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Understanding Blood Sugar Levels, INSULIN RESISTANCE \u0026 Impact on Chronic Diseases - Dr. Rob LustigInsulin resistance and cardiovascular disease -
Associations between insulin levels and cardiovascular disease are confounded by comorbidity. Diabetes Care ; — PubMed CAS Google Scholar. Laakso M. How good a marker is insulin level for insulin resistance?
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The relationship of concentrations of insulin and proinsulin-like molecules with coronary heart disease prevalence and incidence. Liu QZ, Knowler WC, Nelson RG, Saad MF, Charles MA, Liebow IM, Bennett PH, Pettitt DJ.
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Serum insulin and incident coronary heart disease in middle-aged British men. Després J-P, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien P-J. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med ; — Lakka TA, Lakka HM, Salonen JT.
Hyperinsulinemia and the risk of coronary heart disease [Letter]. Lakka H-M, Lakka TA, Tuomilehto J, Salonen JT. Hyperinsulinemia and cardiovascular mortality.
Atherosclerosis ; The heart decreases its ability to use fatty acids, increasing FFA delivery, and leading to intramyocardial lipid accumulation ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines [ ]. This lipid accumulation may contribute to apoptosis, impairing mitochondrial function, cardiac hypertrophy, and contractile dysfunction [ , ] Fig.
For example, diacylglycerol and fatty acyl-coenzyme CoA induce activation of atypical PKC, which results in impaired insulin signal transduction [ ]. Ceramides act as key components of lipotoxic signaling pathways linking lipid-induced inflammation with insulin signaling inhibition [ ].
On other hand, high lipid contents can induce contractile dysfunction independently of insulin resistance [ ]. Therefore, the resultant defect in myocardial energy production impairs myocyte contraction and diastolic function [ 93 , ] Fig. These alterations produce functional changes that lead to cardiomyopathy and heart failure [ , , , ].
In uncontrolled diabetes, the body goes from the fed to the fasted state and the liver switches from carbohydrate or lipid utilization to ketone production in response to low insulin levels and high levels of counter-regulatory hormones [ ]. The ketone bodies generated in the liver enter in the blood stream and are used by other organs, such as the brain, kidneys, skeletal muscle, and heart.
Disruptions in myocardial fuel metabolism and bioenergetics contribute to cardiovascular disease as the adult heart requires high energy for contractile function [ ]. In this situation, the heart uses alternative pathways such as ketone bodies as fuel for oxidative ATP production [ ].
However, there is still controversy around whether this fuel shift is adaptive or maladaptive. The ketogenic diet effect can be mediated by suppressing longevity-related insulin signaling and mTOR pathway, and activation of peroxisome proliferator activated receptor α PPARα , the master regulator that switches on genes involved in ketogenesis [ ].
Several reports suggest that ketogenic diet may be associated with a decreased incidence of risk factors of cardiovascular disease such obesity, diabetes, arterial blood pressure and cholesterol levels, but these effects are usually limited in time [ ].
However other reports indicated that cardiac risk factor reductions corresponded with weight loss regardless of a type of diet used [ ]. Excessive production of ROS leads to protein, DNA, and membrane damage. In addition, ROS exerts deleterious effects on the endoplasmic reticulum. This also contributes to diabetic cardiomyopathy pathogenesis [ , ].
Insulin essentially provides an integrated set of signals allowing the balance between nutrient demand and availability.
Impaired nutrition contributes to hyperlipidemia and insulin resistance causing hyperglycemia. This condition alters cellular metabolism and intracellular signaling that negatively impact cells.
In the cardiomyocyte, this damage can be summarized into three actions: 1 alteration in insulin signaling. All these effects induce cellular events including: 1 gene expression modifications, 2 hyperglycemia and dyslipidemia, 3 activation of oxidative stress and inflammatory response, 4 endothelial dysfunction, and 5 ectopic lipid accumulation, which, favored by obesity, perpetuates the metabolic deregulation.
Overall, insulin resistance contributes to generate CVD via two independent pathways: 1 atheroma plaque formation and 2 ventricular hypertrophy and diastolic abnormality.
Both effects lead to heart failure. Future research is needed to understand the precise mechanism between insulin resistance and its progression to heart failure with a focus on new therapy development. Steinberger J, Daniels SR, American Heart Association Atherosclerosis H, Obesity in the Young C, American Heart Association Diabetes C.
Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee Council on Cardiovascular Disease in the Young and the Diabetes Committee Council on Nutrition, Physical Activity, and Metabolism.
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Furthermore, both nondiabetic individuals with obesity and lean individuals with T2DM manifest a moderate to severe defect in the insulin signaling pathway Fig. Prediabetic individuals with impaired glucose tolerance also manifest insulin resistance involving the glycogen synthetic pathway and share the same insulin signaling defect as subjects with obesity and with T2DM 39 , , Similarly, hypertension — and diabetic dyslipidemia increased plasma triglyceride and FFA concentrations, decreased HDL cholesterol, small dense LDL particles 27 , — , are insulin-resistant states characterized by impaired insulin-mediated glucose disposal involving the nonoxidative pathway of glucose disposal and reduced insulin signaling.
Hypercholesterolemia per se is not an insulin-resistant state but, when present, acts synergistically with other components of the IRS to accelerate atherogenesis — As discussed previously, multiple studies 1 — 3 , 27 , have demonstrated that normal glucose-tolerant individuals with coronary artery disease are as resistant to insulin as are individuals with T2DM and nondiabetic individuals with obesity Fig.
Similar to skeletal muscle, the myocardium of individuals with T2DM with and without coronary artery disease and nondiabetic individuals with coronary artery disease , , has been shown to be resistant to insulin-stimulated glucose disposal. The demonstration that nondiabetic individuals with the IRS are at the same high risk for experiencing a CV event as individuals with diabetes 4 emphasizes the importance of recognizing insulin resistance as a major CV equivalent that deserves specific therapy with insulin-sensitizing agents see the subsequent discussion.
Open white sections represent nonoxidative glucose disposal glycogen synthesis ; filled black sections represent glucose oxidation. To change glucose uptake into SI units, divide by The Claude Bernard Lecture Diabetologia ;— Illustration presentation copyright Endocrine Society Despite the identification of multiple pathophysiologic disturbances Table 1 , a large percentage of the risk for ASCVD in patients with T2DM remains undefined , We postulate that insulin resistance Fig.
b Excess carotid IMT in relationship to the individual components of the insulin resistance metabolic syndrome as listed. Amer, American; F, female; GLU, glucose; HTN, hypertension; M, male; TG, triacylglycerol.
JAMA —, b Adapted with permission from Golden SH, Folsom AR, Coresh J, Sharrett AR, Szklo M, Brancati F: Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the Atherosclerosis Risk in Communities Study. Although utilization of medications, such as angiotensin-converting enzyme inhibitors, other antihypertensive medications, statins, and platelet inhibitory agents, has reduced the incidence of atherosclerotic CV complications, there remain as-of-yet unidentified CV risk factors, in addition to the classical risk factors, that contribute to the high CV risk among optimally treated patients.
Medical therapy typically is directed against a single risk factor or multiple CV risk factors and does not specifically target the underlying pathophysiological defect, that is, insulin resistance, that is responsible for the generation of the cardiometabolic abnormality.
This is evident from a recent publication from the National Swedish Registry in which CV mortality declined significantly in individuals with T2DM from to , but remained markedly higher and reached a plateau compared with NGT individuals.
Insulin resistance and the IRS also have been shown to be associated with subclinical ASCVD. In a retrospective analysis of 10, occupational patients, insulin resistance was independently associated with the coronary calcium score, which is a strong predictor of coronary artery disease, and this association persisted after adjustment for other CV risk factors and preexisting CVD Other studies, including the Framingham Offspring Study, also have demonstrated a strong association between the coronary calcium score, insulin resistance, and inflammatory cytokines in nondiabetic individuals — A similar association between insulin resistance and coronary artery disease in nondiabetic individuals has been demonstrated with ultrasound The IRS also has been reported to be associated with an increased incidence of heart failure in individuals without diabetes and without a prior history of myocardial infarction Similar results have been reported from a large community-based sample of elderly adults Different mechanisms may explain the association between insulin resistance and heart failure.
Insulin is a growth factor and has been shown to impact cardiac structure , Furthermore, insulin activates the sympathetic nervous system and enhances the ability of angiotensin II to activate the MAPK pathway , In the Cardiovascular Health Study, a positive association between the fasting plasma insulin concentration vs adverse echocardiographic features and risk of subsequent heart failure was reported Similar results were reported in the ARIC study in patients with and without antecedent myocardial infarction Insulin resistance, assessed by HOMA-IR, also has been shown to be associated with peripheral arterial disease T2DM is a cardiometabolic disease that affects both the microvasculature retinopathy, nephropathy, neuropathy and macrovasculature heart attack, stroke 25 , The microvascular complications are related to two factors: i the magnitude of elevation in blood glucose concentration, as reflected by the HbA1c, and ii the duration of elevation of the HbA1c , The failure of intensive glycemic control in the ACCORD 89 , ADVANCE 90 , and VADT 91 studies to significantly reduce heart attack and stroke provides further support that hyperglycemia is a weak risk factor for CVD, although it could be argued that it would be difficult for any glucose-lowering therapy to slow the progression of and reverse advanced fibrotic, lipid-laden plaques.
Furthermore, insulin was the primary antidiabetic agent used in these prior trials 89 — 91 , and even small increases in the fasting plasma insulin concentration are associated with the induction of severe insulin resistance 26 , 47 , 48 and weight gain 73 , 74 , which are risk factors for ASCVD 26 , 76 , Furthermore, when used in high doses, insulin can accelerate the atherogenic process see the previous discussion.
Of particular importance, it currently is well established that events portending accelerated atherosclerosis are under way long before the formal diagnosis of diabetes is established, that is, in the prediabetic state as well as in insulin-resistant NGT subjects 5 — 11 , — Sedentary lifestyle and obesity are insulin-resistant states associated with the IRS and increased CV mortality 76 , — Consequently, weight loss and increased physical activity are recommended both by the American Heart Association and American Diabetes Association to reduce CV events and prevent the development of T2DM by improving insulin sensitivity and preserving β -cell function.
Although modest benefits on CV risk factors improved biomarkers of glucose and lipid control, less sleep apnea, reduced liver fat, increased fitness, and enhanced insulin sensitivity and improved quality of life were observed, the trial was stopped because of lack of CV benefit after a median follow-up of 9.
This weight regain and increase in waist circumference i. As reviewed in two meta-analyses, a major problem with lifestyle interventions has been the inability to sustain the weight loss on a long-term basis , The results of a meta-analysis sugest that implementation of a Mediterranean diet can improve adherence and is associated with favorable effects on multiple components of the IRS Consistent with this, a recent study from Spain provided evidence that the Mediterranean diet caused a significant reduction in CV events The only true sensitizing antidiabetic agents are the thiazolidinediones TZDs 25 , 26 , , , , , — and, of these, the only one that is readily available worldwide is pioglitazone.
Metformin is not a true insulin-sensitizing agent , Two large prospective clinical trials — and two prospective anatomical studies , have demonstrated that pioglitazone reduces CV events — and promotes the regression of atherosclerotic lesions , , respectively.
The Prospective Pioglitazone Clinical Trial in Microvascular Events PROactive study was the first study to demonstrate the beneficial effect of any antidiabetic agent to reduce CV events.
In patients with T2DM with a prior CV event and who were treated with pioglitazone or placebo for a period of However, it is well established that peripheral vascular disease is refractory to all therapeutic interventions, including glucose-lowering, lipid-lowering, and blood pressure—lowering therapy , Furthermore, by preventing death, myocardial infarction, and stroke, pioglitazone would make more people available for leg revascularization Analysis of all double-blind, placebo-controlled pioglitazone studies revealed a decrease in CV events in individuals without a prior history of CV events HR, 0.
Consistent with these observations, pioglitazone reduced coronary atherosclerotic plaque volume in the PERISCOPE trial and decreased carotid IMT in the CHICAGO trial Unfortunately, the correlation between improved insulin sensitivity and decrease in CV events was not reported, but such an analysis would be of great clinical and pathophysiologic importance.
Finally, a meta-analysis of randomized control trials reported that pioglitazone significantly reduced the MACE endpoint in people with insulin resistance, prediabetes, and T2DM In summary, multiple studies demonstrate that the insulin-sensitizing antidiabetic agent pioglitazone reduces atherosclerotic CV events in association with enhanced insulin sensitivity.
Improved glucose control cannot explain the reduction in stroke and myocardial infarction because the decrease in HbA1c was quite modest in the PROactive study , and subjects in the IRIS trial were not diabetic Although not well appreciated, analysis of atherosclerotic plaques reveals large amounts of nonesterified fatty acids 81 — 83 , which stimulate inflammatory pathways involved in atherogenesis 64 , 78 , 79 , , Th use of TZDs has been limited in part by uncertainty about the risk for development of heart failure, especially in susceptible patients with diastolic dysfunction Heart failure in patients with T2DM is an ominous sign with a 5-year survival rate of Therefore, it is likely that these individuals really had peripheral edema, not heart failure, and that following diuresis the benefical CV effects of pioglitazone were observed.
Although fat weight gain is common with pioglitazone, the HbA1c consistently declines, and the greater is the weight gain, the greater are the improvements in insulin secretion and insulin sensitivity , , Of note, increased weight gain in the PROactive study was associated with reduced CV mortality Lastly, the year follow-up of a Food and Drug Administration FDA —mandated study involving , patients failed to demonstrate any association of pioglitazone with bladder cancer CV outcome trials with rosiglitazone have been more controversial.
Similar to pioglitazone, rosiglitazone is a potent insulin sensitizer , , improves β -cell function , , , effectively reduces and maintains the reduction in HbA1c [reviewed in Ref. In a meta-analysis of 42 trials by Nissen and Wolski , rosiglitazone was associated with a significant increase HR, 1.
A retrospective data analysis by GlaxoSmithKline confirmed that the incidence of myocardial infarction in rosiglitazone-treated patients with T2DM was increased HR, 1. In the only prospective trial RECORD with rosiglitazone in patients with T2DM mean follow-up of 5.
In the recently published VADT , rosiglitazone was associated with a significant decrease in the risk of the ASCVD composite outcome any major CV event HR, 0. In the VICTORY study , which evaluated the atherosclerotic burden via ultrasound in patients with T2DM, no difference in atherosclerosis progression was observed between rosiglitazone and placebo.
In the DREAM trial , although not designed to evaluate ASCVD events, a trend for increased myocardial infarction was observed in the rosiglitazone group HR, 1. In a meta-analysis of trials in which rosiglitazone was added to insulin-treated patients with T2DM, no difference in CV events was observed compared with insulin monotherapy Overall, the results do not support a beneficial effect of rosiglitazone on adverse CV events in patients with T2DM, and, because of CV safety concerns, the European Medicine Agency removed rosiglitazone from the market , whereas the FDA placed severe restrictions on its use What explains the beneficial results of pioglitazone on ASCVD, whereas the results with rosiglitazone can, at best, be viewed as neutral?
One obvious difference is the divergent effects of the two drugs on plasma lipid levels , , Rosiglitazone increases total and LDL cholesterol levels and has no significant effect on the plasma triglyceride concentration.
In contrast, pioglitazone is neutral with respect to total and LDL cholesterol and significantly reduces plasma triglyceride levels.
Furthermore, pioglitazone reduces the concentration of small atherogenic LDL particles and lipoprotein a levels Although both TZDs increase HDL cholesterol, the increase with pioglitazone is approximately twice as great as that with rosiglitazone , These different effects on the plasma lipid profile most likely are explained by the overlapping but also unique gene expression of the two TZDs and by the ability of pioglitazone to partially activate PPAR α , Another difference between the two TZDs is the consistent improvement in endothelial function observed with pioglitazone vs the more inconsistent results noted with rosiglitazone Metformin is commonly referred to as an insulin-sensitizing agent.
However, studies utilizing the euglycemic insulin clamp have failed to demonstrate that metformin enhances insulin sensitivity in peripheral tissues, including muscle , , — , in the absence of weight loss Fig. Moreover, as reviewed by Natali and Ferrannini , in contrast to the uniform improvement in insulin action with TZDs, reports of enhanced insulin sensitivity with metformin are more sporadic and, when observed, changes in body weight were not provided.
It is noteworthy that following the intravenous administration of radiolabeled metformin, using positron emission tomography, the biguanide can be shown to accumulate in liver and distal small bowel and not in muscle There remains uncertainty about whether metformin reduces risk of CVD among patients with T2DM, for whom it is recommended as first-line drug.
However, the patient population consisted of only patients with obesity with T2DM, and the number of CV events was very small. On the contrary, subjects receiving metformin in the ADOPT study experienced more CV events than did subjects receiving glyburide, although this difference was not statistically significant.
Similarly, in metformin-treated subjects who also were receiving concomitant therapy with a sulfonylurea in the UKPDS, a significant increase in CV events was reported This emphasizes the problem of interpreting results from studies that are markedly underpowered to detect a clinically significant difference in cardiac event rates.
In a meta-analysis of randomized controlled trials with patients with T2DM comparing any dose and preparation of metformin with placebo or lifestyle intervention, metformin was slightly favored in all outcomes, with the exception of stroke ; however, no endpoint achieved statistical significance all-cause mortality HR, 0.
Effect of metformin on insulin sensitivity and hepatic glucose production in T2DM. a Metformin has no effect to improve muscle insulin sensitivity measured with euglycemic insulin clamp in individuals with T2DM in the absence of weight loss.
b The primary effect via which metformin reduces the HbA1c in T2DM is related to the suppression of hepatic glucose production via inhibition of gluconeogenesis Metformin: a review of its metabolic effects.
Diabetes Reviews —, Reprinted with permission from the American Diabetes Association ®. In summary, at the present time it is unclear whether metformin has any CV benefit. Potential mechanisms responsible for the marked reduction in CV mortality have been reviewed , Because the reduction in CV events was evident within 1 to 3 months after the start of empagliflozin, it is unlikely that the early beneficial CV effects can be explained by an antiatherogenic mechanism.
The improvement in insulin sensitivity following a treatment with SGLT2 inhibitors has been observed in animal diabetic models , and human T2DM studies within 2 weeks. The most likely explanation for the increase in insulin sensitivity is the reduction in plasma glucose concentration resulting in amelioration of glucotoxicity.
These hemodynamic effects are rapid in onset and most likely explain, at least in part, the marked reduction in CV mortality observed within 1 to 3 months after initiation of empagliflozin in the EMPA REG OUTCOME trial. Consistent with this scenario, empagliflozin treatment of 3 months decreased left ventricular mass and improved diastolic dysfunction However, the slope of the curve relating the incidence of CV events to time changes significantly after year 1 of empagliflozin therapy, suggesting that mechanisms other than hemodynamic ones contribute to the CV benefits reported in the EMPA REG OUTCOME trial A surprising result in the CANVAS study was the almost twofold increased risk for lower-extremity amputations with canagliflozin compared with placebo HR, 1.
The amputations were observed more often in men and in patients with a history of prior amputation, neuropathy, and peripheral vascular disease The metabolic effects of canagliflozin have been less well studied compared with dapagliflozin and empagliflozin , , but it is reasonable to expect that the reduction in plasma glucose concentration secondary to glucosuria would lead to amelioration of glucotoxicity and a modest improvement in insulin sensitivity.
Nonetheless, as previously reviewed , we think that hemodynamic factors—decreased preload and afterload reduction—represent the most likely mechanism responsible for the beneficial effect of SGLT2 inhibitors on 3-point MACE.
However, at the present time all of these mechanisms remain unproven. Recently, the results of the DECLARE study , which had two primary endpoints, were published. Hospitalization for heart failure plus cardiovascular mortality was significantly reduced HR, 0.
These results are consistent with two real-world studies CVD REAL-1 and CVD REAL-2 , have shown that this SGLT2 inhibitor also reduces the MACE endpoint and CV mortality — Unlike the EMPA REG OUTCOME trial, separation of the Kaplan—Meier curves did not occur until after year 1, suggesting that the CV benefit was more related to antiatherogenic benefits than to any hemodynamic benefits of the two GLP-1 RAs.
GLP-1 RAs do not have a direct insulin-sensitizing effect , , although they can ameliorate insulin resistance secondary to their effect to promote weight loss.
Nonetheless, it seems unlikely that the magnitude of the weight loss would enhance insulin sensitivity sufficiently to have a major impact on the atherosclerotic process Both the myocardium and vasculature express GLP-1 receptors , and GLP-1 RAs exert multiple beneficial effects on CV function: i direct effect to augment myocardial function; ii vasodilatory effect on small vessel blood flow secondary to enhanced nitric oxide production; iii inhibitory effect on the atherogenic process; iv altered autonomic nervous system balance favoring parasympathetic activity; v reduced myocardial injury after an ischemic insult — ; and vi direct anti-inflammatory actions on the myocardium and blood vessels In animal models, GLP-1 RAs have been shown to directly slow the atherogenic process — When viewed in the context of these two factors, it could be argued that the EXSCEL trial was a positive study with respect to CV protection.
Although not yet published, the CV results of the FREEDOM trial have been stated to be neutral. The neutral result of the FREEDOM and possibly EXSCEL trial stand in contrast to those of the LEADER and SUSTAIN-6 trials. Although the ELIXA study failed to demonstrate any CV benefit, lixisenatide is short acting, in the range of 4 to 6 hours, and the patient population acute coronary syndrome was very different than prior CV trials of GLP-1 RAs in diabetes.
The result of the REWIND trial with dulaglutide may help to clarify whether the observed antiatherogenic effects of the GLP-1 RAs represent a class effect. The DPP4 inhibitors exert their major effect by inhibiting glucagon secretion by the pancreatic α -cells and to a lesser extent by increasing insulin secretion — The DPP4 inhibitors have no insulin-sensitizing effect , Four CV outcome trials have been reported with the DPP4 inhibitors [SAVOR-TIMI saxagliptin , ESAMINE alogliptin , TECOS sitagliptin and CARMELINA linogliptin ] — , and all four have failed to demonstrate any CV protective effect in patients with T2DM with established ASCVD.
Macrovascular complications heart attack and stroke remain the major cause of mortality in individuals with the IRS, in nondiabetic people with obesity, and in prediabetic subjects and subjects with T2DM, and the increase in CV mortality cannot be fully accounted for by the classic CV risk factors.
Considerable evidence suggests that insulin resistance and the basic molecular etiology of the insulin resistance can explain a major component of the unexplained CV risk in these populations.
CV outcome trials have demonstrated that three classes of antidiabetic agents can reduce 3-point MACE: TZDs pioglitazone , GLP-1 RAs liraglutide, semaglutide , and SGLT2 inhibitors empagliflozin, canagliflozin. Of these three classes, strong evidence supports that the insulin-sensitizing agent pioglitazone exerts its antiatherogenic effect by improving insulin resistance and multiple components of the IRS.
The current recommended approach in T2D management still focuses on lowering the plasma glucose concentration rather than correcting the underlying metabolic abnormalities that cause the hyperglycemia. However, we now have antidiabetes medications that, in addition to lowering the plasma glucose concentration, also improve CV risk factors and CV events in subjects with T2DM with established CVD.
Thus, these agents should be favored over agents that lower plasma glucose but have no beneficial effects on CV risk factors or CVD. As opposed to pioglitazone, it seems unlikely that either the SGLT2 inhibitors or GLP-1 RAs exert their CV protective effects by enhancing insulin sensitivity.
This raises the intriguing possibility that combination therapy with pioglitazone plus either a SGLT2 inhibitor or GLP-1 RA could provide an additive or even synergistic effect to reduce CV events in high-risk individuals Disclosure Summary: The authors have nothing to disclose.
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Tiange WangMian LiReistance ZengRuying HuYu XuMin ResistanfeZhiyun ZhaoYuhong ChenShuangyuan WangDiseaae LinXuefeng Adaptogen and stress reliefInzulin ChenQing SuYiming CxrdiovascularLulu Insulim Insulin resistance and cardiovascular disease, Xulei CwrdiovascularLi Yan carviovascular, Guijun QinAns WanZhengnan GaoGuixia Wang Insulin resistance and cardiovascular disease, Feixia ShenZuojie LuoYingfen QinLi BMI Weight RangeInsulin resistance and cardiovascular disease HuoQiang LiZhen CardioavscularYinfei Zhang residtance, Chao LiuYoumin WangShengli WuTao YangHuacong DengJiajun ZhaoLixin ShiGuang NingYufang BiWeiqing WangJieli Lu; Association Between Insulin Resistance and Cardiovascular Disease Risk Varies According to Glucose Tolerance Status: A Nationwide Prospective Cohort Study. Diabetes Care 1 August ; 45 8 : — To investigate whether the association between insulin resistance and cardiovascular disease CVD differs by glucose tolerance status. We analyzed a nationwide sample ofadults without CVD at baseline, using data from the China Cardiometabolic Disease and Cancer Cohort Study. Insulin resistance was estimated by sex-specific HOMA of insulin resistance HOMA-IR quartiles for participants with normal glucose tolerance, prediabetes, or diabetes, separately, and by 1 SD of HOMA-IR for the overall study participants. We used Cox proportional hazards models to examine the association between insulin resistance and incident CVD according to glucose tolerance status and evaluate the CVD risk associated with the combined categories of insulin resistance and obesity in prediabetes and diabetes, as compared with normal glucose tolerance. Models were adjusted for age, sex, education attainment, alcohol drinking, smoking, physical activity, and diet quality. Cardiovascular Diabetology annd 17Article number: Resistace this article. Digestive health recipes details. For many years, rresistance disease Insulin resistance and cardiovascular disease has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body.
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