Open research questions in Diabetes, Cardiovascular Risks, and Lipoproteins

What the literature leaves open

• Future work needs to move away from the systemic nature of insulin resistance toward defining insulin resistance phenotypes specific to skeletal muscle, liver, fat tissue, brain, vascular tissue, and pancreatic b-cells. Longitudinal studies are required to clarify whether insulin resistance is upstream of aging phenotypes or if the aging process drives tissue dysfunction that leads to insulin resistance. Biomarkers for insulin resistance-induced aging need to be determined using multi-omic, imaging, metabolomics, proteomics, and single-cell technologies. Future clinical trials are required to evaluate whether strategies to lower or sensitize to insulin alter aging-related outcomes in older people. Trials will need to look at more than just glucose metab- olism; other outcomes that could be studied include frailty, sarcopenia, cognitive decline, cardiovascular events, function, in- flammation, mitochondrial health, and quality of life. Interventions like exercise, caloric restriction, GLP-1 receptor agonists, senolytic drugs, anti-inflammatory drugs, and mitochondrial-targeted ther- apies need to be studied with respect to their differential impact in individuals of differing sex, menopausal status, body habitus, and preexisting frailty. Lastly, hyperinsulinemia, insulin resistance, b- cell dysfunction, and biological aging need to be studied longitudi- nally in humans.

  Insulin resistance, aging biology, and non- communicable chronic diseases: a narrative review of bidirectional mechanisms and translational implications · 2026 · DOI

• However, longitudinal evidence for a causal link between ABSI and cognitive decline or dementia remains scarce, and the two indices have rarely been combined for predictive diseases.

  Association of triglyceride-glucose index (TyG) and a body shape index (ABSI) with cognitive decline and dementia risk · 2026 · DOI

• Abstract While physical activity (PA) is known to reduce stroke risk, the unified biological mechanisms involving metabolic, lipid, and inflammatory pathways remain unclear.

  Mediation effect of TyG-BMI, LDL-C, and CRP on physical activity-stroke risk relationship · 2026 · DOI

• Background While diastolic dysfunction (DD) is a critical heart failure precursor linked to metabolic stress, the specific association between the promising triglyceride-glucose waist circumference (TyG-WC) index and DD remains insufficiently characterized under contemporary diagnostic standards.

  Linear dose-response relationship between TyG-WC index and diastolic dysfunction: insights from restricted cubic spline and machine learning analysis · 2026 · DOI

• The cholesterol, high-density lipoprotein, and glucose index (CHG index) as an emerging composite metabolic marker has shown value in cardiovascular diseases and diabetes, but its predictive role in new-onset stroke among depressed individuals remains unclear.

  Association between the cholesterol-high-density lipoprotein-glucose index and new-onset stroke in middle-aged and older adults with depressive symptoms: a longitudinal cohort analysis · 2026 · DOI

• However, the interplay between glycaemic control as measured by HbA1c, lipid parameters, and kidney function tests (KFT) across different disease durations remains insufficiently studied in the Indian clinical setting.

  GLYCAEMIC CONTROL AND ITS IMPACT ON LIPID PROFILE AND RENAL FUNCTION IN TYPE II DIABETES MELLITUS: A COMPARATIVE ANALYSIS BY DISEASE DURATION · 2026 · DOI

• Though the mechanism of action is not fully known, some of the find- ings say that Farnesoid X Receptor (FXR), a nuclear receptor and transmembrane G protein coupled with Receptor 5 have some role on bile acid metabolism as feedback regulators.

  Gut-Liver-Pancreas Axis-Derived Composite Index for Glycemic Stratification in Type 2 Diabetes - A Cross-Sectional Study. · 2026 · DOI

• However, certain limitations should also be acknowledged. Due to the cross-sectional design, causal relationships between risk factors and the development of diabetes cannot be definitively established. The study was conducted in a specific region of North India, which may limit the generalizability of findings to other populations. Additionally, some variables related to lifestyle behaviors, such as dietary habits and physical activity, were based on self-reported data, which may be subject to recall bias. Despite these limitations, the present study provides important epidemiological evidence regarding the burden and determinants of T2DM in a North Indian population.

  Prevalence and Determinants of Type 2 Diabetes Mellitus in a North Indian Population: a Community-Based Cross-Sectional Study · 2026 · DOI

• There are, however, several limitations of this study. First, defining insulin resistance using a sample-specific HOMA-IR threshold (upper tertile) as the reference standard for ROC evaluation introduces potential circularity, which may inflate the performance estimates of the TyG index. Consequently, the reported results should be interpreted as internal concordance within this specific cohort rather than a universal diagnostic capability. Second, the study population was limited to general practitioners at a single medical center, which restricts the external validity and generalizability of the findings to the broader young adult population. Third, the reported correlations between adiposity markers and insulin resistance indices were not adjusted for potential confounders, such as age, sex, and lifestyle factors, which are known to influence metabolic profiles. Although sex-specific descriptive data were provided, the lack of sex-stratified or sex-adjusted analyses remains a limitation, particularly given the significant influence of sex on fat distribution and triglyceride metabolism. COnCLuSIOn In this study of non-diabetic young adults with obesity, the TyG index demonstrated a high concordance with HOMA-IR, showing 96.9% sensitivity at an optimal cut-off of 4.33. While both were significantly associated with markers of central adiposity (BMI and WC), the TyG index was uniquely characterized by a lack of significant correlation with BF%. These findings suggest that the TyG index is a reliable and accessible surrogate for HOMA-IR in identifying insulin resistance within this specific demographic. However, as a cross-sectional study conducted at a single center, these results represent metabolic associations and should be validated in larger, more diverse populations. Author’s contributions: Conceptualization, Awaluddin RB, Aman AM; methodology, Awaluddin RB, Aman AM; software, Romanian medical JouRnal – Volume 73, no. 1, 2026 54 Romanian medical JouRnal – Volume 73, no. 1, 2026 Zainuddin AA; validation, Awaluddin RB, Aman AM; data curation, Awaluddin RB; writing—original draft preparation, Awaluddin RB; writing—review and editing, Awaluddin RB, Aman AM, Rasyid H., Bakri S., Harjianti T., and Sanusi H.; supervision, Aman AM, Rasyid H., Bakri S., Harjianti T., and Sanusi H.; funding acquisition, Awaluddin RB. All authors have read and agreed to the published version of the manuscript.

  Comparison of the homeostasis model assessment of insulin resistance (HOMA-IR) and the triglyceride-glucose index (TyG index) in non-diabetic young adults with obesity · 2026 · DOI

• Future studies should validate these findings in larger, prospective cohorts and evaluate interventions targeting central obesity and treatment adherence. A multidisciplinary approach should be explored to optimize lipid management in high-risk patients with type 2 diabetes. CONCLUsION In this study of Vietnamese patients with T2DM at very high CV risk, central obesity emerged as an independent factor associated with LDL-C non-attainment despite statin therapy. These findings suggest that lipid goal failure is not merely explained by inadequate pharmacological intensity but also reflects underlying metabolic and behavioral barriers. Addressing these factors through comprehensive strategies – including weight reduction, central obesity management, and lifestyle modification support – may be essential to optimizing LDL-C control and reducing residual cardiovascular risk in this vulnerable population. Ethics and consent to participate: The study was approved by the Ethics Committee for Biomedical Research of Pham Ngoc Thach University of Medicine (No. 986/TĐHYKPNT–HĐĐĐ, January 4, 2024) and the Ethics Committee for Biomedical Research of Nguyen Tri Phuong Hospital (No. 816/NTP–HĐĐĐ, April 22, 2024). Written informed consent was obtained from all participants prior to enrollment. Authors’ contributions: All authors contributed to the conception and overall content of the manuscript. Tri Minh Bui – writing—original draft, literature review; Loc Phuc Tran, Thao Thi Thu Nguyen, Ngoc Tran Minh Vo – literature review; Hung Cao Dinh – writing—review and editing, language editing. All authors reviewed and approved the final version of the manuscript.

  Determinants of LDL-C target non-attainment in patients with type 2 diabetes at very high cardiovascular risk: a cross-sectional analysis of central obesity and metabolic factors · 2026 · DOI

• Future research is recommended to include larger sample sizes, longitudinal study designs, and additional metabolic indicators—such as insulin resistance markers, lipid profiles, and the glycated albumin (GA)/HbA1c ratio—to better clarify causal relationships and improve risk prediction.

  Relationship Between HbA1c Value and Duration of Diagnosed Type 2 Diabetes Mellitus with the Incidence of Fatty Liver Disease at Waled Cirebon Regional General Hospital · 2026 · DOI

• 10. Ethical Considerations The present study has certain limitations. The use of convenience sampling may have introduced selection bias, thereby limiting the generalizability of the findings to the wider population. “The cross-sectional design restricts the ability to establish causal relationships, and the findings should be interpreted as associations. There may be measurement variability in laboratory parameters due to biological variation and technical factors, which could have influenced the results. Ethical clearance for the study was obtained from the Institutional Ethics Committee of Jawaharlal Nehru Medical College, KLE Academy of Higher Education and Research, Belagavi. Permission to conduct the study was obtained from the concerned authorities of the urban field practice areas.

  Pattern of dyslipidemia among patients with type 2 diabetes mellitus in urban areas of Belagavi: A cross-sectional study · 2026 · DOI

• Strengths include comprehensive biochemical profiling, the application of ROC and cluster analy- e10 Arch Med Sci Atheroscler Dis 2025 Samah Alfahl, Walaa Mohammedsaeed, Abdullah Alamri, Amira Elmihy, Fahad Almohammadi, Roaa Alhejli, Rami Aljohani ses, and the focus on an understudied population. While the results are preliminary, they contrib- ute to the growing evidence that metabolic risk may be underrecognized in young adults with nor- mal BMI.

  Lipid ratios as early screening markers of dyslipidemia in normal-BMI university students: a cross-sectional epidemiologic study · 2026 · DOI

• Insulin resistance and adiposity are closely linked to cardiometabolic risk, but the comparative value of single-time and cumulative average triglyceride-glucose (TyG)-based indices for predicting new-onset CVD remains uncertain.

  Association of 14 triglyceride-glucose (TyG)-related indices with new-onset cardiovascular disease in middle-aged and older adults: evidence from the CHARLS and ELSA aging cohorts · 2026 · DOI

• Conclusion This systematic review supportsed the predictive value of multiple lipid biomarkers for the risk of T2D, especially some composite indicators such as the HTW, LAP, TyG index, AIP, VAI and TG/HDL-C ratio, but larger-scale and longer-term prospective studies are warranted to validate these associations.

  Lipid biomarkers for the prediction of type 2 diabetes risk, an umbrella review and updated meta-analyses of prospective observational studies · 2026 · DOI

• Abstract Background Growing evidence supports a role for high intrapancreatic fat deposition (IPFD) in the pathogenesis of type 2 diabetes mellitus (T2DM); however, the magnitude of this association and the extent to which it is influenced by body mass index (BMI), liver fat content (LFC), and age remain uncertain.

  Burden of Intrapancreatic Fat Deposition in Type 2 Diabetes and the Role of Obesity: A Systematic Review and Meta-Analysis · 2026 · DOI

• However, the relationship between visceral fat area (VFA) and remnant cholesterol–based indices, including residual cholesterol (RC) and the less-validated RC-inflammation index (RCII), remains uncertain.

  Visceral fat area and remnant cholesterol in type 2 diabetes: Nonlinear associations and thresholds · 2026 · DOI

• BackgroundLifestyle interventions can increase the probability of remission of prediabetes to normal glucose tolerance, but their economic value remains unclear.

  One-year within-trial and lifetime-horizon modeled health economic evaluation of the risk-stratified Prediabetes Lifestyle Intervention Study (PLIS) for prediabetes remission in Germany · 2026 · DOI

• The cross-sectional design of the study limits the ability to establish causal relationships between risk factors and the development of diabetes. The study was conducted at a single rural health training centre using convenience sampling, which may limit the generalizability and external validity of the findings. In addition, physical activity levels and family history of diabetes were assessed based on self-reported information and are therefore subject to recall bias.

  Assessment of type 2 diabetes risk using the Indian diabetes risk score and its association with selected risk factors among adults attending a rural health training centre in central India: a cross-sectional study · 2026 · DOI

• The study had several limitations, which could have affected the results of the OGTT. Apart from securing a state of over- night fasting, we could not secure standardization of the dietary intake for 3 days prior to the OGTT as recommended. Furthermore, we had to allow the study participants to walk slowly to a nearby restroom during the OGTT if requested. Regarding insulin indices, we acknowledge that HOMA-IR as well as the Matsuda index are indirect surrogates derived from the OGTT rather than clamp-based measures. Due to the “field conditions”, we were only able to collect simple anthropometric and estimated aerobic fitness data. Thus, neither body composition nor fitness could be measured with high precision. Finally, the results presented should be interpreted with caution and need replication in other inde- pendent datasets among Maasai or other agro-pastoralist groups with similar lifestyle and -conditions. In conclusion, in rural Maasai men and women of wide ranges of age (17–65 years) and BMI (14.0–30.9 kg/m2) and without having DM, fasting and OGTT-derived plasma glucose concentrations showed a higher average fasting concentration in men, while women exhibited higher aver- age 120 min. insulin, 120 min. GLP-1 and tAUC GLP-1 concentrations. A larger sample size and inclusion of more sophisticated methodologies should be included in future studies to investigate sex-specific biology in this unique population known to have a low prevalence of DM despite growing obesity at the population level.

  Differences in physiological response to an oral glucose tolerance test in adult Maasai men and women · 2026 · DOI

• Several limitations should be considered when interpreting the findings of this study. First, the cross-sectional design precludes causal inference regarding the relationship between thyroid function and the TyG index. Second, direct measures of insulin resistance, such as HOMA-IR or hyperinsulinemic– euglycemic clamp techniques, were not available. As a result, the TyG index was used both as a surrogate indicator of insulin resistance–related metabolic risk and as the primary outcome variable in association and ROC analyses, which limits the diagnostic and clinical interpretability of the findings. Accordingly, TyG-derived cut-off values should be interpreted as markers of increased metabolic risk rather than as validated diagnostic thresholds for insulin resistance. ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT In addition, a pooled multivariable regression model including thyroid function group as an independent predictor of the TyG index was not performed; instead, regression analyses were conducted separately within each thyroid function category. While this approach allowed identification of group-specific determinants of the TyG index, it may limit direct between-group comparisons. Furthermore, although the overall sample size was adequate for the primary analyses, subgroup analyses may have been underpowered for more detailed stratification by sex or body mass index. Behavioral factors such as dietary intake, physical activity, and alcohol consumption could not be systematically assessed due to the retrospective nature of data collection. Thyroid disease duration and medication status were also not fully captured, and undiagnosed dysglycemia could not be entirely excluded despite the exclusion of individuals with known diabetes. Finally, systemic inflammation was assessed using the CRP/albumin ratio; additional inflammatory biomarkers, such as interleukin-6 or tumor necrosis factor-α, were not measured and may have provided a more comprehensive characterization of inflammatory status. Future studies incorporating longitudinal designs, direct measures of insulin sensitivity, and broader panels of metabolic and inflammatory biomarkers are warranted to validate and extend these findings and to clarify the clinical utility of the TyG index across different thyroid function states.

  Triglyceride-glucose index as a marker of metabolic and inflammatory risk across different thyroid function states · 2026 · DOI

• Further to understand temporal variations of lipid ratios in association with glycemic status. Larger sample size, comprehensive measures of lifestyle and advanced lipid profiling should be considered to improve sensitivity or specificity of predictions by lipid ratios. Furthermore, evaluation of these markers in other ethnic groups would increase their clinical relevance is necessary longitudinal research to REFERENCES 1. Chatterjee S, Khunti K, Davies MJ. Type 2 Diabetes. The Lancet. 2017 Feb 9;389(10085):2239–51. doi: 10.1016/S0140-6736(17)30058-2. 2. Zheng Y, Ley SH, Hu FB. Global Aetiology and Epidemiology of Type 2 Diabetes Mellitus and Its Complications. Nature Reviews Endocrinology. 2018 Dec 8;14(2):88–98. doi: 10.1038/nrendo.2017.151. 3. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin England). trials. 10.1016/S0140- 2010;375(9716):735–42. 6736(09)61965-6. 4. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. Introduction and Methodology: Standards of Care in Diabetes—2023. Diabetes Care. 2022 Dec 12;46(1):1–4. doi: 10.2337/dc23-Sint.

  Lipid Profile And Its Association With Glycemic Status In Type 2 Diabetes Mellitus: A Cross-Sectional Retrospective Study From South India · 2026 · DOI

• Emerging evidence increasingly supports the concept that HDL functionality rather than HDL cholesterol concentra- tion alone and provides a more informative framework for cardiovascular risk assessment. Cholesterol efflux capacity, particularly through ABCA-1 mediated pathways, repre- sents a key mechanistic component of reverse cholesterol transport and has demonstrated consistent inverse asso- ciations with cardiovascular outcomes. However, HDL mediated atheroprotection is multifactorial, encompassing antioxidative, anti-inflammatory and endothelial protective functions. Advances in HDL particle characterization using techniques such as nuclear magnetic resonance spectroscopy and Lipoprint analysis have further highlighted the struc- tural heterogeneity of HDL and its relevance to cardiovas- cular risk. While HDL particle number and size show robust associative relationships with outcomes in population based studies, their predictive value appears more variable in car- diometabolic disease states, underscoring the importance of contextual interpretation and methodological harmonization across platforms. Importantly, both apoA-1-dependent and apo A-1 independent pathways contribute to HDL function- ality and clinical associations. Metrics such as cholesterol efflux capacity and HDL particle profiling should therefore be viewed as integrative measures of the overall HDL pool rather than surrogates for isolated molecular mechanisms. Lifestyle mechanisms, including intermittent fasting, may modulate HDL functionality through indirect effects on metabolic regulation, inflammation, and HDL composi- tion rather than uniform enhancement of efflux pathways. These observations reinforce the need to assess functional aspects of HDL endpoints when evaluating the cardiovascu- lar impact of dietary and metabolic interventions.

  High Density Lipoprotein Assessment Revisited: A Review of Foundational Understanding and Recent Developments in Function, Particle Size, and Cardiometabolic Impact · 2026 · DOI

• investigation A primary strength of this is the detailed assessment of the dose-response relationship between insulin resistance and cognitive status. By utilizing restricted cubic splines rather than treating cognitive impairment as a binary outcome, we identified a distinctive threshold-dependent association for severe impairment. Additionally, the application of hierarchical clustering allowed us to visualize a specific “metabolic-inflammatory” phenotype, offering mechanistic insight into how the TyG index captures residual risk beyond traditional hemodynamic factors. However, several methodological the cross-sectional design limitations warrant consideration: First, inherently precludes causal inference. While our findings suggest that metabolic dysregulation accelerates neurodegeneration, we cannot rule out reverse causality, where cognitive decline leads to poorer self-care and subsequent metabolic deterioration.

  Threshold effects of insulin resistance on cognitive function in coronary heart disease: the non-linear diagnostic value of the triglyceride-glucose index · 2026 · DOI

• These data show that hypertension, hypercholesterolemia, and prediabetes are associated with MCI in the NHPI community, suggesting that preventive strategies to reduce chronic conditions may also potentially slow cognitive decline in underrepresented/understudied NHPI.

  Comorbid Conditions Are Associated With Cognitive Impairment in Native Hawaiians and Pacific Islanders · 2024 · DOI

Most-cited papers in Diabetes, Cardiovascular Risks, and Lipoproteins

• Prevalence of the Metabolic Syndrome Among US Adults · JAMA · 2002 · 5,035 citations
• Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021 · The Lancet · 2023 · 3,857 citations
• The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-aged Men · JAMA · 2002 · 3,593 citations
• Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes · New England Journal of Medicine · 2013 · 2,525 citations
• Diabetes and Atherosclerosis · JAMA · 2002 · 2,159 citations
• The Obese Without Cardiometabolic Risk Factor Clustering and the Normal Weight With Cardiometabolic Risk Factor Clustering · Archives of Internal Medicine · 2008 · 1,350 citations
• Cause-Specific Excess Deaths Associated With Underweight, Overweight, and Obesity · JAMA · 2007 · 1,167 citations
• Glucose Tolerance and Cardiovascular Mortality · Archives of Internal Medicine · 2001 · 1,146 citations
• Fasting Serum Glucose Level and Cancer Risk in Korean Men and Women · JAMA · 2005 · 785 citations
• Prevalence of the Metabolic Syndrome and Its Relation to All-Cause and Cardiovascular Mortality in Nondiabetic European Men and Women · Archives of Internal Medicine · 2004 · 783 citations

Most recent work

• The Cardiovascular Burden of Diabetes: Risk Factors, Clinical Phenotypes, and Personalized Cardiometabolic Management · Journal of Clinical Medicine · 2026
• Comment on Liu et al. Low-Carbohydrate Diets of Varying Macronutrient Quality and Risk of Type 2 Diabetes in Three U.S. Prospective Cohort Studies. Diabetes Care 2025;48:2095–2102 · Diabetes Care · 2026
• Screening gaps for prediabetes in US young adults under current American diabetes Association criteria · Diabetes Research and Clinical Practice · 2026
• Prevalence and Determinants of Type 2 Diabetes Mellitus in a North Indian Population: a Community-Based Cross-Sectional Study · MAEDICA – a Journal of Clinical Medicine · 2026
• Lipid ratios as early screening markers of dyslipidemia in normal-BMI university students: a cross-sectional epidemiologic study · Archives of Medical Science - Atherosclerotic Diseases · 2026
• Pancreatic fat and the risk of future dysglycemia: a systematic review and meta-analysis · The Journal of Clinical Endocrinology & Metabolism · 2026
• Cause-specific years of life lost attributable to non-optimal body mass index by county, sex, race, and ethnicity in the USA, 2000–2019: a systematic analysis of health disparities · BMC Medicine · 2026
• Metabolic syndrome risk scores and their correlates amongst hypertensive patients attending university of Port Harcourt teaching hospital · World Journal of Biology Pharmacy and Health Sciences · 2026
• Community and health workers perspectives on barriers to diabetes and hypertension screening in North Eastern India: a qualitative study · BMC Health Services Research · 2026
• Cumulative exposure and dynamic trajectories of the C-reactive protein-triglyceride-glucose index (CTI) versus the cholesterol, high-density lipoprotein, and glucose index (CHG) for incident hypertension prediction: a national cohort study · Cardiovascular Diabetology · 2026

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