A Resurgence of the Idea of Hypertriglyceridemia and Lower Serum (HDL-C) as Predictive Factors for Insulin Resistance (IR) & Type 2 Diabetes Mellitus Development: A Narrative Review

Over the last 2 decades, obesity has been believed to be a problem of looks; nevertheless, escalating proof has illustrated that fat accrual, in addition to ectopic fat accrual, portrays the etiopathogenetic factors for various diseases, with escalating insight that obesity is a disease on its own. From the time duration of 1975 to 2016, the incidence of obesity has escalated three fold which continues to escalate [1]. The elevation in the complete quantities of obese persons might take place secondary to changes in a plethora of factors. These are inclusive of i) changes in dietary habits, ii) lifestyle, as well as iii) ingestion of a diet with considerable energy-dense foods. In general, obese persons with a body mass index (BMI) of 25 kg/m² are considered to be overweight; a BMI of 30 kg/m² is defined as obese. Nevertheless, simple dependence on weight, as well as height, for the evaluation of obesity, might not be dependable. Thereby, including waist circumference(WC), waist: hip ratio, body fat rates(BFR), visceral fat quantities, subcutaneous(s/c) fat quantities, along with other pointers might escalate the specificity of classification [2].

Having reviewed the different significant etiopathogeneses and role of different anti-obesity agents, comprehensively inclusive of perspectives on dietary control, for instance. Use of Mediterranean diet (MD) diet, ii)very low-calorie ketogenic diet (VLCKD) in the therapy of obesity, iii) bariatric surgery, iv)role of gut microbiota in obesity, type 1 diabetes mellitus (T1DM),v) role of probiotics in nonalcoholic fatty liver disease(NAFLD)along with other co-morbidities of obesity, type 2 diabetes mellitus( T2DM ), and vi) role of epigenetic generation controlling on the initiation and development of T1DMvib), use of epiphyto drugs in our endeavor to find the proper therapy, epigenetics in obesity, vii) how diabesity is escalating substantially [3-20]. Here we have concentrated on the significance of hypertriglyceridemia as well as lower high-density lipoprotein cholesterol (HDL-C) quantities in DM, along with its avoidance by taking care of such factors.

Historical background of insulin resistance

The idea of insulin resistance (IR) was first posited in the 1930s [21]. Two kinds of diabetic patients were discriminated by their blood sugar reactions to insulin therapy. Additionally, detailing the manner insulin-insensitive kind portrays the earliest research into IR. In the 1960s, hypertriglyceridemia was observed to be associated with IR [22,23]; however, no validation in the form of an etiological factor could be invented. In 1982, Steiner and Vranic posited “hypertriglyceridemia-IR-hyperinsulinemia vicious cycle” [24], which highlighted that hypertriglyceridemia possesses the capacity of resulting in IR, whereas IR, as well as restorative hyperinsulinemia, were capable of exacerbating hypertriglyceridemia. They indicated the plausibility of avoidance of T2D by intervening to control hypertriglyceridemia. This was a pathfinding postulate at that time, despite its focus on hypertriglyceridemia in view of the restricted accessibility of studies on blood lipid profiles in that decade.

Nevertheless, at the Banting lecture by American Diabetes Association, held in New Orleans in 1988, Reaven coined the term “syndrome X,” which was subsequently altered to the more widely accepted “metabolic syndrome”.They detailed the collection of metabolic abnormalities, including i) dyslipidemia, ii) hypertension, iii) hyperglycemia, in addition to iv) central obesity, with IR postulated as the shared etiology [25]. Subsequently, plenty of corroboration has embraced the dominant posit that IR possesses the capability of stimulating dyslipidemia [26]. Apart from positing that i) IR, besides being an elemental disorder, escalated the risk of generating type 2 Diabetes mellitus(T2DM), ii) it further escalated the risk of generating cardiovascular diseases(CVD) [25]. This represented an archetype switching, since in that period cardiovascular problems were attributed to cholesterol with regard to evaluation of risk, along with management. The generation of T2DM was further associated with a complicated risk factor for cardiovascular outcomes.

Compensatory hyperinsulinemia given IR possesses the capability of stimulating i) escalated flux of free fatty acids(FFA), ii) increased triglycerides in the liver, and iii)along with diminishing high-density lipoprotein cholesterol (HDL-C). Thereby, by the 1990s, dyslipidemia was thought to be a side onlooker instead of an etiological factor.

Decades went by, in addition to knowledge of dyslipidemia escalated drastically. Recently, greater validation, inclusive of outcomes obtained from genome-wide association studies (GWAS), has displayed the old “vicious cycle” posit [27,28]. Nevertheless, Li, et al. [29] pointed out that it is better to replace the term “hypertriglyceridemia” with “dyslipidemia” since it is not acknowledged what kind of dyslipidemia results in IR. They posited revising the earlier position that said: “dyslipidemia is an etiological factor of insulin resistance”. They gave clarification that they were concentrating on “dyslipidemia” instead of “lipotoxicity”. The latter term, which was proposed by Unger practically two decades back [30,31], implies ectopic lipid accumulation in the cells of non-adipose tissues(AT), for instance, liver, muscle, along heart [32]. Recently, it has been presumed that lipotoxicity is one of the major mechanistic modes of IR. Although lipotoxicity is correlated with hypertriglyceridemia toa certain magnitude, they do not portray the same abnormality. Li, et al. concentrated on “dyslipidemia” because of their capability of avoiding T2D in the early insulin-resistant stage by attenuating dyslipidemia.

Homage paid to Reaven by Després JP

As per executive summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), given by Grundy, et al. [33], five criteria were selected inclusive of (i)waist circumference(WC), ii)triglycerides, iii) high-density lipoprotein (HDL) – cholesterol, iv) blood pressure(BP) v)along with glucose). Nevertheless, the manner such variables were selected in addition to expositions for the same isolation of waist cut off continues to be uncharted. Additionally, the definitions of metabolic syndrome (MetS), along with reasoning given, generally get confused with the clinical gadgets (five criteria) that have been posited for the diagnosis [34,35].

Given the determination of IR or circulating quantities of insulin was not plausible on a large scale with regards to clinical scenario, aggregation of specialists evaluated the probability of isolating persons at risk of insulin-resistant stage by using frequently utilized clinical gadgets in a basic clinical scenario [33]. Due to robust correlation amongst abdominal obesity in addition to IR, it was decided by them to utilize of waist circumference (WC) in the form of a crude index for abdominal adiposity, along with subsequently posited sex-specific waist circumference quantities [33]. Nevertheless, such WC thresholds were dependent on the association amongst WC as well as body mass index (BMI) with their definitions of obesity (in males: 102 cm = 30 kgm² in addition to female: 88 cm = 30 kgm²) [36]. Therefore, WC thresholds were i) estimated from BMI levels by definitions of obesity, and ii) of greater significance were not dependent on clinical results. Additionally, due to WC along with BMI being correlated [37], escalated waist values found alone are not capable of evaluating abdominal accrual with precision [38]. For example, WC 104cm in case of a male in his middle age years with BMI 26 kg/m² does not represent an akin phenotype in contrast to an age-matched male control who possesses the analogous abdominal circumference; however, with BMI levels of 32 kgm² is different. In such a cited example, a male with BMI 26 kg/m² is abdominally obese (a greater risk kind of obesity), while a male with BMI of 32 kg/m² possesses the properties of generalized obesity. For these reasons Ross, et al. [38], in a consensus statement with regards to utilization of the WC, stated WC is not supposed to be utilized in the form of an only adiposity index, however instead its interpretation in addition to BMI, for the preciseness of differentiation of abdominally obese (greater risk kind) from generalized abdominally obese (lesser risk kind) individuals [38].

About ordinary metabolic biomarkers of IR as well as the rest of the indexes of MetS, i) triglycerides, ii) HDL – HDL-cholesterol quantities, iii) along with blood glucose, are capable of getting obtained with ease from ordinary laboratories. iv) While BP estimation is performed as a routine in primary centres. Depending on these, it was posited that persons illustrating a combination of three of such five criteria possessed the probability of being labelled as having IR. Prospective assessments have further illustrated that any such combination was anticipative of escalated generation of T2DM in addition to CVD [39-41].

Since it had been pointed out that the waist cut off originally posited in all probability was substantially greater, their levels were subsequently diminished in balanced criteria posited by the joint interim statement of the International Diabetes Federation Task Force [42]. Variable studies have illustrated that a subgroup of persons who met/did not meet clinical criteria of MetS (balanced or not) were substantially unique one of risk of generating CVD along with T2DM [39-41]. Obviously, utilization of the variable waist cut-off reading formed variable prevalence readings; subgroups isolated were nonetheless observed to illustrate various magnitudes of risk.

Moving from syndrome X, IR / MetS to escalated visceral adiposity

Given that Reaven GM possessed the capability of finding non obese persons with IR in addition to persons with obesity who possessed insulin sensitivity, therefore, in his original definitions of syndrome X, obesity was omitted. About that early imaging studies estimating adiposity with the utilization of computed tomography (CT) Matsuzawa, et al. [43], as well as Després JP, et al. [44], pointed the existence of considerable heterogeneity in fat accrual(visceral vis a vis subcutaneous(s/c) [43,44]. Furthermore, subgroup evaluation displayed remarkable differences in i) glucose tolerance in addition to ii)plasma insulin along withiii) lipoprotein quantities amongst persons with equivalent overweight/obese greater or lesser visceral adipose tissue(VAT) [45]. Subsequently, a plethora of substantially large cardiometabolic imaging studies have illustrated that escalated accrual of VAT(not subcutaneous(s/c) is a key associate of the characteristics of IR, explaining why Reaven GM was not capable of observing association amongst full body fatness; his syndrome revolved around body fat organization [34,35,46,47].

Hepatic fat: Equivalent culprit in visceral adiposity

With the accessibility of magnetic resonance spectroscopy, non-invasive determination of hepatic fat accrual is feasible with greater precision. Utilization of such methodologies, escalated hepatic fat has been observed to be correlated with an imperatively akin constellation of metabolic aberrations, the manner found in visceral adiposity [48]. Nevertheless, it is of greater significance that isolated escalated hepatic fat (without escalated VAT) represents a genuinely occasional event since it is the commonest kind linked to VAT [49]. Therefore, recently, its clarification has been that maximum inimical adiposity phenotype is escalated VAT as well as hepatic fat, that is maximum kind of IR or MetS [49]. Dependent on that, Després JP, et al. [35,50] posited that a constellation of metabolic aberrations where escalated visceral adiposity / hepatic fat was a characteristic, be labelled as Reaven syndrome [35,50].

Position of role of hypertriglyceridemia/ lesser HDL – HDL-cholesterol in IR

Unveiling if dyslipidemia is plausibly implicated in the form of an etiological factor of IR is important, since it has a plethora of implications for the early diagnosis, in addition to avoidance of T2D. LDL-C has been excluded as a germane factor, as there is no validation to embrace an etiological association amongst IR. Nevertheless, the role of statins needs further exploration given the existence of numerous indications that such drugs possess actions beyond diminishing LDL that influence the predisposition to develop diabetes. Hypertriglyceridemia, as well as lower HDL-C, have been illustrated to be autonomous, long-term anticipators of insulin sensitivity in longitudinal studies. Whereas certain studies on genes associated with hypertriglyceridemia, along with /or lesser HDL-C, have displayed that such genes are further correlated with insulin sensitivity [29].

Additionally, regulating hypertriglyceridemia as well as lowering HDL-C has resulted in the postponement of onset of IR in certain intervention studies. Extra genetic, Mendelian randomization, in addition to systems biology studies, are now possible and required to corroborate the etiological part of hyperlipidemia in IR, along with its mechanistic modes in IR. Such studies would result in the acquisition of urgently required understanding for avoidance of IR, as well as the further generation of T2DM was what Li, et al. [29], concluded in 2014 [29].

Role of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein1 [GPIHBP1]

In diabetes, the dysfunction of insulin liberation as well as IR aids in the generation of hypertriglyceridemia, since the enzymatic action of lipoprotein lipase (LPL) is based on insulin activity. The transportation of LPL to endothelial cells, in addition to its sustenance of enzymatic activity, is obtained by the generation of lipolytic complex based on the plethora of A) positive (i) glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1[GPIHBP1], ii) apolipoprotein C-II [APOC2], iii) APOA5, iv) heparan sulfate proteoglycan [HSPG], v) lipase maturation factor 1 [LFM1], along with vi) sel-1 suppressor of lin-12-like [SEL1L]). Furthermore, B) negative controllers (i) APOC1, ii) APOC3, iii) angiopoietin-like proteins [ANGPTL]3, iv) ANGPTL4, as well as v) ANGPTL8. Amongst the controllers, GPIHBP1 portrays a critical molecule, for the translocation of LPL from parenchymal cells to the luminal surface of capillary endothelial cells, as well as ii) sustenance of lipolytic activity; that is, a) hydrolysis of triglyceride (TG) into free fatty acids (FFA) as well as ii) monoglyceride, in addition, tob) i) The transformation from chylomicron to chylomicron remnant in the exogenous pathway, along with ii) from very low-density lipoprotein(VLDL) to low-density lipoprotein (LDL) in the endogenous pathway. The null mutation of GPIHBP1 results in robust hypertriglyceridemia as well as pancreatitis. In addition to ii) GPIGBP1 autoantibody syndrome, further results in robust hypertriglyceridemia as well as recurrent episodes of acute pancreatitis. III) In patients with T2DM, the escalated serum triglyceride quantities negatively correlate with circulating LPL quantities, in addition to b) positively correlating with circulating APOC1, APOC3, ANGPTL3, ANGPTL4, along ANGPTL8 quantities. As compared to that, c) circulating GPIHBP1 quantities are not changed in patients with higher serum triglyceride quantities, whereas they are ii) escalated in T2DM patients with diabetic retinopathy along with nephropathy. The circulating regulators of lipolytic complex might work in the form of innovative biomarkers [51] (Figures 1,2 for detailed GPIHBP1 working.

Role of serum high-density lipoprotein cholesterol level (HDL-C) Inadequacy

Lesser serum high-density lipoprotein cholesterol level (HDL-C) < 40 mg/dL in men as well as < 50 mg/dL in women is a significant autonomous risk factor for CVD, in addition to being found in patients with hypertriglyceridemia, obesity, IR, along with diabetes. Patients with substantially inadequate quantities of HDL-C (< 20 mg/dL) without secondary etiological factors are substantially less common (< 1% of the population). These patients might possess homozygous, compound heterozygous, or heterozygous abnormalities implicating the i) apolipoprotein (APO) AI, ii)ABCA1, or iii) lecithin: cholesterol acyl transferase genes, correlated with Apo A-I inadequacy, 2) ApoA-I variants, a)Tangier Disease, b)Familial Lecithin: Cholesteryl Ester Acyltransferase insufficiency, c)as well as and Fish Eye Disease. There is considerable variability in the laboratory in addition to clinical manifestation; DNA assessment is imperative for diagnosis. These patients possess the capability of generating i) premature CVD, ii) neuropathy, iii) kidney failure, iv) hepatosplenomegaly, in addition to v) anemia. Optimization of full non-HDL risk factors needs to be the goal of treatment [52] (Figures 3-5 for detailed HDL-C Inadequacy working correlated diseases.

Role of Saroglitazar (a dual PPAR-α/γ agonist) in improvementof glycemic regulation as well as lipid parameters

Krishnappa, et al. [53] conducted a randomized double-blind study in patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] that got recruited from 39 regions in India. Patients received once/day doses of either saroglitazar (a dual PPAR-α/γ agonist) or pioglitazone (1:1:1 allocation ratio for a total of 24 weeks. Patients were continued in a double blind extension period for an extra 32 weeks. Effectiveness analyses of glycemic criterion [HbA1c (Primary endpoint at week 24), FPG as well as PPG] in addition to other lipid specifications (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were performed at week 12, 24, along 56, as well as contrast to the baseline quantities. The effectiveness evaluations were performed by utilizing the paired t-test as well as the ANCOVA model.

A total of 1155 patients were recruited in their study. They observed that baseline properties were similar amongst the three treatment groups. Within group mean (± SD) i) change in HbA1c (%) from baseline of the saroglitazar (2 mg as well as 4 mg) in addition to pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg along with - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant diminishing from baseline in HbA1c was found in every treatment group at week 24 with p - value < 0.016. There was a significant diminishing of TG, LDL-C, VLDL-C, TC, as well as Non HDL-C, with a significant increase in HDL-C from baseline quantity levels (< 0.016). Most of the AEs were ‘mild’ to ‘moderate’ in severity and were resolved by the completion of the study.

Thereby, they concluded that Saroglitazar efficaciously resulted in improvement of glycemic regulation as well as lipid guidelines over 56 weeks in patients of T2DM receiving background metformin therapy, in addition to possessing an attractive probability to diminish the cardiovascular risk in T2DM patients.

Introduction of newer parameters replacing HOMA-IR

The TyG index, which is based on fasting triglyceride (FTG) as well as glucose levels [54]. It has been acknowledged to be a greater dependable marker for assessing IR in contrast to the euglycemic-hyperinsulinaemic clamp test (The gold standard for diagnosis of IR) [55] in addition to their)) homeostasis model assessment-estimated insulin resistance (HOMA-IR) index [56,57]. Additionally, its ease of use, along with being cheap, makes the TyG index a viable gadget for all, regardless of diabetes status, since it depletes the requirement for insulin quantification [58]. 

Canonical methodologies for evaluating IR, for instance, the hyperinsulinemic-euglycemic clamp as well as the homeostatic model assessment of IR, are operationally complex & time-consuming [56]. In recent years, triglyceride-glucose (TyG) index-associated indicators—including i) TyG index [59], ii) triglyceride-glucose body mass index (TyG-BMI) [60], iii) triglyceride-glucose waist circumference (TyG-WC) [61], in addition to iv) triglyceride-glucose waist-to-height ratio (TyG-WHtR) [62]—have emerged as superior surrogate markers for IR, demonstrating remarkable value in the evaluation of metabolism-associated disorders.

Calculation of such variables might be attained by the utilization of the following formulas: TyG = Ln[fasting TyG (mg/dL) × fasting glucose (FG) (mg/dL)/2]; [63], BMI = body mass(kg)/height (m²); WHtR = waist circumference (WC, cm)/height (cm); TyG-BMI =TyG × BMI; [64], TyG-WC = TyG × WC; [64], TyG-WHtR = TyG × WHtR [65].

Association amongst Visceral Adiposity Index (VAI) with diabetes mellitus development

Diabetes mellitus (DM) is a metabolic disease with a plethora of risk factors. Individuals with DM possess a predisposition to various complications, as well as the disease represents a robust threat to human health. As per the International Diabetes Federation, in 2021, about 537 million people worldwide had been diagnosed with DM; in addition to its prevalence keeps escalating: the number of individuals with DM is projected to grow to 643 million by 2030, along with 783 million by 2045 [66]. Type 2 diabetes mellitus (T2DM) is the maximum pronounced kind of DM, as it has been observed to be a key contributor for greater than 90% of total patients with DM [67,68]. Additionally as it has been determined that there will be around 439 million people with T2DM by 2030 [69].

This kind of appalling growth rate possesses significant ramifications for the worldwide health system. In addition to reducing the global growth of T2DM would be a significant step toward curbing economic burdens, along with improvement of people’s health along well-being [70]. Obesity has been found to aid in the generation of T2DM. Obesity canonically is a chronic, relapsing, in addition, toa disease with a plethora of etiological factors that influence each organ system as well as generally result in metabolic abnormalities or other correlated comorbidities that influence physical as well as mental health [71]. The risk of T2DM has been observed to be about sevenfold greater in individuals who by definition are obese (body mass index (BMI) > 30) in contrast to individuals who are not believed to be overweight (BMI < 25) [72], along with substantially greater quantities of visceral fat deposits as well as ectopic fat have been demonstrated to be earlier ignored risk factors for T2DM [73]. As per that, in a study employing multiparametric magnetic resonance imaging (MRI), quantities of visceral adipose tissue(VAT) were shown to correlate with a greater risk of developing T2DM [74]. Whereas MRI, as well as computed tomography (CT), are clinically precise in addition to dependable in the analyses of visceral fat, these methodologies are complicated, needing costly equipment, along with a plethora of inimical sequelae [75].

Therefore, there is the existence of requirement for developing methodologies that are of greater ease in utilization, practicality, taken into account user-friendly, as well as have safety as well as tolerability to assess visceral fat. In this regard, Marco Amato, et al. [76], posited a new index, correlated with the Visceral Adiposity Index (VAI), for the assessment of visceral fat; this evaluation gadget is dependent on the outcomes of canonical biochemical investigations quantifying blood triglyceride (TG) as well as high-density lipoprotein (HDL) quantities in addition to the anthropometric indices BMI in addition to waist circumference index (WC) [76]. The VAI is regarded as a surrogate measure of the visceral fat profile and visceral fat impairment, which exhibits greater sensitivity along with specificity in contrast to canonical parameters [77]. The outcomes of VAI assessment have been broadly utilized to evaluate heart failure, hyperuricemia, cardiovascular, along with cerebrovascular diseases, stroke, as well as other diseases [78-81]. In addition to recent studies have illustrated non-linear correlations amongst VAI in addition to fasting glucose quantities along with indexes of renal function [72,75].

With the idea of conducting an exhaustive assessment on the use of VAI in the clinical diagnosis of T2DM, the present study employed information from a substantially greater number of archetypal sources of data: the National Health and Nutrition Examination Survey (NHANES) from the United States National Centers for Disease Control and Prevention. Zhou, et al. [82], utilized knowledge from this study to delve into associations amongst VAI as well as T2DM, which yielded clinical gadgets for early risk assessment, prevention, diagnosis, in addition to treatment. Dependent on the NHANES 2007–2018, 11, 214 subjects who were aged ≥ 20 years were included in a cross-sectional study. Multifactorial logistic regression evaluation, as well as smoothed curve fitting assessment, were conducted to evaluate association amongst VAI in addition to the prevalence of T2DM, as well as the stability along incidence amongst subgroups. In a fully adjusted continuous model, the collected population risk of T2DM escalated 0.43 times with every 1-unit escalation in VAI [odds ratio (OR) = 1.43; 95% confidence interval (CI) 1.35–1.50]. Inthe fully adjusted categorical model with VAI scores stratified by quartiles, outcomes illustrated a greater benefit between T2DM subjectswho participated in the second, third, as well as fourth quartiles (Q2: OR 1.35, 95% CI-1.06–1.71; Q3: OR 2.46, 95% CI 1.95–3.11; Q4: OR 4.42, 95% CI 3.55–05.50). In contrast to Q1, the prevalence of T2DM in the full population escalated 3.42 times -fold in Q4. The aforementioned outcomes pointed out that VAI was positively correlated with the prevalence of T2DM, which was commensurate in addition to nonlinear with, the smoothed curve-fitting assessment (P for non-linear = 0). Subgroup assessment subsequent to adjusting for covariates illustrated that, keeping with the overall population outcomes, it was further observed that there was a crosstalk amongst sex as well as hypertension in the subgroups. VAI was positively correlated with the prevalence of T2DM; in addition, to was greater prevalent in women, non-hypertensive, in contrast to men, hypertensive populations.

Role of nutraceuticals for pharmacological treatments of MetS

Earlier, we had reviewed the part of nutrigenomics on various metabolic disorders, therapeutic potential of herbal preparations in DM [83,84]. Dama, et al. [85], recently, further expanded on nutraceuticals in metabolic diseases. The enhanced prevalence of metabolic as well as cardiometabolic situations generally has properties of i) oxidative stress(OS), ii) along with chronic inflammation, poses significant health challenges worldwide. Accordingly, i) canonical therapeutic approaches might fail in managing such health situations, ii) attention is escalating toward nutraceuticals worldwide; iii)with compounds getting attained from natural sources with plausible therapeutic advantageous actions getting shown to iv) plausibly embrace with in addition to, in certain cases, v) replace pharmacological treatments, particularly for persons who do not qualify for canonical pharmacological treatments. This review by Dama, et al. [85], probes the field of mushrooming nutraceutical-dependent pharmacological modulation as an attractive approach for ameliorating i) OS in addition to ii)inflammation in a) metabolic as well as b) cardiometabolic situations. Drawing from a substantially greater body of research, the review by Dama, et al. [85], emphasizes how variable nutraceutical drugs, for instance, i) polyphenols, ii) omega-3 fatty acids, as well as iii) antioxidants, illustrate antioxidative along anti-inflammatory characteristics. All these are capable of getting classified in the form of innovative nutraceutical-dependent agents, that possess the capability of controlling pathways to ameliorate OS - as well as inflammation-correlated - metabolic diseases. By exploring the mechanistic modes by which nutraceuticals crosstalk with OS pathways in addition to immune reactions, this review emphasizes their probability of i) restoring redox balance, along with ii) mitigating chronic inflammation. Furthermore, the botherations along with prospects of nutraceutical-dependent interventions are described, encompassing i) bioavailability enhancement, ii) individualized treatment strategies, as well as iii) clinical translation. Via an exhaustive evaluation of the most scientific reports, this article reinforces the probability of nutraceutical-dependent pharmacological treatment modulation in the form of an innovative avenue for fighting OS as well as inflammation in the complicated topography of metabolic situations, especially accelerating their influence on cardiovascular health [85] (Figures 6,7).

Thereby, the concept of Reaven hypertriglyceridemia IR-hyperinsulinemia has resurfaced with escalated quantities of TG as well as HDL quantities working in the anticipation of T2DM generation. Compensatory hyperinsulinemia due to IR stimulates i) escalated flux of free fatty acids (FFA), ii) increases triglycerides in the liver, and iii) along with diminished high-density lipoprotein cholesterol (HDL-C).

We have reviewed lipid metabolism in extensive detail, thereby not detailing here inclusive of ceramides, diacylglycerol (DGA), protein kinase A (PKA), Poly Unsaturated Fatty Acids (PUFA) in obesity [86-88]. Briefly, studies in humans displayed that escalated quantities of free fatty acids (FFAs) as well as triglycerides (TGs) are intricately correlated with diminished insulin sensitivity. In addition to interventions, for instance, metformin along with omega-3 fatty acids display plausible advantages. In animal models, high-fat diets disturb insulin signaling as well as elevate inflammation, with lipid mediators, for instance, diacylglycerol (DAG), in addition to ceramides possessing significant parts. DAG activates protein kinase C, which causes impairment of insulin signaling, whereas ceramides hamper Akt/PKB, which further aids in IR [89]. With regards to this, in contrast to earlier utilized homeostatic model of insulin resistance (HOMA-IR), it is better to estimate indices associated with visceral adiposity, for instance, the cheaper TyG indices: TyG-BMI, TyG-WC, TyG-WHtR, in addition to VAI, in contrast to the costly computed tomography, magnetic resonance imaging (MRI). Further, we have emphasized the deeper part of the role played by GPIHBP1 in TG metabolism and how LPL translocation & its null mutation, along with autoantibody syndrome, result in generation of robust hypertriglyceridemia, as well as HDL-C& its inadequacy, as well as its associated syndromes. Collectively, these suggest that it is visceral¬ subcutaneous(s/c fat which is significant leading to metabolic in addition tocardiometabolic situations, generally have properties of oxidative stress(OS) along with chronic inflammation (although ferroptosis along with other programmed cell death mechanistic modes are implicated in development of metabolic abnormalities or other associated comorbidities of T2DM by lipid peroxidation [90]. Here we have just emphasized on recent resurgence of how hypertriglyceridemia, as well as HDL-C Inadequacy, is instrumental in T2DM generation, be it the cause of IR, inclusive of polycystic ovary syndrome (PCOS).

Additionally, we have described the role of Saroglitazar for improvement of glycemic regulation as well as lipid parameters, apart from that of variable nutraceuticals in metabolic diseases.

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13. Kaur KK, Allahbadia GN, Singh M. Are we any closer to unraveling the mechanism of interactions among susceptibility genes towards type 1 diabetes, gut microbiota along with environmental factors, specifically early diet patterns: a systematic review. J Endocrinol Surg Endocrinol. 2021;2(1):10–34. Available from: https://www.researchgate.net/publication/349915934_Are_we_Any_Close_to_Unraveling_the_Mechanism_of_Interactions_Among_Susceptibility_Genes_Towards_Type_1_Diabetes_Gut_Microbiota_Along_with_Environmental_Factors_Specifically_Early_Diet_Patterns_-A_Syst
14. Kaur KK, Allahbadia GN, Singh M. Diabetic cardiomyopathy: an update on its pathophysiology with specific emphasis on epigenetics modifications besides treatment: a systematic review. BOHR Int J Curr Res Diabetes Prev Med. 2022;1(1):1–16. Available from: http://dx.doi.org/10.54646/bijrdpm.001
15. Kaur KK, Allahbadia GN, Singh M. De novo lipogenesis inhibitors: as the other innovative agents for therapy of metabolic diseases (obesity, NAFLD/NASH, CVD). Adv Obes Weight Manag Control. 2022;12(3):78–93. Available from: https://medcraveonline.com/AOWMC/AOWMC-12-00367.pdf
16. Kaur KK, Allahbadia GN, Singh M. Identification of women of polycystic ovary syndrome (PCOS) at risk for generation of metabolic disease in normal weight PCOS: is there a role of flutamide? A short communication. CPQ Med. 2023;14(2):1–5. Available from: https://www.researchgate.net/publication/367497075_Identification_of_Women_of_Polycystic_Ovary_Syndrome_PCOS_At_Risk_for_Generation_of_Metabolic_Disease_in_Normal_Weight_PCOS_Is_There_a_Role_of_Flutamide-A_Short_Communication
17. Kaur KK, Allahbadia GN, Singh M. Very low calorie ketogenic diet (VLCKD) possesses further advantageous actions over Mediterranean diet in terms of better enhancement of gut microbiota in type 2 diabetes mellitus patients: a short communication. J Diab Metab Disord. 2023;10(1):48–54. Available from: https://doi.org/10.15406/jdmdc.2023.10.00252
18. Kaur KK, Allahbadia GN, Singh M. Inventing the immunomodulatory action of food plants with utilization of metabolomics: a narrative review. Acta Sci Nutr Health. 2023;7(10):21–36. Available from: https://actascientific.com/ASNH/pdf/ASNH-07-1308.pdf
19. Kaur KK, Allahbadia GN, Singh M. The significance of gut microbiota controlling epigenetic modifications in obesity with its therapeutic impact: a narrative review. Adv Obes Weight Manag Control. 2025;15(1):1–10. Available from: https://www.researchgate.net/profile/Kulvinder-Kochar-Kaur/publication/389465035_AOWMC-15-00413gm-obes_-epigen-The_significance_of_gut_microbiota_controlling_of_epigenetic_modifications_in_obesity_with_its_therapeutic_impact_a_narrative_review/links/67c30cda8311ce680c791a3b/AOWMC-15-00413gm-obes-epigen-The-significance-of-gut-microbiota-controlling-of-epigenetic-modifications-in-obesity-with-its-therapeutic-impact-a-narrative-review.pdf
20. Kaur KK, Allahbadia GN, Singh M. An update on targeting epigenetic modifications in obesity correlated diseases, for instance cancers, type 2 diabetes, and cardiovascular diseases (CVD) for their avoidance along with therapy: a narrative review. J Clin Med Images. Forthcoming 2025.
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