = 28), lipid metabolic indicators (n = 26), liver health indicators (n = 34), and body composition indicators (n = 24). High-quality evidence indicates that high-intensity interval training improves insulin resistance and low-density lipoprotein cholesterol levels. High-quality evidence also indicates sodium-glucose cotransporter-2 (SGLT-2) inhibitors improved liver proton density fat fraction and fatty liver index, while glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly liraglutide, enhanced subcutaneous adipose tissue (SAT). Moderate-quality evidence shows that dipeptidyl peptidase-4 (DPP-4) inhibitors enhanced insulin resistance and GLP-1RAs benefited triglycerides, aspartate transaminase, liver fat, and visceral adipose tissue. SGLT-2 inhibitors improved controlled attenuation parameter, body mass index (BMI), SAT, visceral fat mass, and moderate-intensity continuous training improved triglycerides and high-density lipoprotein cholesterol. Fifty-six outcomes were rated as low-quality evidence, and five as very low-quality.
Discussion:
GLP-1RAs, SGLT-2 inhibitors, DPP-4 inhibitors, exercise, and Chinese Herbal Medicines benefited liver health, glycemic control in T2DM with MAFLD, and impacted body composition and lipid metabolism.
DOI: https://doi.org/10.37349/eemd.2025.101443
This article belongs to the special issue Innovative Strategies for Diabetes and Metabolic Disorders: Current and Future Directions
Background:
Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition during pregnancy, poses a significant and growing public health challenge in India. With India housing the world’s largest diabetes population, the rising prevalence of GDM has profound implications for maternal and neonatal health, contributing to complications including preeclampsia, macrosomia, neonatal hypoglycaemia, and increased lifelong risk of type 2 diabetes mellitus (T2DM) for both mother and child.
Methods:
We conducted a systematic literature search of PubMed, Embase, Google Scholar, and Cochrane Library for studies published between January 2019 and December 2024, with seminal works from 2015–2018. Search terms included “gestational diabetes mellitus”, “India”, “screening”, “prevalence”, “management”, and “health systems”. Eligible studies included peer-reviewed articles, government reports, and systematic reviews focusing on Indian populations. Two reviewers independently screened and extracted data. The PRISMA 2020 framework guided reporting.
Results:
From 2,847 initial records, 156 studies met the inclusion criteria. GDM prevalence in India ranges from 7.2% to 21.4%, with substantial regional variations. Southern states consistently report higher prevalence (15–22%) compared to northern (10–17%) and eastern regions (8–15%). Key challenges identified include low awareness among pregnant women (32% rural, 58% urban) and healthcare providers, inconsistent adoption of evidence-based guidelines (41% of facilities following standardized protocols), severe resource and infrastructural constraints, and significant socioeconomic barriers. Laboratory facilities for oral glucose tolerance test (OGTT) are available in only 34% of community health centers and 12% of primary health centers. Digital health interventions show promise but face implementation barriers, including limited smartphone penetration (45% in rural areas) and inadequate Accredited Social Health Activist (ASHA) workforce training (34% completion rate).
Discussion:
Despite the escalating burden of GDM in India, numerous unmet needs persist across the care continuum. This review proposes actionable recommendations, including simplified, cost-effective screening strategies, capacity building, integration into existing maternal health programs, and robust postpartum follow-up systems. Success requires sustained commitment to collaborative research, policy initiatives, and integrated, equitable, and sustainable GDM care approaches.
Background:
Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition during pregnancy, poses a significant and growing public health challenge in India. With India housing the world’s largest diabetes population, the rising prevalence of GDM has profound implications for maternal and neonatal health, contributing to complications including preeclampsia, macrosomia, neonatal hypoglycaemia, and increased lifelong risk of type 2 diabetes mellitus (T2DM) for both mother and child.
Methods:
We conducted a systematic literature search of PubMed, Embase, Google Scholar, and Cochrane Library for studies published between January 2019 and December 2024, with seminal works from 2015–2018. Search terms included “gestational diabetes mellitus”, “India”, “screening”, “prevalence”, “management”, and “health systems”. Eligible studies included peer-reviewed articles, government reports, and systematic reviews focusing on Indian populations. Two reviewers independently screened and extracted data. The PRISMA 2020 framework guided reporting.
Results:
From 2,847 initial records, 156 studies met the inclusion criteria. GDM prevalence in India ranges from 7.2% to 21.4%, with substantial regional variations. Southern states consistently report higher prevalence (15–22%) compared to northern (10–17%) and eastern regions (8–15%). Key challenges identified include low awareness among pregnant women (32% rural, 58% urban) and healthcare providers, inconsistent adoption of evidence-based guidelines (41% of facilities following standardized protocols), severe resource and infrastructural constraints, and significant socioeconomic barriers. Laboratory facilities for oral glucose tolerance test (OGTT) are available in only 34% of community health centers and 12% of primary health centers. Digital health interventions show promise but face implementation barriers, including limited smartphone penetration (45% in rural areas) and inadequate Accredited Social Health Activist (ASHA) workforce training (34% completion rate).
Discussion:
Despite the escalating burden of GDM in India, numerous unmet needs persist across the care continuum. This review proposes actionable recommendations, including simplified, cost-effective screening strategies, capacity building, integration into existing maternal health programs, and robust postpartum follow-up systems. Success requires sustained commitment to collaborative research, policy initiatives, and integrated, equitable, and sustainable GDM care approaches.
DOI: https://doi.org/10.37349/eemd.2025.101442
Aim:
Baicalin and ginsenoside Rb1 show the ability to promote adipocyte browning, but their effects, especially combined treatment, and the related mechanisms under pathological conditions are less known. The study investigated the regulation of browning markers by baicalin and Rb1 under lipid overload and explored the potential implication of a serine/threonine protein kinase G protein-coupled receptor kinase 2 (GRK2).
Methods:
The 3T3-L1 cells under palmitic acid (PA) stimulation and male ICR mice on a high-fat diet (HFD) challenge were used to evaluate the effects of drugs.
Results:
GRK2 silencing and overexpression inversely regulated the protein abundance of PGC-1α and UCP-1 in 3T3-L1 adipocytes. Baicalin, Rb1, and their combination decreased the PA-induced elevation of GRK2 while increasing the thermogenetic markers at the protein and mRNA levels. In vivo, the tested drugs restored the expression of thermogenetic and mitochondrial biogenetic markers in the inguinal white adipose tissue (WAT) of HFD-fed mice. Consistently, the drug-treated mice displayed an improved metabolic profile. The baicalin-Rb1 combination showed a more potent effect in some examinations, and its effect was comparable to that of GRK2 inhibitor paroxetine or AMP-activated protein kinase activator metformin.
Conclusions:
Baicalin and Rb1, alone or in combination, improved the browning of adipocytes during differentiation and prevented the whitening shift of WAT on an HFD, which was associated with the downregulation of GRK2. The study expands the understanding of the anti-obesity effects of baicalin and Rb1 and the potential of Scutellariae Radix-Ginseng Radix et Rhizoma compatibility for treating obesity-associated metabolic diseases.
Aim:
Baicalin and ginsenoside Rb1 show the ability to promote adipocyte browning, but their effects, especially combined treatment, and the related mechanisms under pathological conditions are less known. The study investigated the regulation of browning markers by baicalin and Rb1 under lipid overload and explored the potential implication of a serine/threonine protein kinase G protein-coupled receptor kinase 2 (GRK2).
Methods:
The 3T3-L1 cells under palmitic acid (PA) stimulation and male ICR mice on a high-fat diet (HFD) challenge were used to evaluate the effects of drugs.
Results:
GRK2 silencing and overexpression inversely regulated the protein abundance of PGC-1α and UCP-1 in 3T3-L1 adipocytes. Baicalin, Rb1, and their combination decreased the PA-induced elevation of GRK2 while increasing the thermogenetic markers at the protein and mRNA levels. In vivo, the tested drugs restored the expression of thermogenetic and mitochondrial biogenetic markers in the inguinal white adipose tissue (WAT) of HFD-fed mice. Consistently, the drug-treated mice displayed an improved metabolic profile. The baicalin-Rb1 combination showed a more potent effect in some examinations, and its effect was comparable to that of GRK2 inhibitor paroxetine or AMP-activated protein kinase activator metformin.
Conclusions:
Baicalin and Rb1, alone or in combination, improved the browning of adipocytes during differentiation and prevented the whitening shift of WAT on an HFD, which was associated with the downregulation of GRK2. The study expands the understanding of the anti-obesity effects of baicalin and Rb1 and the potential of Scutellariae Radix-Ginseng Radix et Rhizoma compatibility for treating obesity-associated metabolic diseases.
DOI: https://doi.org/10.37349/eemd.2025.101441
This article belongs to the special issue Regulators of Glucose Homeostasis, Lipid Metabolism and Energy Balance
As women transition to menopause, their risk of cardiovascular disease increases. The risk is mediated by a cluster of abnormalities, the ‘metabolic syndrome’: dyslipidemia, insulin resistance, hypertension, and obesity. The risk is proportional to the duration of menopause, although ethnic differences were reported. Other contributing factors include estrogen deficiency, inflammatory markers, history of gestational diabetes mellitus, preeclampsia, and polycystic ovary syndrome. Susceptibility to metabolic syndrome is mediated by genetic and lifestyle factors. Intervention to prevent metabolic syndrome must begin early with physical exercise, proper nutrition, and, where indicated, nutritional supplements. Although initial results of the Women’s Health Initiative suggested that hormone therapy after menopause led to adverse outcomes, further studies, such as the Early versus Late Intervention Trial with Estradiol (ELITE) study and the Kronos Early Estrogen Prevention Study (KEEPS), showed cardiovascular benefits if hormone replacement is begun early in women not at high risk of cardiovascular disease. A personalized preventive approach must be applied.
As women transition to menopause, their risk of cardiovascular disease increases. The risk is mediated by a cluster of abnormalities, the ‘metabolic syndrome’: dyslipidemia, insulin resistance, hypertension, and obesity. The risk is proportional to the duration of menopause, although ethnic differences were reported. Other contributing factors include estrogen deficiency, inflammatory markers, history of gestational diabetes mellitus, preeclampsia, and polycystic ovary syndrome. Susceptibility to metabolic syndrome is mediated by genetic and lifestyle factors. Intervention to prevent metabolic syndrome must begin early with physical exercise, proper nutrition, and, where indicated, nutritional supplements. Although initial results of the Women’s Health Initiative suggested that hormone therapy after menopause led to adverse outcomes, further studies, such as the Early versus Late Intervention Trial with Estradiol (ELITE) study and the Kronos Early Estrogen Prevention Study (KEEPS), showed cardiovascular benefits if hormone replacement is begun early in women not at high risk of cardiovascular disease. A personalized preventive approach must be applied.
DOI: https://doi.org/10.37349/eemd.2025.101440
This article belongs to the special issue Metabolic Syndrome in Menopause
Background:
Emerging evidence suggests that genetic variations in taste receptor genes may influence dietary behaviors, energy homeostasis, and metabolic risk, contributing to type 2 diabetes mellitus (T2DM) pathogenesis. The objective of this study is to evaluate the association between single nucleotide polymorphisms (SNPs) in taste receptor genes and T2DM.
Methods:
This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022351880). A comprehensive literature search was conducted across PubMed, ScienceDirect, Cochrane Library, and Google Scholar through June 2025. Original studies examining SNPs in taste receptor genes among individuals with T2DM were included. Quality assessment was performed independently by using the Newcastle-Ottawa scale.
Results:
Sixteen studies involving diverse populations met the inclusion criteria. Significant associations with T2DM were observed for SNPs in type 2 taste receptor gene family R member 3 (TAS2R3; rs11763979), TAS2R4 (rs2233998), TAS2R7, TAS2R9, TAS2R38, TAS2R50, cluster determinant 36 (CD36; rs1761667, rs3211956, rs7755), carbonic anhydrase VI gene (CA6; rs2274327), transient receptor potential vanilloid-1 (TRPV1; rs161364, rs8065080), transient receptor potential cation channel subfamily M gene member 5 (TRPM5; rs4929982), and TRPM8 (rs12472151). These polymorphisms may alter taste perception and gut hormone responses [e.g., glucagon-like peptide 1 (GLP-1)], affecting dietary intake, satiety, insulin secretion, and glucose regulation.
Discussion:
The findings suggest that genetic variations in taste receptor genes may contribute to T2DM through behavioral and metabolic mechanisms. Incorporating gustatory phenotyping with genotypic profiling could enable personalized dietary strategies and inform novel therapeutic approaches targeting taste-mediated gut signaling. Further large-scale, multi-ethnic, and mechanistic studies are warranted to confirm these associations and elucidate their clinical implications.
Background:
Emerging evidence suggests that genetic variations in taste receptor genes may influence dietary behaviors, energy homeostasis, and metabolic risk, contributing to type 2 diabetes mellitus (T2DM) pathogenesis. The objective of this study is to evaluate the association between single nucleotide polymorphisms (SNPs) in taste receptor genes and T2DM.
Methods:
This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines and was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022351880). A comprehensive literature search was conducted across PubMed, ScienceDirect, Cochrane Library, and Google Scholar through June 2025. Original studies examining SNPs in taste receptor genes among individuals with T2DM were included. Quality assessment was performed independently by using the Newcastle-Ottawa scale.
Results:
Sixteen studies involving diverse populations met the inclusion criteria. Significant associations with T2DM were observed for SNPs in type 2 taste receptor gene family R member 3 (TAS2R3; rs11763979), TAS2R4 (rs2233998), TAS2R7, TAS2R9, TAS2R38, TAS2R50, cluster determinant 36 (CD36; rs1761667, rs3211956, rs7755), carbonic anhydrase VI gene (CA6; rs2274327), transient receptor potential vanilloid-1 (TRPV1; rs161364, rs8065080), transient receptor potential cation channel subfamily M gene member 5 (TRPM5; rs4929982), and TRPM8 (rs12472151). These polymorphisms may alter taste perception and gut hormone responses [e.g., glucagon-like peptide 1 (GLP-1)], affecting dietary intake, satiety, insulin secretion, and glucose regulation.
Discussion:
The findings suggest that genetic variations in taste receptor genes may contribute to T2DM through behavioral and metabolic mechanisms. Incorporating gustatory phenotyping with genotypic profiling could enable personalized dietary strategies and inform novel therapeutic approaches targeting taste-mediated gut signaling. Further large-scale, multi-ethnic, and mechanistic studies are warranted to confirm these associations and elucidate their clinical implications.
DOI: https://doi.org/10.37349/eemd.2025.101439
Background:
Diabetes mellitus and vitamin D deficiency (VDD) are widespread global health concerns with overlapping metabolic risks. Emerging evidence suggests a bidirectional relationship: VDD exacerbates insulin resistance, whereas diabetes mellitus disrupts vitamin D metabolism.
Methods:
This meta-analysis was registered prospectively (PROSPERO CRD42025639951). We conducted a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library from their inception to January 2025 for observational studies examining the bidirectional associations between VDD and diabetes mellitus. Studies were eligible if they (1) employed cohort or case-control designs, (2) defined VDD as serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL, and (3) diagnosed diabetes mellitus according to the American Diabetes Association (ADA) criteria. Two reviewers independently extracted data and assessed study quality using the Newcastle-Ottawa scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models (STATA 15.1 and RevMan 5.4).
Results:
Among 53 studies (n = 552,032), individuals with VDD had a 53% increased risk of developing type 2 diabetes mellitus (T2DM) (OR = 1.53, 95% CI: 1.38–1.70). Conversely, individuals with type 1 diabetes mellitus (T1DM) and T2DM had a 2.02-fold and 2.62-fold increased risk of VDD, respectively. Subgroup analyses demonstrated stronger associations in Asian populations (T1DM: OR = 2.21; Europe: OR = 1.65; P < 0.05 for regional difference) and among normal-weight T2DM patients (OR = 7.68, compared to obese: OR = 5.21).
Discussion:
This meta-analysis reveals a bidirectional link between VDD and diabetes mellitus, emphasizing subtype- and phenotype-specific risk profiles. Clinically, routine monitoring of serum 25(OH)D levels is recommended for diabetic patients, particularly in high-risk subgroups such as individuals with T1DM or lean T2DM phenotypes, and suggests targeted vitamin D supplementation for high-risk groups. On a public health scale, fortifying staple foods with vitamin D in regions with high deficiency rates, such as Asia, could alleviate the dual burden of VDD and diabetes mellitus.
Background:
Diabetes mellitus and vitamin D deficiency (VDD) are widespread global health concerns with overlapping metabolic risks. Emerging evidence suggests a bidirectional relationship: VDD exacerbates insulin resistance, whereas diabetes mellitus disrupts vitamin D metabolism.
Methods:
This meta-analysis was registered prospectively (PROSPERO CRD42025639951). We conducted a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library from their inception to January 2025 for observational studies examining the bidirectional associations between VDD and diabetes mellitus. Studies were eligible if they (1) employed cohort or case-control designs, (2) defined VDD as serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL, and (3) diagnosed diabetes mellitus according to the American Diabetes Association (ADA) criteria. Two reviewers independently extracted data and assessed study quality using the Newcastle-Ottawa scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models (STATA 15.1 and RevMan 5.4).
Results:
Among 53 studies (n = 552,032), individuals with VDD had a 53% increased risk of developing type 2 diabetes mellitus (T2DM) (OR = 1.53, 95% CI: 1.38–1.70). Conversely, individuals with type 1 diabetes mellitus (T1DM) and T2DM had a 2.02-fold and 2.62-fold increased risk of VDD, respectively. Subgroup analyses demonstrated stronger associations in Asian populations (T1DM: OR = 2.21; Europe: OR = 1.65; P < 0.05 for regional difference) and among normal-weight T2DM patients (OR = 7.68, compared to obese: OR = 5.21).
Discussion:
This meta-analysis reveals a bidirectional link between VDD and diabetes mellitus, emphasizing subtype- and phenotype-specific risk profiles. Clinically, routine monitoring of serum 25(OH)D levels is recommended for diabetic patients, particularly in high-risk subgroups such as individuals with T1DM or lean T2DM phenotypes, and suggests targeted vitamin D supplementation for high-risk groups. On a public health scale, fortifying staple foods with vitamin D in regions with high deficiency rates, such as Asia, could alleviate the dual burden of VDD and diabetes mellitus.
DOI: https://doi.org/10.37349/eemd.2025.101438
This article belongs to the special issue Innovative Strategies for Diabetes and Metabolic Disorders: Current and Future Directions
Circadian rhythms are present in almost every cell of the body and play important roles in various physiological processes. The central circadian clock in the suprachiasmatic nucleus (SCN) is synchronized to the environmental light-dark cycle and ensures a temporal order for the peripheral clocks, which in turn modulate tissue and organ function. This temporal organization is crucial for the precise timing of bodily processes, including sleep, glucocorticoid release, and the function of the glymphatic system. Sleep and the glymphatic system are significantly impacted by the rhythmic secretion of glucocorticoids. One important function of the glymphatic system is the clearance of waste metabolites, which most likely happens during sleep. Disruptions within the SCN, glucocorticoid rhythms, sleep, or glymphatic clearance have been implicated in compromised brain health. This review explores the current knowledge on the interdependence of the SCN, glucocorticoids, sleep, and the glymphatic system, and emphasizes their importance in homeostasis and pathology; in particular, Alzheimer’s disease.
Circadian rhythms are present in almost every cell of the body and play important roles in various physiological processes. The central circadian clock in the suprachiasmatic nucleus (SCN) is synchronized to the environmental light-dark cycle and ensures a temporal order for the peripheral clocks, which in turn modulate tissue and organ function. This temporal organization is crucial for the precise timing of bodily processes, including sleep, glucocorticoid release, and the function of the glymphatic system. Sleep and the glymphatic system are significantly impacted by the rhythmic secretion of glucocorticoids. One important function of the glymphatic system is the clearance of waste metabolites, which most likely happens during sleep. Disruptions within the SCN, glucocorticoid rhythms, sleep, or glymphatic clearance have been implicated in compromised brain health. This review explores the current knowledge on the interdependence of the SCN, glucocorticoids, sleep, and the glymphatic system, and emphasizes their importance in homeostasis and pathology; in particular, Alzheimer’s disease.
DOI: https://doi.org/10.37349/eemd.2025.101437
This article belongs to the special issue The HPA Axis in Health and Disease
Aim:
This analysis examined the prevalence and incidence of type 2 diabetes mellitus (T2DM) and co-morbid lung disease in the UK Biobank population.
Methods:
Non-communicable inflammatory lung diseases, body mass index (BMI), age, glycated haemoglobin (HbA1c), sex, smoking status, diabetes status, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) data were obtained. Participants were categorised by BMI: lean (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥ 30 kg/m2). Fisher’s exact test identified lung disease prevalence and incidence. Kruskal-Wallis assessed lung function variance and its correlation with HbA1c. Cox regression analysed the impact of confounders on time to lung disease events.
Results:
Overweight and obesity increased the prevalence and incidence of chronic obstructive pulmonary disease, asthma, and bronchitis, but this was not evident in cases of bronchiectasis in those without T2DM (P < 0.05–0.0001). Conversely, T2DM increased lung disease risk across all BMIs (P < 0.0001) and reduced FEV1 and FVC even after HbA1c normalisation (P < 0.0001). FEV1 and FEV1/FVC were negatively correlated with HbA1c. Age, diabetes, being a woman, smoking, reduced FEV1 and FEV1/FVC ratio, but not BMI, were factors in lung disease development in T2DM.
Conclusions:
Inflammatory lung conditions are more common in T2DM patients, regardless of BMI. The pattern of lung decline suggests restrictive impairment, despite a high risk of obstructive disorders. This data adds to the evidence that the lungs are a target organ of diabetes damage.
Aim:
This analysis examined the prevalence and incidence of type 2 diabetes mellitus (T2DM) and co-morbid lung disease in the UK Biobank population.
Methods:
Non-communicable inflammatory lung diseases, body mass index (BMI), age, glycated haemoglobin (HbA1c), sex, smoking status, diabetes status, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) data were obtained. Participants were categorised by BMI: lean (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥ 30 kg/m2). Fisher’s exact test identified lung disease prevalence and incidence. Kruskal-Wallis assessed lung function variance and its correlation with HbA1c. Cox regression analysed the impact of confounders on time to lung disease events.
Results:
Overweight and obesity increased the prevalence and incidence of chronic obstructive pulmonary disease, asthma, and bronchitis, but this was not evident in cases of bronchiectasis in those without T2DM (P < 0.05–0.0001). Conversely, T2DM increased lung disease risk across all BMIs (P < 0.0001) and reduced FEV1 and FVC even after HbA1c normalisation (P < 0.0001). FEV1 and FEV1/FVC were negatively correlated with HbA1c. Age, diabetes, being a woman, smoking, reduced FEV1 and FEV1/FVC ratio, but not BMI, were factors in lung disease development in T2DM.
Conclusions:
Inflammatory lung conditions are more common in T2DM patients, regardless of BMI. The pattern of lung decline suggests restrictive impairment, despite a high risk of obstructive disorders. This data adds to the evidence that the lungs are a target organ of diabetes damage.
DOI: https://doi.org/10.37349/eemd.2025.101436
This article belongs to the special issue Current Views on Pathogenesis, Diagnosis and Management of Type 2 Diabetes Mellitus and Its Complications and Related Conditions
Diabetes affects approximately 463 million people worldwide, and this number is projected to reach 700 million by 2045. The most significant cause of increased mortality among diabetic patients is cardiovascular disease, with heart failure (HF) being one of the most commonly observed conditions within this group. Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, accounts for more than 90% of all diabetes cases. Patients with T2DM have twice the risk of developing HF compared to non-diabetic individuals. The connection between diabetes mellitus (DM) and HF extends beyond the complications of ischemic heart disease, encompassing metabolic disturbances such as glucose toxicity and lipotoxicity resulting from insulin resistance, as well as vascular endothelial dysfunction, microcirculatory abnormalities, and capillary insufficiency. Lifestyle modifications for individuals with T2DM involve engaging in regular physical activity, maintaining a balanced diet, quitting smoking, and reducing alcohol consumption. For patients with reduced ejection fraction HF [heart failure with reduced ejection fraction (HFrEF)] and T2DM, guideline-recommended medical therapies [including ARNI, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors] should be considered. Recent large randomized controlled trials have demonstrated that SGLT2 inhibitors improve cardiovascular outcomes, including all-cause mortality, independent of diabetes status. This review will focus on the epidemiology, pathophysiology, risk factors for HF development, and treatment approaches in diabetic patients, particularly those with T2DM and systolic HF.
Diabetes affects approximately 463 million people worldwide, and this number is projected to reach 700 million by 2045. The most significant cause of increased mortality among diabetic patients is cardiovascular disease, with heart failure (HF) being one of the most commonly observed conditions within this group. Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, accounts for more than 90% of all diabetes cases. Patients with T2DM have twice the risk of developing HF compared to non-diabetic individuals. The connection between diabetes mellitus (DM) and HF extends beyond the complications of ischemic heart disease, encompassing metabolic disturbances such as glucose toxicity and lipotoxicity resulting from insulin resistance, as well as vascular endothelial dysfunction, microcirculatory abnormalities, and capillary insufficiency. Lifestyle modifications for individuals with T2DM involve engaging in regular physical activity, maintaining a balanced diet, quitting smoking, and reducing alcohol consumption. For patients with reduced ejection fraction HF [heart failure with reduced ejection fraction (HFrEF)] and T2DM, guideline-recommended medical therapies [including ARNI, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors] should be considered. Recent large randomized controlled trials have demonstrated that SGLT2 inhibitors improve cardiovascular outcomes, including all-cause mortality, independent of diabetes status. This review will focus on the epidemiology, pathophysiology, risk factors for HF development, and treatment approaches in diabetic patients, particularly those with T2DM and systolic HF.
DOI: https://doi.org/10.37349/eemd.2025.101435
This article belongs to the special issue Current Views on Pathogenesis, Diagnosis and Management of Type 2 Diabetes Mellitus and Its Complications and Related Conditions
Aim:
This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research.
Methods:
The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed.
Results:
In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only.
Conclusions:
Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.
Aim:
This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research.
Methods:
The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed.
Results:
In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only.
Conclusions:
Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.
DOI: https://doi.org/10.37349/eemd.2025.101433
Aim:
Hormone pulsatility is an important aspect of the hypothalamic-pituitary-adrenal (HPA) axis in health and disease. We use the properties of simple mathematical models to determine whether hormone pulsatility reflects the presence of a time delay in the production of hormones and/or is related to the impulsive nature of hormone secretion.
Methods:
The predictions of two models for HPA pulsatility are compared. The first model assumes pulsatility arises because of a time delay in the synthesis of glucocorticoids (GCs). The second model suggests that pulsatility reflects the impulsive nature of hormone secretion. The generation of oscillations by the second mechanism does not require a time delay.
Results:
The time delay for the synthesis of GC (0–10 minutes) may not be long enough to account for the oscillations in adrenocorticotrophin (ACTH) and GC observed with constant corticotrophin-releasing hormone (CRH) infusion in rats. A simple mechanism for hormone release, illustrated using an integrate-and-fire mechanism, reproduces the observed hormone pulsatility.
Conclusions:
The water solubility of CRH and ACTH draws attention to the role played by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the calcium-dependent exocytosis of peptide hormones. Abnormalities in SNARE proteins are anticipated to cause changes in the amplitude modulation of ACTH and CRH hormone pulses. In mice, a mutation in a SNARE protein causes abnormalities in the HPA axis. Mutations in SNARE proteins occur in many neurodegenerative and neuropsychiatric diseases. Abnormalities in HPA function also occur in these disorders. The identification of SNARE protein mutations in exosomes in serum and cerebrospinal fluid in humans may make it possible to determine whether there exists a causal relationship between an SNARE protein mutation and abnormalities in the HPA axis in this patient group.
Aim:
Hormone pulsatility is an important aspect of the hypothalamic-pituitary-adrenal (HPA) axis in health and disease. We use the properties of simple mathematical models to determine whether hormone pulsatility reflects the presence of a time delay in the production of hormones and/or is related to the impulsive nature of hormone secretion.
Methods:
The predictions of two models for HPA pulsatility are compared. The first model assumes pulsatility arises because of a time delay in the synthesis of glucocorticoids (GCs). The second model suggests that pulsatility reflects the impulsive nature of hormone secretion. The generation of oscillations by the second mechanism does not require a time delay.
Results:
The time delay for the synthesis of GC (0–10 minutes) may not be long enough to account for the oscillations in adrenocorticotrophin (ACTH) and GC observed with constant corticotrophin-releasing hormone (CRH) infusion in rats. A simple mechanism for hormone release, illustrated using an integrate-and-fire mechanism, reproduces the observed hormone pulsatility.
Conclusions:
The water solubility of CRH and ACTH draws attention to the role played by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the calcium-dependent exocytosis of peptide hormones. Abnormalities in SNARE proteins are anticipated to cause changes in the amplitude modulation of ACTH and CRH hormone pulses. In mice, a mutation in a SNARE protein causes abnormalities in the HPA axis. Mutations in SNARE proteins occur in many neurodegenerative and neuropsychiatric diseases. Abnormalities in HPA function also occur in these disorders. The identification of SNARE protein mutations in exosomes in serum and cerebrospinal fluid in humans may make it possible to determine whether there exists a causal relationship between an SNARE protein mutation and abnormalities in the HPA axis in this patient group.
DOI: https://doi.org/10.37349/eemd.2025.101434
This article belongs to the special issue The HPA Axis in Health and Disease
The glucocorticoid receptor (GR) signaling pathway is essential for supporting the integrity of the intestinal barrier, regulating the gut microbiome, and preserving systemic homeostasis in critically ill patients. GR signaling limits bacterial translocation and systemic inflammation by suppressing pro-inflammatory cytokines, reinforcing tight junction proteins, and promoting epithelial renewal. Additionally, physiological levels of glucocorticoids (GCs) stimulate glutamine and proline metabolism, supporting intestinal maturation, with potential clinical relevance. GR signaling modulates inter-organ communication via the gut-lung and gut-brain axes, improving outcomes. Probiotics enhance GC therapy by restoring microbial balance, increasing short-chain fatty acid (SCFA) production, and modulating immune responses. Vitamins A, C, D, and E contribute to gut resilience by stabilizing tight junctions, mitigating oxidative stress, and strengthening mucosal immunity. Specifically, vitamin D balances T-cell subsets and promotes antimicrobial peptides; vitamin C supports collagen synthesis, antioxidant defenses, and immune function; vitamin A promotes immune tolerance and epithelial regeneration; and vitamin E mitigates oxidative damage and excessive cytokine release. GCs, probiotics, and vitamins counteract key drivers of critical illness, including hyperinflammation and dysbiosis, while maintaining strong safety profiles. This integrative approach leverages these interventions’ distinct yet complementary roles to provide a multi-layered defense against gut dysfunction. GCs reduce excessive inflammation and restore immune balance; probiotics enhance microbial diversity and strengthen gut-associated immunity; and vitamins support epithelial integrity and antioxidant defenses. Targeting multiple pathways simultaneously protects the gut barrier and modulates systemic immunity, potentially reducing complications such as sepsis, multiple organ dysfunction syndrome (MODS), and prolonged intensive care unit (ICU) stays. Incorporating these elements into critical care practice offers a novel strategy to mitigate gut dysfunction, reduce systemic inflammation, and enhance immune resilience. This approach may lower infection rates, decrease the incidence of sepsis and MODS, and accelerate recovery by targeting GR signaling, restoring microbial homeostasis, and reinforcing epithelial integrity.
The glucocorticoid receptor (GR) signaling pathway is essential for supporting the integrity of the intestinal barrier, regulating the gut microbiome, and preserving systemic homeostasis in critically ill patients. GR signaling limits bacterial translocation and systemic inflammation by suppressing pro-inflammatory cytokines, reinforcing tight junction proteins, and promoting epithelial renewal. Additionally, physiological levels of glucocorticoids (GCs) stimulate glutamine and proline metabolism, supporting intestinal maturation, with potential clinical relevance. GR signaling modulates inter-organ communication via the gut-lung and gut-brain axes, improving outcomes. Probiotics enhance GC therapy by restoring microbial balance, increasing short-chain fatty acid (SCFA) production, and modulating immune responses. Vitamins A, C, D, and E contribute to gut resilience by stabilizing tight junctions, mitigating oxidative stress, and strengthening mucosal immunity. Specifically, vitamin D balances T-cell subsets and promotes antimicrobial peptides; vitamin C supports collagen synthesis, antioxidant defenses, and immune function; vitamin A promotes immune tolerance and epithelial regeneration; and vitamin E mitigates oxidative damage and excessive cytokine release. GCs, probiotics, and vitamins counteract key drivers of critical illness, including hyperinflammation and dysbiosis, while maintaining strong safety profiles. This integrative approach leverages these interventions’ distinct yet complementary roles to provide a multi-layered defense against gut dysfunction. GCs reduce excessive inflammation and restore immune balance; probiotics enhance microbial diversity and strengthen gut-associated immunity; and vitamins support epithelial integrity and antioxidant defenses. Targeting multiple pathways simultaneously protects the gut barrier and modulates systemic immunity, potentially reducing complications such as sepsis, multiple organ dysfunction syndrome (MODS), and prolonged intensive care unit (ICU) stays. Incorporating these elements into critical care practice offers a novel strategy to mitigate gut dysfunction, reduce systemic inflammation, and enhance immune resilience. This approach may lower infection rates, decrease the incidence of sepsis and MODS, and accelerate recovery by targeting GR signaling, restoring microbial homeostasis, and reinforcing epithelial integrity.
DOI: https://doi.org/10.37349/eemd.2025.101432
Iatrogenic hypoparathyroidism is a serious complication that can arise from neck surgery, predominantly during thyroidectomy, parathyroidectomy, and laryngectomy; it can be transient or permanent, requiring lifelong treatment. Early detection and treatment are crucial to prevent severe hypocalcemia, which is potentially fatal. This case report describes a 59-year-old male with a history of well-differentiated squamous cell carcinoma of the vocal cords who developed severe postoperative hypoparathyroidism following total laryngectomy with right hemithyroidectomy. Despite initial treatment with cholecalciferol by nasogastric tube, the patient experienced recurrent severe hypocalcemia, requiring intravenous administration of calcitriol due to his inability to swallow. This case highlights the risk factors for triggering postoperative hypoparathyroidism, such as previous surgery or radiotherapy in the cervical region, underlines the importance of careful monitoring of postoperative hypoparathyroidism and proposes the use of intravenous calcitriol as an effective strategy in acute treatment when oral administration is not feasible.
Iatrogenic hypoparathyroidism is a serious complication that can arise from neck surgery, predominantly during thyroidectomy, parathyroidectomy, and laryngectomy; it can be transient or permanent, requiring lifelong treatment. Early detection and treatment are crucial to prevent severe hypocalcemia, which is potentially fatal. This case report describes a 59-year-old male with a history of well-differentiated squamous cell carcinoma of the vocal cords who developed severe postoperative hypoparathyroidism following total laryngectomy with right hemithyroidectomy. Despite initial treatment with cholecalciferol by nasogastric tube, the patient experienced recurrent severe hypocalcemia, requiring intravenous administration of calcitriol due to his inability to swallow. This case highlights the risk factors for triggering postoperative hypoparathyroidism, such as previous surgery or radiotherapy in the cervical region, underlines the importance of careful monitoring of postoperative hypoparathyroidism and proposes the use of intravenous calcitriol as an effective strategy in acute treatment when oral administration is not feasible.
DOI: https://doi.org/10.37349/eemd.2025.101431
Hormone replacement therapy (HRT) is essential for alleviating menopausal symptoms and mitigating complications linked to type 2 diabetes mellitus (T2DM) in postmenopausal women. Studies indicate that HRT may contribute to better glycemic control, improved lipid metabolism, and enhanced kidney function, which could help lower the risk of diabetes-related complications. Early initiation of HRT near menopause has shown cognitive and metabolic benefits, while transdermal estrogen is preferred for women with cardiovascular risk due to its safer profile. However, HRT is associated with risks, including thromboembolic events and increased risks of breast and endometrial cancers, necessitating individualized evaluations. Despite its potential, significant gaps remain regarding HRT’s long-term safety and efficacy, its interaction with modern diabetes therapies, and its impact on diverse populations. The optimization of estrogen replacement therapy (ERT) strategies requires further exploration, particularly regarding patient screening, individualized treatment regimens, and personalization of care based on risk factors such as metabolic status, cardiovascular health, and diabetes severity. Current evidence supports the cautious use of HRT in strictly screened postmenopausal women with T2DM, adhering to key principles including early intervention (within 10 years of menopause), low-dose and short-duration therapy (usually < 5 years), and integration of lifestyle interventions (e.g., diet, exercise). Future research should focus on defining clear screening criteria, optimizing treatment regimens, and personalizing ERT to maximize benefits while mitigating risks. This review examines the benefits, risks, and optimization strategies of HRT in postmenopausal women with T2DM. It focuses on its metabolic, cardiovascular, cognitive, and renal effects and emphasizes personalized treatment approaches.
Hormone replacement therapy (HRT) is essential for alleviating menopausal symptoms and mitigating complications linked to type 2 diabetes mellitus (T2DM) in postmenopausal women. Studies indicate that HRT may contribute to better glycemic control, improved lipid metabolism, and enhanced kidney function, which could help lower the risk of diabetes-related complications. Early initiation of HRT near menopause has shown cognitive and metabolic benefits, while transdermal estrogen is preferred for women with cardiovascular risk due to its safer profile. However, HRT is associated with risks, including thromboembolic events and increased risks of breast and endometrial cancers, necessitating individualized evaluations. Despite its potential, significant gaps remain regarding HRT’s long-term safety and efficacy, its interaction with modern diabetes therapies, and its impact on diverse populations. The optimization of estrogen replacement therapy (ERT) strategies requires further exploration, particularly regarding patient screening, individualized treatment regimens, and personalization of care based on risk factors such as metabolic status, cardiovascular health, and diabetes severity. Current evidence supports the cautious use of HRT in strictly screened postmenopausal women with T2DM, adhering to key principles including early intervention (within 10 years of menopause), low-dose and short-duration therapy (usually < 5 years), and integration of lifestyle interventions (e.g., diet, exercise). Future research should focus on defining clear screening criteria, optimizing treatment regimens, and personalizing ERT to maximize benefits while mitigating risks. This review examines the benefits, risks, and optimization strategies of HRT in postmenopausal women with T2DM. It focuses on its metabolic, cardiovascular, cognitive, and renal effects and emphasizes personalized treatment approaches.
DOI: https://doi.org/10.37349/eemd.2025.101430
This article belongs to the special issue Metabolic Syndrome in Menopause
Pediatric adrenocortical tumors (pACTs) are rare endocrine neoplasms with variable prognosis, commonly associated with germline pathogenic variants (PVs) in the tumor suppressor gene TP53. Here, we report the case of a 3.1-year-old female presenting with virilization and Cushing syndrome due to a left-sided adrenal mass. The tumor was completely resected and confirmed as stage II adrenocortical carcinoma (ACC) based on the Wieneke index. Comprehensive molecular profiling revealed heterozygous germline PVs in BRCA2 [c.9382C>T p.(Arg3128*)] and CHEK2 [c.1232G>A p.(Trp411*)]. These findings suggest a potential role of impaired DNA damage repair in ACC pathogenesis, as both PVs are associated with hereditary breast and ovarian cancer (HBOC) syndromes and genomic instability. This case expands the genetic spectrum of pACT and underscores the importance of advanced molecular analyses in identifying rare germline alterations that may inform personalized treatment strategies and cancer prevention programs. Although no additional treatment was required in this case, BRCA2 status highlights the potential for tailored therapeutic approaches, including poly(ADP-ribose) polymerase (PARP) inhibitors, in selected patients. Further research is warranted to explore the specific contributions of BRCA2 and CHEK2 PVs to ACC tumorigenesis and their implic ations for targeted therapies.
Pediatric adrenocortical tumors (pACTs) are rare endocrine neoplasms with variable prognosis, commonly associated with germline pathogenic variants (PVs) in the tumor suppressor gene TP53. Here, we report the case of a 3.1-year-old female presenting with virilization and Cushing syndrome due to a left-sided adrenal mass. The tumor was completely resected and confirmed as stage II adrenocortical carcinoma (ACC) based on the Wieneke index. Comprehensive molecular profiling revealed heterozygous germline PVs in BRCA2 [c.9382C>T p.(Arg3128*)] and CHEK2 [c.1232G>A p.(Trp411*)]. These findings suggest a potential role of impaired DNA damage repair in ACC pathogenesis, as both PVs are associated with hereditary breast and ovarian cancer (HBOC) syndromes and genomic instability. This case expands the genetic spectrum of pACT and underscores the importance of advanced molecular analyses in identifying rare germline alterations that may inform personalized treatment strategies and cancer prevention programs. Although no additional treatment was required in this case, BRCA2 status highlights the potential for tailored therapeutic approaches, including poly(ADP-ribose) polymerase (PARP) inhibitors, in selected patients. Further research is warranted to explore the specific contributions of BRCA2 and CHEK2 PVs to ACC tumorigenesis and their implic ations for targeted therapies.
DOI: https://doi.org/10.37349/eemd.2025.101429
Diabetes mellitus is a major risk factor for both cardiovascular and chronic kidney disease (CKD) while CKD is also associated with cardiovascular morbidity. In fact, cardiovascular disease is the leading cause of death in patients with diabetes mainly from heart failure or myocardial infarction. The newer therapeutic agents in diabetes have positive impact on both cardiovascular and renal outcomes. Thus, the American Diabetes Association (ADA)’s annual update on the Standards of Medical Care in Diabetes is an important resource for all caregivers involved in diabetes management as it incorporates the latest scientific research, clinical evidence, and emerging technologies in diabetes management. The 2025 guidelines present significant updates that reflect a deeper understanding of diabetes management, emphasizing expanded usage of technologies such as continuous glucose monitoring, personalized pharmacological approaches, and lifestyle interventions. This commentary provides an analysis of the key updates in the 2025 ADA guidelines exploring implications for clinical practice, laboratory assessments, and public health policy. Where relevant, comparisons to the 2024 version will be made.
Diabetes mellitus is a major risk factor for both cardiovascular and chronic kidney disease (CKD) while CKD is also associated with cardiovascular morbidity. In fact, cardiovascular disease is the leading cause of death in patients with diabetes mainly from heart failure or myocardial infarction. The newer therapeutic agents in diabetes have positive impact on both cardiovascular and renal outcomes. Thus, the American Diabetes Association (ADA)’s annual update on the Standards of Medical Care in Diabetes is an important resource for all caregivers involved in diabetes management as it incorporates the latest scientific research, clinical evidence, and emerging technologies in diabetes management. The 2025 guidelines present significant updates that reflect a deeper understanding of diabetes management, emphasizing expanded usage of technologies such as continuous glucose monitoring, personalized pharmacological approaches, and lifestyle interventions. This commentary provides an analysis of the key updates in the 2025 ADA guidelines exploring implications for clinical practice, laboratory assessments, and public health policy. Where relevant, comparisons to the 2024 version will be made.
DOI: https://doi.org/10.37349/eemd.2025.101428
Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.
Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.
DOI: https://doi.org/10.37349/eemd.2025.101427
This article belongs to the special issue Regulators of Glucose Homeostasis, Lipid Metabolism and Energy Balance
The glucocorticoid receptor alpha (GRα), a vital component of the ancient glucocorticoid (GC) signaling system, is essential for vertebrate survival. It regulates fertility, fetal development, organ function, vascular and neural integrity, metabolism, immune responses, and stress adaptation. While GRα’s anti-inflammatory properties have been acknowledged since the mid-20th century, its crucial role as the master regulator of homeostatic corrections in both health and critical illness has only recently come to light. In critical illness, GRα facilitates a seamless transition through three essential phases of homeostatic correction. Initially, in the Priming Phase, it activates immune responses and mobilizes energy reserves to defend against stressors like infection and injury, enhancing glucose metabolism, supporting mitochondrial function, and strategically deploying immune cells to areas of damage. Next, during the Modulatory Phase, GRα fine-tunes inflammatory responses, manages oxidative stress, regulates vascular tone, and maintains cellular integrity. Finally, in the Restorative Phase, GRα plays a crucial role in resolving inflammation, initiating tissue repair, supporting cellular regeneration, facilitating debris clearance, and reestablishing anatomical and physiological balance for long-term recovery. GRα coordinates complex molecular interactions, including co-regulation with pro-inflammatory transcription factors, ensures mitochondrial stability, and metabolic balance under stress. However, depleted bioenergetic and micronutrient reserves in critically ill patients can impair GRα’s capacity, increasing morbidity and mortality risks. This review highlights the need to reassess current GC treatment strategies and integrate micronutrient support to optimize GRα function. Such an approach could strengthen immediate immune defenses, enhance long-term recovery, reduce GC dose and duration, and minimize adverse effects.
The glucocorticoid receptor alpha (GRα), a vital component of the ancient glucocorticoid (GC) signaling system, is essential for vertebrate survival. It regulates fertility, fetal development, organ function, vascular and neural integrity, metabolism, immune responses, and stress adaptation. While GRα’s anti-inflammatory properties have been acknowledged since the mid-20th century, its crucial role as the master regulator of homeostatic corrections in both health and critical illness has only recently come to light. In critical illness, GRα facilitates a seamless transition through three essential phases of homeostatic correction. Initially, in the Priming Phase, it activates immune responses and mobilizes energy reserves to defend against stressors like infection and injury, enhancing glucose metabolism, supporting mitochondrial function, and strategically deploying immune cells to areas of damage. Next, during the Modulatory Phase, GRα fine-tunes inflammatory responses, manages oxidative stress, regulates vascular tone, and maintains cellular integrity. Finally, in the Restorative Phase, GRα plays a crucial role in resolving inflammation, initiating tissue repair, supporting cellular regeneration, facilitating debris clearance, and reestablishing anatomical and physiological balance for long-term recovery. GRα coordinates complex molecular interactions, including co-regulation with pro-inflammatory transcription factors, ensures mitochondrial stability, and metabolic balance under stress. However, depleted bioenergetic and micronutrient reserves in critically ill patients can impair GRα’s capacity, increasing morbidity and mortality risks. This review highlights the need to reassess current GC treatment strategies and integrate micronutrient support to optimize GRα function. Such an approach could strengthen immediate immune defenses, enhance long-term recovery, reduce GC dose and duration, and minimize adverse effects.
DOI: https://doi.org/10.37349/eemd.2025.101426
