D Glucose

Glucose, specifically d-glucose, is a fundamental monosaccharide and the primary source of energy for living organisms. It is a simple sugar that plays a central role in cellular metabolism, fueling essential biological processes from brain function to muscle activity. Maintaining glucose homeostasis, or stable blood glucose levels, is critical for health.

Biological Basis

In humans, glucose is derived primarily from the digestion of carbohydrates in food. Once absorbed into the bloodstream, it is transported to cells throughout the body. The hormone insulin, produced by the pancreas, is essential for facilitating the uptake of glucose into most cells, where it is then metabolized to produce adenosine triphosphate (ATP) through cellular respiration. Excess glucose can be stored as glycogen in the liver and muscles or converted into fat for long-term energy reserves.

A key indicator of long-term blood glucose levels is glycated hemoglobin (HbA1c). This forms when glucose in the blood non-enzymatically binds to hemoglobin, a protein in red blood cells.^[1]Since red blood cells have a lifespan of about three months, HbA1c reflects the average blood glucose concentration over the preceding two to three months.^[2] Several genes, including G6PC2, GCK, HK1, and SLC30A8, have been identified in genome-wide association studies (GWAS) as influencing glycated hemoglobin levels.^[3]

Clinical Relevance

Dysregulation of glucose metabolism is a hallmark of several significant health conditions. Persistently high blood glucose levels, a condition known as hyperglycemia, are characteristic of diabetes mellitus. Measures such as Fasting Plasma Glucose (FPG) and Hemoglobin A1c (HbA1c) are critical diagnostic tools for diabetes and pre-diabetes.^[4] An HbA1c level of 7.0% or more is considered diagnostic for drug-requiring diabetes. ^[3]

Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with diabetes-related traits, including FPG, HbA1c, and incident diabetes mellitus.^[4]These genetic variations can influence various aspects of glucose metabolism, such as insulin secretion and sensitivity, highlighting the complex genetic architecture underlying these traits.^[3]Studies like the Framingham Heart Study and the Women’s Genome Health Study have contributed significantly to identifying genetic variants impacting glucose regulation^[4]. ^[3]

Social Importance

Diabetes mellitus, characterized by chronic hyperglycemia, represents a global health crisis. It is a leading cause of morbidity and mortality worldwide^[5]. ^[3]The disease and its complications, such as cardiovascular disease, kidney failure, and nerve damage, place an immense burden on individuals, healthcare systems, and national economies.^[6] The heritability of type 2 diabetes and its parental transmission underscore the importance of understanding the genetic factors involved ^[7]. ^[4]Research into the genetic determinants of glucose levels and diabetes risk is crucial for developing personalized prevention strategies, early diagnostic methods, and more effective treatments to mitigate the widespread impact of this condition.

Limitations

Methodological and Statistical Constraints

The interpretation of findings related to glucose metabolism, particularly as reflected by glycated hemoglobin, is subject to several methodological and statistical limitations. While the primary study utilized a substantial discovery cohort of 14,618 women, the independent replication sample was considerably smaller, comprising only 455 non-diabetic Caucasian participants.^[3]This disparity in sample size can impact the statistical power for robust replication, as evidenced by individual SNPs showing non-significant P-values in the replication cohort when analyzed separately, only achieving significance in a multiple regression model or when combined with the larger discovery sample.^[3] Such reliance on combined analyses or specific modeling choices to achieve significance highlights potential instability of associations in smaller, independent datasets.

Furthermore, the identified genetic variants, such as those at the HK1locus, collectively explained a small proportion of the total variance in glycated hemoglobin concentration (0.7%).^[3]This limited effect size suggests that while these genetic associations are statistically significant, they contribute modestly to the overall variability of the trait. In contrast, common clinical covariates like age, sex, menopause, and body mass index accounted for a substantially larger 9.5% of the variance.^[3]This considerable gap between explained variance and total heritability, often termed “missing heritability,” indicates that a large number of genetic and non-genetic factors influencing glucose metabolism remain undiscovered, underscoring the complexity of the trait.

Population Specificity and Generalizability

The generalizability of findings is constrained by the specific characteristics of the study populations. The primary analysis was conducted exclusively among Caucasian women in the Women’s Genome Health Study, with replication also performed in a cohort of non-diabetic Caucasians. ^[3]This predominant focus on individuals of European ancestry limits the direct applicability of these results to other ethnic and racial groups, where genetic architecture, allele frequencies, and environmental exposures can differ significantly. While some studies explore multiethnic cohorts, the foundational research for glycated hemoglobin discussed here remains largely confined to a specific demographic.^[8]

Additionally, the selection criteria for participants, which included the exclusion of individuals with self-reported diabetes, glycated hemoglobin levels of 7.0% or more, or those on anti-diabetic medications, create a highly specific non-diabetic cohort.^[3]While essential for investigating glucose regulation in a healthy population, this stringent exclusion process restricts the interpretation of findings to individuals without overt diabetes or significant metabolic dysfunction. Consequently, the identified genetic associations may not fully capture the genetic influences on glucose metabolism across the entire spectrum of metabolic health, including pre-diabetic or diabetic states.

Environmental and Unaccounted Influences

Despite adjusting for several clinical covariates such as age, sex, menopause, and BMI, the studies may not fully account for the complex interplay of environmental factors and gene-environment interactions that influence glucose metabolism.^[3]Lifestyle elements, dietary habits, physical activity levels, and other unmeasured environmental exposures can significantly modulate glycated hemoglobin levels. For example, information on lipid-lowering therapy was not always available or considered in some cohorts, which could introduce confounders when examining metabolic traits.^[8] The absence of comprehensive data on a broader range of environmental variables means that some observed genetic associations could be indirectly influenced by unmeasured or residual confounding factors.

Furthermore, a significant portion of the variability in glycated hemoglobin remains unexplained by the current genetic models and measured clinical covariates, highlighting remaining knowledge gaps.^[3]This suggests that many other genetic factors, including rare variants, structural variations, or complex epistatic interactions, as well as their interactions with environmental factors, are yet to be elucidated. Current genome-wide association studies, even with extensive SNP coverage, may not capture all relevant genetic variations. For instance, sex-specific genetic associations might remain undetected if only sex-pooled analyses are performed, further limiting the comprehensive understanding of genetic influences on glucose regulation.^[9]

Variants

The regulation of d-glucose metabolism involves a complex interplay of genes and their variants, influencing pathways from glucose uptake and utilization to cellular signaling and stress responses. Genetic variations, such as single nucleotide polymorphisms (SNPs), can subtly alter gene function, contributing to individual differences in metabolic health and susceptibility to conditions like diabetes and dyslipidemia.^[4] Understanding the roles of specific variants in genes like PFKP, VAV2, LINC00639, and FAF1 provides insight into the intricate genetic architecture underlying metabolic traits.

The variant rs2388595 is associated with the PFKP(Phosphofructokinase, Platelet) gene, which encodes the platelet-type phosphofructokinase. This enzyme is a critical regulatory point in glycolysis, the metabolic pathway that breaks down d-glucose to produce energy.^[10] By controlling the rate of glycolysis, PFKPplays a crucial role in maintaining cellular energy homeostasis and responding to changes in glucose availability. Variations inPFKPcan therefore influence how efficiently the body processes d-glucose, potentially affecting glucose levels and energy balance.

Another significant variant, rs2797826 , is located within the VAV2 gene. VAV2acts as a guanine nucleotide exchange factor (GEF) for Rho family GTPases, which are key regulators of the actin cytoskeleton, cell migration, and cell growth.^[11]In the context of glucose metabolism, Rho GTPases are implicated in insulin signaling and glucose transport, affecting how cells take up d-glucose from the bloodstream. Alterations inVAV2 function due to variants like rs2797826 could impact the efficiency of insulin-mediated glucose uptake and cellular responses to glucose, thereby influencing overall metabolic regulation.

The variant rs28568565 is associated with LINC00639and Y_RNA, representing long intergenic non-coding RNAs and small non-coding RNAs, respectively. While not coding for proteins, these non-coding RNAs are increasingly recognized for their diverse regulatory roles in gene expression, chromatin modification, and cellular processes . Such regulatory functions can indirectly influence metabolic pathways, including those governing d-glucose metabolism, by modulating the expression of genes involved in glucose transport, insulin signaling, or energy production. Therefore, variants within these non-coding RNA regions may contribute to subtle yet significant changes in metabolic regulation.

Finally, rs115363550 is a variant located in the FAF1 (Fas Associated Factor 1) gene. FAF1 is known to interact with the Fas death receptor and plays a role in apoptosis (programmed cell death), as well as inflammation and cell cycle regulation. ^[4]While its direct link to d-glucose metabolism is still being explored, cellular stress, inflammation, and apoptosis are all processes that can impact insulin sensitivity and pancreatic beta-cell function, which are critical for maintaining healthy glucose levels. Thus, variations inFAF1 could indirectly influence metabolic health by affecting cellular integrity and inflammatory responses in metabolically active tissues.

Key Variants

RS ID	Gene	Related Traits
rs2388595	PFKP	pyruvate measurement platelet volume protein measurement phosphoenolpyruvic acid measurement D-Glucose measurement
rs28568565	LINC00639 - Y_RNA	D-Glucose measurement
rs115363550	FAF1	D-Glucose measurement ATP measurement
rs2797826	VAV2	D-Glucose measurement

Classification, Definition, and Terminology of D-Glucose

Fundamental Definitions and Nomenclature of Glucose Traits

D-glucose is a monosaccharide critical to human metabolism, serving as a primary energy source. Within clinical and research contexts, its levels in the body are precisely defined through various quantitative traits. Fasting Plasma Glucose (FPG) represents the glucose concentration in plasma after an overnight fast, a fundamental measure for assessing glucose homeostasis.^[12]Hemoglobin A1c (HbA1c), also known as glycated hemoglobin, reflects the average plasma glucose concentration over the preceding two to three months, formed by the non-enzymatic glycosylation of hemoglobin.^[1] Another important measure, time-averaged FPG (tFPG), provides a long-term perspective by calculating the mean of serial FPG measurements taken over several years. ^[4]

These glucose traits are central to defining and understanding conditions related to metabolic health. Terms like “glycemia” refer broadly to the presence of glucose in the blood, while “hyperglycemia” specifically denotes elevated blood glucose levels.^[4] The accurate measurement and interpretation of FPG, HbA1c, and tFPG are essential for both clinical diagnosis and research into the genetic and environmental determinants of diabetes and related metabolic disorders. ^[2] The consistent nomenclature ensures standardized communication and comparability across studies, facilitating the advancement of scientific understanding in this field.

Clinical Classification and Diagnostic Criteria for Diabetes

The classification of diabetes mellitus relies on specific diagnostic criteria primarily involving glucose traits. Diabetes is operationally defined by a combination of factors, including chart-review-confirmed diagnoses, ongoing hypoglycemic treatment, or a Fasting Plasma Glucose (FPG) level consistently greater than 125 mg/dl on two or more separate occasions.^[4] For instance, in the Framingham Heart Study Offspring cohort, over 99% of diagnosed cases were identified as Type 2 diabetes, highlighting its prevalence. ^[4]Glycated hemoglobin (HbA1c) also serves as a key diagnostic biomarker, with a level of 7.0% or more proposed as indicative of drug-requiring diabetes.^[13]

While precise thresholds provide categorical diagnoses, understanding glucose metabolism also involves a dimensional approach. Metabolic risk factors are known to worsen continuously across the entire spectrum of nondiabetic glucose tolerance, indicating a gradual progression rather than an abrupt onset of disease.^[14]This perspective acknowledges that even within “normal” ranges, variations in glucose traits can signify different levels of metabolic risk. Therefore, both categorical definitions for clinical diagnosis and a dimensional understanding of glucose tolerance are critical for comprehensive patient assessment and risk stratification.

Measurement Approaches and Associated Biomarkers

The precise measurement of glucose traits is fundamental for accurate diagnosis and research. Fasting Plasma Glucose (FPG) is typically ascertained from blood samples collected after an overnight fast, with data often gathered across multiple examinations over many years to establish longitudinal trends.^[4]Hemoglobin A1c (HbA1c) is measured using standardized methods, such as the Tina-Quant turbidimetric inhibition immunoassay, which is calibrated against the International Federation of Clinical Chemists (IFCC) reference method to ensure consistency and reliability.^[15]An Oral Glucose Tolerance Test (OGTT), involving a 75-gram glucose load, is also employed to assess glucose regulation in subjects without a prior diabetes diagnosis.^[4]

Beyond direct glucose measures, several related quantitative traits serve as important biomarkers for comprehensive metabolic phenotyping. These include insulin traits like fasting insulin, Homeostasis Model-Assessed Insulin Resistance (HOMA-IR), which estimates insulin resistance and beta-cell function from fasting glucose and insulin levels^[16]and Gutt’s 0–120 min insulin sensitivity index (ISI_0-120).^[17]Other relevant biomarkers, such as plasma adiponectin and resistin concentrations, are also measured, providing additional insights into metabolic pathways and their association with diabetes-related traits.^[4]Strict exclusion criteria, such as non-fasting status, existing diabetes, or medication use, are applied to ensure the validity of glucose and insulin measurements in research studies.^[12]

Biological Background of D-Glucose

D-glucose is a fundamental monosaccharide and the primary energy source for most living organisms. Its precise regulation, known as glucose homeostasis, is critical for maintaining cellular function and overall physiological stability. Disruptions in glucose regulation can lead to significant health consequences, including metabolic disorders like type 2 diabetes. The body employs intricate molecular, cellular, and genetic mechanisms to control glucose uptake, metabolism, and storage, ensuring a constant supply of energy while preventing harmful fluctuations in blood glucose levels.^[10]

Glucose Metabolism and Homeostasis

Glucose metabolism is a complex network of biochemical pathways that ensure the efficient utilization and storage of glucose. Upon entering cells, glucose is often phosphorylated, a crucial initial step catalyzed by enzymes such as hexokinase (HK1) and glucokinase (GCK). HK1, for instance, is the rate-limiting enzyme in erythrocyte glucose metabolism, converting glucose into glucose-6-phosphate, thereby trapping it within the cell for glycolysis.^[3]This initial phosphorylation is vital for the subsequent breakdown of glucose to generate ATP, the cell’s main energy currency.GCKplays a similar role, particularly in the liver and pancreatic beta cells, where it acts as a glucose sensor regulating insulin secretion and hepatic glucose output.^[3]The tight control of these enzymatic steps is central to maintaining stable blood glucose levels, preventing both hypoglycemia and hyperglycemia.

Beyond immediate energy production, glucose also participates in various other metabolic processes. It can be stored as glycogen in the liver and muscles, a process influenced by insulin, or converted into fat for long-term energy storage. Conversely, when glucose supply is low, the body can generate glucose through gluconeogenesis, or break down glycogen stores (glycogenolysis), processes that are carefully regulated by hormones like glucagon and insulin. The balance between glucose uptake, utilization, and production is continuously adjusted through complex signaling pathways, ensuring that the body’s energy demands are met under diverse physiological conditions.^[10]

Genetic Regulation of Glucose Levels

Genetic factors play a significant role in determining an individual’s glucose concentration and their predisposition to metabolic diseases. Several genes have been identified that influence fasting blood glucose levels and glycated hemoglobin concentrations. For example, variations within theGCK and G6PC2genes are unequivocally associated with fasting blood glucose levels in healthy individuals.^[18]These genes encode proteins critical for glucose sensing and regulation, particularly in the liver and pancreas. Furthermore, novel associations have been found between variations in theHK1, SLC30A8, GCK, and G6PC2genes and glycated hemoglobin concentrations, an indicator of average blood glucose over several weeks.^[3]

Specific genetic polymorphisms can significantly impact glucose-related traits. A coding non-synonymous polymorphism within theSLC30A8gene, for instance, has been linked to a protective effect against type 2 diabetes and shown to influence insulin secretion following a glucose challenge.^[19] This particular variant, rs13266634 , is associated with lower glycated hemoglobin levels, highlighting how genetic variations in key biomolecules can modulate systemic glucose metabolism.^[3] Other genes, such as FTO, have also been implicated in influencing adiposity, insulin sensitivity, leptin levels, and resting metabolic rate, further underscoring the complex genetic architecture underlying glucose homeostasis and diabetes-related metabolic traits.^[20]

Cellular and Organ-Specific Glucose Dynamics

Glucose handling varies significantly across different cell types and organs, reflecting their specialized metabolic roles. Erythrocytes, or red blood cells, are highly dependent on glucose for energy and are unique in that their internal glucose concentration directly influences the level of glycated hemoglobin. Glucose enters erythrocytes via glucose transporters, after whichHK1 initiates glycolysis, the primary metabolic pathway in these cells. ^[3]The non-enzymatic attachment of glucose to hemoglobin within these cells, known as glycation, forms glycated hemoglobin, which serves as a long-term marker of blood glucose exposure due to the erythrocyte’s 120-day lifespan.^[1]

The pancreas, particularly its beta cells, plays a central role in systemic glucose regulation by secreting insulin. The zinc transporterSLC30A8is crucial in pancreatic beta cells, where it facilitates the transport of zinc into secretory vesicles, a process essential for the proper maturation and storage of insulin.^[21]Muscle tissue is another vital site for glucose metabolism, recognized for its significant role in insulin-sensitive glucose uptake.HK1is expressed in muscle, where it contributes to glucose utilization, affecting systemic glucose levels and insulin sensitivity.^[3]These organ-specific functions and interactions are tightly coordinated to maintain overall glucose balance throughout the body.

Glucose in Health and Disease Pathogenesis

The precise control of glucose is paramount for health, and its dysregulation is a hallmark of several pathophysiological conditions, most notably type 2 diabetes. This metabolic disorder is characterized by chronically increased blood glucose concentrations, leading to significant morbidity and mortality.^[3]The persistent elevation of glucose contributes to the non-enzymatic glycosylation of proteins, where glucose slowly attaches to amino groups on proteins like hemoglobin.^[1] This process results in the formation of advanced glycation end products (AGEs), which are implicated in the long-term complications of diabetes, affecting various tissues and organs. ^[22]

Glycated hemoglobin (HbA1c) is a widely used clinical measure that reflects the average blood glucose concentration over the preceding 8-12 weeks, providing a more comprehensive assessment of glycemia than single fasting glucose measurements.^[2]This marker is invaluable for diagnosing diabetes, monitoring treatment effectiveness, and assessing the risk of diabetes-related complications. Understanding the molecular and genetic determinants influencing glucose levels and glycated hemoglobin is crucial for identifying individuals at risk, developing targeted interventions, and ultimately preventing the progression of glucose-related diseases.^[3]

Pathways and Mechanisms

Glucose Transport and Cellular Uptake

D-glucose uptake into cells is primarily facilitated by members of the solute carrier family 2 (SLC2A), known as facilitative glucose transporters. A notable member,SLC2A9 (also referred to as GLUT9), serves as a crucial transporter influencing both glucose and urate metabolism. This protein’s functional significance extends beyond glucose transport, as it is a newly identified urate transporter that significantly impacts serum urate concentrations and excretion, with common variants in its gene, such as those inGLUT9, being associated with serum uric acid levels.^[23]

The precise trafficking and substrate selectivity of SLC2A proteins, including GLUT9, are modulated by specific molecular features. For instance, alternative splicing of GLUT9 transcripts can alter its cellular localization and function, thereby influencing its role in metabolic processes. ^[24]Furthermore, a conserved hydrophobic motif within the exofacial vestibule of fructose-transportingSLC2A proteins is critical for determining their substrate selectivity, highlighting the intricate molecular mechanisms governing the transport of various monosaccharides. ^[25] The dual role of SLC2A9in transporting both glucose and urate exemplifies pathway crosstalk, where a single transporter can exert systemic effects on multiple metabolic pathways, influencing conditions like gout and metabolic syndrome.^[23]

Core Glucose Metabolism and Its Regulation

Following cellular uptake, D-glucose enters core metabolic pathways such as glycolysis, initiating its catabolism for energy production. A key enzyme in this process is hexokinase 1 (HK1), the red blood cell-specific isozyme that phosphorylates glucose, trapping it within the cell.^[26] Genetic variations in HK1have been associated with glycated hemoglobin levels in non-diabetic populations, suggesting its regulatory influence on long-term glucose control.^[3] Abnormalities in erythrocyte glycolytic enzymes, including HK1, can impact cellular energy status and function. ^[27]

The liver and pancreas play central roles in systemic glucose homeostasis, regulated by enzymes like glucokinase, whose activity is modulated by the glucokinase regulatory protein (GCKR). Polymorphisms within GCKR are associated with altered fasting serum triacylglycerol levels, reduced insulinemia, and a decreased risk of type 2 diabetes, highlighting its role in metabolic regulation and flux control. ^[28] Another critical gene, G6PC2, encoding a glucose-6-phosphatase catalytic subunit, significantly influences fasting plasma glucose levels, with specific polymorphisms impacting beta-cell function and contributing to glucose regulation.^[18]These genes illustrate intricate gene regulation and allosteric control mechanisms that fine-tune glucose metabolism to maintain systemic balance.

Hormonal Signaling and Metabolic Integration

D-glucose homeostasis is tightly regulated by complex hormonal signaling pathways, predominantly involving insulin. Glucose-induced insulin secretion from pancreatic beta-cells relies on the zinc transporterZnT-8 (SLC30A8), which localizes to insulin secretory granules and is functionally characterized for its role in this process.^[21] Genetic variants in SLC30A8, alongside those in KCNJ11 (encoding the Kir6.2 subunit) and ABCC8(encoding the SUR1 subunit of the pancreatic beta-cell KATP channel), are strongly associated with susceptibility to type 2 diabetes, underscoring their critical roles in insulin secretion and beta-cell function.^[19]

Beyond insulin secretion, a broader network of signaling cascades and transcription factors orchestrates metabolic responses to glucose. The nuclear receptorPPAR-γ, for instance, has polymorphisms associated with a decreased risk of type 2 diabetes, indicating its role in gene regulation impacting insulin sensitivity and glucose utilization.^[29] Furthermore, the FTOgene influences diabetes-related metabolic traits, adiposity, insulin sensitivity, leptin levels, and resting metabolic rate, demonstrating extensive pathway crosstalk between glucose metabolism, lipid metabolism, and energy balance.^[20] These intricate interactions, involving genes like LEPR, HNF1A, and IL6R, are crucial for systems-level integration of metabolic pathways and maintaining overall energy homeostasis. ^[28]

Glucose Homeostasis and Disease Pathogenesis

Dysregulation of D-glucose pathways is central to the pathogenesis of numerous metabolic diseases. Type 2 diabetes, for example, is characterized by impaired glucose homeostasis, with genetic variants in numerous loci, includingCDKAL1, IGF2BP2, CDKN2A/B, and HHEX, contributing to susceptibility. ^[19]Maturity-onset diabetes of the young (MODY2) specifically arises from functional mutations in genes like glucokinase, demonstrating how specific genetic defects can lead to distinct forms of glucose dysregulation.^[30]

The chronic elevation of blood glucose leads to non-enzymatic glycosylation of proteins, forming glycated hemoglobin (HbA1c), a key diagnostic and monitoring marker for diabetes.^[1]Beyond diabetes, glucose metabolism is intricately linked to lipid metabolism, with common variants at numerous loci contributing to polygenic dyslipidemia and influencing risk for coronary artery disease.^[31]The interplay between glucose and urate transport, particularly viaSLC2A9, also highlights how dysregulation in one pathway can contribute to conditions like gout, showcasing the emergent properties of complex metabolic networks and offering potential therapeutic targets.^[23]

Clinical Relevance of D-Glucose

D-glucose, a fundamental monosaccharide, plays a central role in human metabolism, and its circulating levels are critical indicators for a range of clinical conditions. The measurement and interpretation of glucose levels, often reflected through direct plasma glucose or glycated hemoglobin (HbA1c), provide essential insights into metabolic health, disease risk, and treatment efficacy.

Diagnostic and Monitoring Applications

Glucose levels are paramount in the diagnosis and ongoing management of diabetes mellitus. A glycated hemoglobin (HbA1c) level of 7.0% or more has been proposed as a diagnostic criterion for drug-requiring diabetes.^[13]Assays of glycemia, including the glycosylated hemoglobin assay, offer crucial clinical information for both establishing a diabetes diagnosis and guiding subsequent treatment decisions.^[32]The strong correlation between HbA1c levels and mean glucose concentrations over time makes it an invaluable tool for monitoring long-term glycemic control, reflecting average glucose levels over several months.^[2]Effective monitoring and intensive blood-glucose control, as demonstrated in large clinical trials, are vital for preventing or delaying the development and progression of severe long-term complications associated with both type 1 and type 2 diabetes.^[22]

Prognostic Value and Risk Stratification

Beyond its diagnostic utility, glucose and glycated hemoglobin levels offer significant prognostic value and aid in risk stratification, even in individuals without a formal diagnosis of diabetes. Fasting insulin, glucose, and glycated hemoglobin have shown independent associations with an increased risk of stroke and coronary heart disease in older women.^[33]While some studies suggest HbA1c effectively predicts the onset of diabetes, its predictive power for cardiovascular disease in non-diabetic women has been a subject of ongoing research.^[34]Conversely, other extensive investigations have robustly linked HbA1c to overall cardiovascular disease and mortality in the adult population, establishing it as a valuable marker for cardiovascular risk.^[35] These insights enable healthcare providers to identify high-risk individuals early, facilitating the implementation of targeted prevention strategies and fostering personalized medicine approaches.

Genetic Determinants and Associated Conditions

The clinical relevance of glucose is further illuminated by its complex genetic architecture, with specific genetic variants influencing glucose homeostasis and metabolic comorbidities. Genome-wide association studies have identified common genetic variants within theG6PC2/ABCB11 genomic region and polymorphisms within the G6PC2gene that are significantly associated with fasting glucose levels.^[18]Furthermore, specific single nucleotide polymorphisms (SNPs) at theG6PC2, GCK, and HK1loci have demonstrated associations with glycated hemoglobin concentration, with some variants also affecting insulin secretion following an intravenous glucose challenge.^[3]Beyond its direct role in diabetes, glucose metabolism is intertwined with other physiological processes and disease states; for instance, the glucose transporterSLC2A9has been linked to serum urate levels and hyperuricaemia.^[11]A deeper understanding of these genetic influences provides valuable insights into the multifactorial nature of glucose-related disorders and may inform the development of novel therapeutic or preventive interventions.

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