|Year : 2020 | Volume
| Issue : 1 | Page : 22-27
Insulin resistance in non diabetic individuals with acute myocardial infarction and its relationship with acute phase reactants
Smita Nath1, Rina Mohanty2, Uttam Kumar Patnaik3
1 Department of Medicine, NDMC Medical College and Hindu Rao Hospital, New Delhi, India
2 Department of Medicine, SCB Medical College and Hospital, Cuttack, Odisha, India
3 Department of Cardiology, SCB Medical College and Hospital, Cuttack, Odisha, India
|Date of Submission||04-Mar-2019|
|Date of Acceptance||15-Jul-2019|
|Date of Web Publication||27-Mar-2020|
Dr. Smita Nath
Department of Medicine, NDMC Medical College and Hindu Rao Hospital, New Delhi - 110 007
Source of Support: None, Conflict of Interest: None
Aim: The current study was undertaken to assess the prevalence of insulin resistance (IR) in nondiabetic individuals with acute myocardial infarction (AMI) and to study the relationship between IR and acute-phase reactants in patients with AMI and to ascertain its prognostic significance.
Materials and Methods: One hundred nondiabetic individuals with AMI were part of the study. A detailed physical examination and estimation of fasting blood sugar, 2 hPost prandial blood sugar (PPBS), fasting serum insulin, highly sensitive c-reactive protein (hsCRP), and lipid profile was done at admission and then after 3 months of follow-up. IR was calculated using Homeostatic model assessment IR (HOMA IR) and HOMA B method. HOMA IR value of >2 was considered as IR.
Results: In the present study, the prevalence of IR was 63% (males = 63.4% females = 60.8%). hsCRP levels were elevated in 87.4% (hsCRP = 3.187 ± 1.4109 [mg/l]) of insulin-resistant individuals and 86.5% normal individuals (hsCRP = 3.950 ± 1.390 [mg/L]). At the end of 3 months, hsCRP levels in the group with IR was 2.346 ± 0.883 mg/L and in the group with no IR was 1.779 ± 0.875 mg/L (P = 0.043). The prevalence of metabolic syndrome in the study population was 24%. Mortality rate was higher in patients with IR at 3.2%.
Conclusion: The study shows that the prevalence of IR is high, even in nondiabetic patients with coronary artery disease.Level of Hs CRP which is a marker of inflammation was found to be raised in the entire study population irrespective of insulin resistance status. However, in patients with IR, the level of hsCRP remained high even on follow-up study. IR and acute-phase reactants like hsCRP can be used in addition to the traditional risk factors to evaluate the progress and outcome of cardiovascular disease.
The following core competencies are addressed in this article: Medical knowledge, Patient care, Practice-based learning and improvement, and Systems-based practice.
Keywords: Acute phase reactants, cardiovascular disease, insulin resistance
|How to cite this article:|
Nath S, Mohanty R, Patnaik UK. Insulin resistance in non diabetic individuals with acute myocardial infarction and its relationship with acute phase reactants. Int J Acad Med 2020;6:22-7
|How to cite this URL:|
Nath S, Mohanty R, Patnaik UK. Insulin resistance in non diabetic individuals with acute myocardial infarction and its relationship with acute phase reactants. Int J Acad Med [serial online] 2020 [cited 2020 May 25];6:22-7. Available from: http://www.ijam-web.org/text.asp?2020/6/1/22/281460
| Introduction|| |
Coronary heart disease (CHD) is a major cause of disability and death around the world, and more than one-third of deaths in cohorts above 35 years of age is attributed to it. The Indian subcontinent has one the highest burdens of CHD-related morbidity and mortality globally. The demographic data from 2003 estimated the prevalence of CHD in rural India between 3% and 4%. In urban India, the prevalence was between 8% and 10%, bringing the total disease burden to 29.8 million. The global burden of disease study from 2013 revealed that CHD was responsible for 17.3 million deaths worldwide.
The evolution of risk factors for CHD has been extensively assessed by population-based epidemiological studies like Framingham Heart study. In addition to the traditional risk factors for CHD identified by Farmingham heart study, the presence of insulin resistance (IR) and increased levels of pro-inflammatory markers like highly sensitive c-reactive protein (hsCRP) have shown a direct correlation with evolution, progression, and outcome of CHD. The risk of new-onset cardiovascular disease (CVD) in patients with metabolic syndrome in the absence of diabetes is 1.5–3 fold. The glycemic status and IR in nondiabetic patients admitted to hospital with acute myocardial infarction (AMI) and their mortality rate is interrelated. As a result, the involvement of IR in pathogenesis of CHD has emerged as an intriguing question with potential to bring about tectonic shift in the current understanding of CHD risk factors.
It is postulated that the antiatherogenic effects of insulin are blunted due to IR, thus linking IR to numerous nontraditional risk factors for CHD, including markers of coagulation and systemic inflammation, oxidative stress, and dysregulated adipokine signaling., A growing body of evidence suggests that the relationship between atherosclerosis, inflammation, and IR is causal and not just complimentary. IR is defined as resistance to metabolic effects of insulin, including suppressive effects of insulin on endogenous glucose production, stimulatory effects of insulin on peripheral (especially skeletal muscle) glucose uptake, glycogen synthesis, and inhibitory effects of insulin on adipose tissue. Its presence is associated with clustering of cardiovascular risk factors including diabetes mellitus, hypertension, raised levels of very low density lipoprotein, high triglycerides, and low plasma high-density lipoprotein cholesterol.
Atherosclerosis is recognized as a pro-inflammatory and prothrombotic state associated with elevated levels CRP. It adds prognostic information at all the levels of traditional risk factors as identified by Framingham Heart study. In addition to clustering with conventional risk factors, more recent evidence indicates that IR is linked with “nontraditional” CHD risk factors and proartherosclerotic inflammatory state. The hypothesis of our study was that in nondiabetic patients with CHD, nontraditional inflammatory markers like IR contribute to the morbidity and mortality. Our secondary objective was to establish a positive correlation between IR and markers of inflammation like hsCRP.
| Materials and Methods|| |
One hundred nondiabetic patients with AMI were taken up as cases. Patients excluded from study were those with diabetes mellitus, acute infections, and comorbid conditions such as hypertension, chronic renal failure, cirrhosis of liver, and malignancy. The diagnosis of acute myocardial infarction was made based on the criteria for acute, evolving, and recent AMI laid down by Universal definition of myocardial infarction. Type 2 DM was diagnosed based on criteria given by American Diabetes Association. IR was calculated by Homeostasis model assessment (HOMA IR) and HOMA B methods. HOMA IR >2 was used to define IR., An hsCRP level >3 mg/L was considered high in accordance with AHC/CDC scientific statement summary., Waist-to-hip ratio (WHR) and body mass index (BMI) were defined according to criteria given by NCEP: ATP III 2001 and IDF criteria for metabolic syndrome. WHR of more 0.9 in females and 1.0 in males was considered abnormal. hsCRP was estimated by a CRP enzyme-linked immunosorbent assay kit (Immunodiagno, Bensheim, Germany) and its intra- and inter-assay coefficient of variation were 6.5% and 10.4%, respectively. Serum insulin was determined by electrochemiluminescence immunoassay method after an overnight fasting. Appropriate approval was obtained from institutional ethics committee of SCB Medical college vide number ECR/84/SCB/0R/2013. Written consent of the participants was duly obtained.
The data were analyzed using SPSS software version (23: SPSS Inc., Chicago, IL, USA). Mean difference and standard deviation of various groups of patients was calculated. Student's t-test was used to determine the statistical significance of mean difference. Pearson's correlation coefficient was used to determine degree of correlation between parameters. The sample size calculated using α error of 0.05% and β error of 80% was 180. However, for logistic reasons, 100 patients were included in the study.
| Results|| |
A total of 100 individuals were included in our study, of which 77 were male and 23 were female. The age distribution of the study population did not show a wide range of variation, and the mean age of the study population was 62.4 ± 10.014 years. 44% of our patients were between 60 and 69 years of age out of whic41.5% were males and 52.22% were females. The prevalence of IR in males was 63.4%, and in females, it was slightly lower at 60.8%. The overall prevalence of IR was 63%. Most of the patients showing IR were in age group of 60–69 years which included 40.8% male and 57.2% females. Mean fasting serum insulin level in the group with HOMA IR >2 was 16.457 ± 9.851 (μIu/ml). In the group with HOMA IR <2, the mean fasting serum insulin was 4.573 ± 1.972 (μIu/ml). The difference was statistically significant (P < 0.001). The Pearson correlation coefficient between the mean fasting serum insulin level and HOMA IR was 0.992. The value of HOMA B in the insulin-resistant individuals was 184 ± 72.671. In patients without IR, HOMA B was 132.276 ± 54.568. The difference in HOMA B levels was statistically significant (P < 0.001). The Pearson correlation coefficient between HOMA IR and HOMA B level was 0.859. The prevalence of dyslipidemia in the group showing IR was 65%, and in the group without IR was 32%. The prevalence of metabolic syndrome was 24%. Family history of CVD was present in 2% of insulin-resistant patients. Mean BMI in the group showing IR was 22.468 ± 5.110, and in the group with no IR, mean BMI was 21.464 ± 5.791 (P = 0.265). The prevalence of central obesity in our study participant was 100%. The waist–hip ratio of male patients showing IR was 1.2905 ± 0.175 and that of the female patients with IR was 1.254 ± 0.953. In the study population without IR, the WHR of male and female patients was 1.0139 ± 0.0219 and 0.930 ± 0.032, respectively. P value in both the scenarios was < 0.001. hsCRP was elevated in 87.4% of individuals with IR and 86.5% of normal individuals. The hsCRP levels in patients with IR was 3.187 ± 1.4109 (mg/L). In patients without IR, the hsCRP value was slightly higher at 3.950 ± 1.390 (mg/L). However, the difference was not statistically significant (P = 0.383).
A total of 45 study participants were followed up after a period of 3 months. At the end of 3 months, hsCRP levels in the group with IR was 2.346 ± 0.883 mg/L and in the group with no IR, was 1.779 ± 0.875 mg/L (P = 0.016). Multivessel disease was present in 50% patients with IR. In normal study population, the prevalence of multivessel disease was 21.7%. Mortality rate was higher in patients with IR at 3.2%. It was 2.8% in patients without IR.
| Discussion|| |
IR is increasingly recognized as a chronic low-level inflammatory state. Hyperinsulinemia and insulin action were initially proposed as the common preceding factors of hypertension, low level of high-density lipoprotein, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of CHD. A total of 100 individuals were included in our study, of which 77 were male and 23 were female. The biochemical profile of study population is listed in [Table 1]. The age distribution of the study population did not show a wide range of variation, and the mean age of the study population was 62.4 ± 10.014 years. In study conducted by Choi et al., the mean age of study individuals was 58.4% ±6.0. 73.3% of the patients includedin this study were male. In another study done by Das et al., the mean age of normoglycemic CAD patients was found to be 57 ± 7.34 years, and the male: female ratio was 18:2.
The Homeostasis assessment model (HOMA) developed by Matthew et al. was used in our study. The prevalence of IR in males and females was 63.4% and 60.8%, respectively. The overall prevalence of IR was 63%. The reliability of HOMA method to determine IR has been validated, as HOMA-IR score have been shown to closely mirror the IR values obtained by the euglycemic glucose clamp technique in the assessment of insulin sensitivity. The HOMA method utilizes single fasting plasma value of glucose and corresponding fasting plasma insulin levels. In our study, HOMA IR >2 was taken as IR. HOMA IR score of 1 is considered ideal. The normal value of IR as assessed by HOMA-IR Indian population is between 2 and 2.5. Bonora et al. also found a mean HOMA IR score of 2.06 ± 0.14 in nondiabetic population., The value of HOMA B in the insulin-resistant individuals was 184 ± 72.671. In individuals without IR, it was 132.276 ± 54.568 (P < 0.001). In normal population, beta-cell function is assumed to be 100. In our study, beta cell dysfunction was present in the individuals showing IR, and difference in beta cell functions of the two groups was statistically significant.
Analysis of BMI and WHR ratio in the current study revealed that the prevalence of central obesity was 100%. We observed that our patients had lower BMI but higher WHR as compared to their western counterparts. Indian population differs from Caucasians and African Americans in their body composition, as they do not have generalized obesity but tend to have higher intra-abdominal fat mass and excess truncal subcutaneous fat., Mean BMI of male and female patients showing IR was 23.183 ± 1.746 and 23.058 ± 2.063, respectively. In the group without IR, the mean BMI in male and female patients was 22.531 ± 2.034 and 22.291 ± 1.910, respectively. Although central obesity was present in all the individuals included in the study, there was statistically significant difference in WHR of the different groups. In insulin-resistant group, the WHR of male patients was 1.2905 ± 0.175, and in the group without IR, the WHR of male patients was 1.0139 ± 0.0219. The difference was statistically significant (P < 0.001). Similar patterns were observed in the female patients also. The WHR of female patients with IR was 1.254 ± 0.953. In female patients without IR, WHR was 0.930 ± 0.032. The difference between WHR was statistically significant (P < 0.001). Relative increases in visceral versus subcutaneous adipose tissue with increasing waist circumference in Asians and Asian Indians may explain the greater prevalence of central obesity in these populations compared with African-American cohorts where subcutaneous fat predominates. It is also possible that visceral fat is a marker for, but not the source of, excess postprandial free fatty acids (FFAs) and IR in obesity and metabolic syndrome. The percentage of dyslipidemia was higher in the group showing IR. The overall prevalence of dyslipidemia in the group showing IR was 65% and in the group without IR was 32. Pearson TA et al. in 2003 showed that the incidence of dyslipidemia in normoglycemic individuals with IR was 66%.
In the current study, we observed that even after excluding hypertension and diabetes mellitus, several risk factors for CHD as defined by NCEP ATPIII criteria were present in our study group. Risk factors associated with CAD in our study population is listed in [Figure 1].100% of our patients had central obesity. However, the percentage of dyslipidemia was higher in the group showing in IR. 20% individuals in both the groups were smokers. The prevalence of metabolic syndrome was 24%. Family history was present in 2% insulin-resistant patients. In our study in addition to IR and elevated hsCRP, predominant risk factors for CHD were advanced age, hypertriglyceridemia, and central obesity. These data are comparable with findings of Joshi 2005. The AHA/CDC Scientific Statement Summary (Circulation 2003) considers hsCRP as a global indicator of future cardiovascular events in adults without previous history of cardiovascular disease (CHD), with acceptable precision levels down to or below 0.3 mg/L. hsCRP enhances risk assessment and therapeutic outcomes in primary CHD prevention. In our study, although hsCRP levels were not significantly high, mild elevation was present in 87.4% individuals with IR (hsCRP = 3.187 ± 1.4109 [mg/L]) and 86.5% of normal individuals (hsCRP = 3.950 ± 1.390 [mg/L]). The difference was statistically insignificant (P = 0.383).
It was observed that the incidence of anterior wall myocardial infarction was highest at 46% followed by inferior wall AMI which was present in 45% cases. Non-ST elevated myocardial infarction (NSTEMI) was present in 6% cases. The incidence of lateral wall AMI was 3%. However, a different trend was observed in patients showing IR. In these individuals, the incidence of inferior wall AMI was highest at 57.5% followed by anterior wall AMI at 36.5%. The incidence of NSTEMI and lateral wall AMI was observed to be 4%. Three patients included in the study succumbed to complication of AMI. Mortality rate was slightly higher in patients with IR at 3.2%. It was 2.8% in patients without IR. Multivessel disease was present in 50% patients with IR. In study population without IR, the prevalence of multivessel disease was 21.7%.
A total of 45 study participants were followed up after a period of 3 months. During this period, no new cardiovascular events or deaths were reported. The biochemical parameters of the patients at the end of 3 months are listed in [Table 2]. At the end of 3 months, hsCRP levels in the group with IR was 2.346 ± 0.883 mg/L and in the group with no IR was 1.779 ± 0.875 mg/L. The fall in hsCRP levels was more marked in patients without IR, and the difference was statistically significant (P < 0.043) indicating that in patients with IR, persistent low-grade inflammation is present. The findings were on par with the study done by Choi et al. which shows that the hsCRP levels and IL-6 concentration decreased significantly (P < 0.0001); however, IR and serum adiponectin did not change significantly.
| Conclusion|| |
The conclusions drawn from our study reveals that there was high prevalence of IR, even in nondiabetic patients with CHD and theses patients had significantly higher WHR and central obesity despite having normal BMI. The pattern of rise in acute-phase reactants was similar in patients showing IR as well as those with no IR. However, the hsCRP levels remained significantly high at the end of 3 months in insulin-resistant individuals pointing toward a persistence of low-grade chronic inflammatory state. We also observed higher prevalence of multivessel CHD and a slightly higher mortality rate in insulin-resistant patients. Our study is an initiative toward better understanding of the role played by IR in nondiabetic cardiovascular disease population in Indian population. Data from Asian population regarding nontraditional risk factor for CAD are scarce. Hence, our aim was to increase the volume and diversity of available data regarding role played by IR in CAD. In resource-limited country like India, with increasing burden of noncommunicable diseases, studies aimed at nontraditional risk factor may play a vital role in designing primary prevention strategy. IR and acute-phase reactants like hsCRP can predict the outcome and risk of future cardiovascular events in CHD patients; however, longer term studies are needed for this purpose. IR, central obesity, and associated metabolic abnormalities might underlie high rate of CHD in Indian population.
The study would have produced more robust result if a larger cohort could have been studied for a longer period as atherosclerosis is a chronic process.
A longer follow-up period would have allowed us to better study the pattern of inflammatory markers as well as progression of CAD in detailed manner.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Ethical conduct of research
Appropriate approval was obtained from institutional ethics committee of SCB Medical college vide number ECR/84/SCB/0R/2013. The authors declare that they followed applicable EQUATOR Network (http://www.equator-network.org/) research reporting guidelines.
| References|| |
Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al.
Heart disease and stroke statistics – 2008 update: A report from the American heart association statistics committee and stroke statistics subcommittee. Circulation 2008;117:e25-146.
Goyal A, Yusuf S. The burden of cardiovascular disease in the Indian subcontinent. Indian J Med Res 2006;124:235-44.
] [Full text]
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the global burden of disease study 2013. Lancet 2015;385:117-71.
D'Agostino RB Sr., Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al.
General cardiovascular risk profile for use in primary care: The Framingham heart study. Circulation 2008;117:743-53.
Windgassen EB, Funtowicz L, Lunsford TN, Harris LA, Mulvagh SL. C-reactive protein and high-sensitivity C-reactive protein: An update for clinicians. Postgrad Med 2011;123:114-9.
Libby P, Ridker PM, Hansson GK; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: From pathophysiology to practice. J Am Coll Cardiol 2009;54:2129-38.
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045-51.
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Meigs JB, et al.
Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: The Bruneck study. Diabetes Care 2007;30:318-24.
Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction, Jaffe AS, Apple FS, et al.
Universal definition of myocardial infarction. Circulation 2007;116:2634-53.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9.
Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al.
Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: Studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23:57-63.
Singh Y, Garg MK, Tandon N, Marwaha RK. A study of insulin resistance by HOMA-IR and its cut-off value to identify metabolic syndrome in urban Indian adolescents. J Clin Res Pediatr Endocrinol 2013;5:245-51.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd
, Criqui M, et al.
Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the centers for disease control and prevention and the American heart association. Circulation 2003;107:499-511.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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). JAMA 2001;285:2486-97.
Joshi SR. Metabolic syndrome – emerging clusters of the Indian phenotype. J Assoc Physicians India 2003;51:445-6.
Choi KM, Lee KW, Kim SG, Kim NH, Park CG, Seo HS, et al.
Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus. J Clin Endocrinol Metab 2005;90:175-80.
Das S, Bhoi SK, Baliarsinha AK, Baig MA. Autoimmunity, insulin resistance and beta cell function in subjects with low body weight type 2 diabetes mellitus. Metab Syndr Relat Disord 2007;5:136-41.
[Table 1], [Table 2]