Low Grade Systemic Inflammation Health And Social Care Essay

ABSTRACT

Objective: Aim of the study was to evaluate the beta cell function, insulin sensitivity and low grade systemic inflammation in different categories of glucose tolerance in Myanmar.

Methodology: A cross-sectional study was conducted on 202 Myanmar subjects of both sexes, age between 45-65 years old. Fasting blood glucose, insulin, C-peptide and hs-CRP levels were measured. A 75g oral glucose tolerance test was performed. Insulin resistance and beta cell function were assessed by homeostasis-model-assessment (HOMA).

Results: The subjects were categorized as normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and Diabetes Mellitus (DM) according to WHO-2006 criteria. Fasting serum insulin, C-peptide and hs-CRP levels and insulin resistance index (HOMA-IR) progressively increased from NGT through prediabetes (IFG, IGT) to DM (p<0.01). Beta cell function did not change significantly in any other group as compared to normal group.

Conclusion: After multivariate analysis, increased in fasting C-peptide or hs-CRP or HOMA-IR index were significantly associated with development of diabetes and they may be regarded as risk factor for diabetes. It was also found out that insulin resistance was a predominant feature in deterioration of the glucose tolerance in Myanmar subjects.

Key words: beta cell function, insulin resistance, glucose intolerance

Introduction

Population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity were generally regarded as contributing factors for the rising prevalence of Diabetes Mellitus (DM). The total number of people with DM is projected to rise from 171 million in 2000 to 366 million in 20301. Urbanization is associated with changes in life style with physical inactivity, unhealthy diet and obesity, which have been implicated as contributing factors for rapid development of Type 2 Diabetes Mellitus (T2DM)2,3. In Myanmar, the prevalence of DM and combined IFG and IGT (prediabetes) were 11.8% ( 95% CI-10.1-13.4%) and 13.4% ( 95% CI-12.0-14.8%) respectively4.

The natural history and pathogenesis of T2DM indicates that this disease has a prolonged prediabetic phase5. Consequently, there is an opportunity to identify patients at high risk for developing diabetes and institute primary prevention strategies. Patients with prediabetic state, which include IFG and IGT, are at significant risk for development of diabetes. Compared with normoglycemic persons, patients with IFG and IGT frequently are associated with metabolic syndrome 6.

One important factor that is usually associated with glucose intolerance is hyperinsulinaemia. This relationship is thought to be mediated by insulin resistance. Although both fasting insulin and fasting C-peptide have been employed as a measure of insulin resistance, C-peptide is not metabolized by the liver and is therefore a more reliable index of prehepatic insulin than the fasting insulin. In recent studies, C-peptide measurement has been used as an alternative, reliable surrogate for assessing pancreatic insulin secretion and elevated C-peptide level have been shown to precede the development of T2DM in Japanese American men7.

The homeostatic model assessment (HOMA) is a validated method to measure to measure insulin resistance from fasting glucose and insulin. The original model HOMA1-IR, first published by Mattews et al.8 in 1985, has been widely used. Then, the model was updated with some physiological adjustments to a computer version (HOMA2-IR) providing more accurate index9. Onishi et al.10 investigated that lower HOMA-β and higher HOMA-IR are significant risk factors for the future development of prediabetes among Japanese with normal glucose tolerance.

Chronic systemic inflammation can induce insulin resistance. Type 2 Diabetes is a manifestation of an ongoing acute phase response that is primarily characterized by alterations of the so-called acute phase protein, such as C-reactive protein (CRP). CRP is an acute-phase reactant synthesized in the liver in response to cytokines, especially interleukin-6 (IL-6). In epidemiological studies, circulating CRP levels significantly predict the risk of T2DM11. There is still controversy about whether low-grade inflammation is an intermediate factor between obesity and insulin resistance or whether it has an independent effect on the development of T2DM through a mechanism separate from obesity. Niehoff et al.12 also reported that CRP was not related to insulin resistance after adjustment for parameters of body composition. However, data on CRP and diabetes are limited in Asia13. Thus, CRP might provide an adjunctive measure for identifying subjects with the highest risk of progression to diabetes who would derive the greatest benefits from preventive measure.

Most importantly, insulin resistance has been associated with increased cardiovascular risk and chronic sub-clinical inflammation in several populations and predominant defect in beta cell function or insulin resistance appears differ among ethnic groups14. Therefore, this study conducted to evaluate the beta cell function, insulin resistance and low-grade inflammation in adults with different categories of glucose tolerance in Myanmar.

MATERIALS AND METHODS

This cross-sectional study consisted of 202 urban Myanmar subjects of both sexes (ages- 45 to 65 year) by simple random sampling method. Subjects were excluded from the study if they were known to have diabetes, any disease and medication that might influence glucose metabolism. This research was approved by the Institutional ethical committee review board, and signed informed consent was obtained from all participants. The clinical examination consisted of a medical history, physical examination, and anthropometric measurements (height, weight and BMI). Plasma glucose, insulin, C-peptide and hs-CRP were measured after an overnight 10-h fast and then the subjects underwent a 75-g oral glucose tolerance test. The glucose tolerance was classified according to the WHO (2006) criteria15 for fasting and 2-hr glucose levels. Plasma glucose levels were determined by glucose oxidase method with Humalyzer 2000 (Human, Weisbaden, Germany). The serum insulin, C-peptide and hs-CRP were determined by ELISA methods with EIA-2935, EIA-1293 and EIA-4584 of DRG, Germany respectively. Insulin resistance and beta cell function were assessed by homeostasis model assessment (HOMA2-IR and HOMA2-β) by HOMA-2 calculator model16. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared.

Statistical Analysis were performed using computer based statistical package of statistical product and service solution (SPSS) software version v. 16.0 and descriptive statistics of numerical variables were expressed as mean ± SD. Description of categorical variables was expressed as percentage. Comparisons among groups were analyzed by analysis of variance (ANOVA) test with Bonferroni method for continuous variables. Pearson’s correlation analysis was used to determine the relationships between variables. Stepwise logistic regression was used to evaluate the significant factors associated with diabetes. A receiver operating characteristic (ROC) curve was used to determine the cutoff values. Level of significance was set at p<0.05.

RESULTS AND DISCUSSION

The baseline anthropometric and metabolic characteristics of the study groups across glucose tolerance levels are presented in table 1. Out of the total 202 subjects, there were 111 (54.95%) in NGT group, 10 (4.9%) in IFG group, 31 (15.35%) in IGT group and 50 (24.75%) in DM group according to the WHO (2006) criteria. It was found that nearly half of the subjects in the study group showed to have decreased glucose tolerance. The sex distribution of the present study showed that the females were the majority which representing 64.9% of the study population. Only DM group had older and higher blood pressure than NGT group (p<0.05), and there were no significant differences between groups with regard to BMI, age. The mean BMI (26.06 ± 5.56) of the present study could be considered as overweight category (BMI ≥ 25 & < 30) according to the standard BMI for Asians17. In the present study, there was a large increase in proportion of prediabetes and T2DM as compare to the previous study in rural and urban area of Yangon Division, Myanmar4. This may be due to the life style changes of urbanization in present days. The prevalence of diabetes in Asian populations has increased rapidly in recent decades.

By the study of Tint-Swe-Latt et al..19 in 2004 reported that diabetes mellitus is by far the most common metabolic disorder in Myanmar. Therefore the increased prevalence of prediabetes and diabetes results obtained in the present study firmly supported that prevention and control of diabetes should be a top public health priority in Myanmar.

The mean fasting insulin, C-peptide and hs-CRP levels progressively increased from NGT through prediabetes to the newly diagnosed diabetes (p<0.01). The mean fasting insulin level of DM group was significantly higher than NGT, IFG, IGT groups and the level of IGT was significantly higher than that of NGT (p<0.01). It could be explained by the higher level of insulin resistance and a consequence compensatory increase in beta cell mass and hypertrophy of existing beta cells to meet the increased demand and to avoid more severe hyperglycemia. Reasner (2010)20 also discussed that the initial defect in the pathogenesis of diabetes is insulin resistance, but the body is able to overcome this defect for a period of time through increased insulin production. According to the above reason the mean fasting insulin level in IGT and DM group was 1.9 fold and 2.8 fold compared with the levels in NGT group respectively in the present study.

Human C-peptide provides an accurate assessment of residual beta cell function and thus has been widely used as a marker of insulin secretion in patients with diabetes21. In the present study, as like as fasting insulin level, the mean fasting C-peptide level in DM group was significantly higher than NGT, IFG, IGT groups and the level of IGT as well as IFG was significantly higher than that of NGT group (p<0.05). Therefore, the current study highlighted the fact that fasting C-peptide give the more accurate discrimination than the fasting insulin in assessing the insulin secretion and high C-peptide levels have been interpreted as representing hypersecretion of insulin as a compensatory response to insulin resistance.

The mean fasting hs-CRP level in DM group was also significantly higher than NGT, IFG, IGT groups and the level of IGT was significantly higher than that of NGT (p<0.05). The trend of increase in mean fasting hs-CRP levels of the present study was nearly similar to those found in other studies22,23,24.25 and it could also be explained by progress in low-grade inflammation as a potential dynamic in pathogenesis of T2DM. Snijder et al..26 in the Hoorn study also stated that CRP level progressively increased as the glucose metabolism deteriorates. Ridker et al.27 also stated that CRP was an important predictor of T2DM. In the Hong Kong cardiovascular risk factor prevalence study, subjects with IGT with highest CRP concentration were three fold risk of either remaining in IGT or progressive to diabetes compared to these subjects with lowest CRP concentration22 and in the Hisayama study in Japan, increased CRP level was a significant predictor of incident diabetes in both gender of the general Japanese population28.

With regard to insulin resistance, there was also progressive increase in HOMA2-IR across the glucose tolerance levels (p<0.01). The mean HOMA-IR in DM group was significantly higher than that of NGT, IFG, IGT groups and the mean HOMA-IR of IGT was significantly higher than that of NGT (p<0.01). The HOMA2-IR is a more accurate representation of the metabolic process because it models the feedback relationship between insulin and glucose in the various organs in the body29. Therefore the current study used the HOMA-2 computer model in which the mean fasting insulin level to compute HOMA2-IR that determines the resistant to insulin action, and C-peptide to compute HOMA2-ß which determines pancreatic insulin secretion. There was a marked increase in HOMA2-IR with the deterioration of glucose tolerance. The magnitude of the incremental increase in HOMA2-IR in subjects with IFG, IGT, and DM group was 1.6-, 1.9-, and 3.1- fold greater than in subjects with NGT respectively. The findings of present study concerning HOMA2-IR were comparable with the previous studies30,31,32. However, the HOMA2-IR indexes of some studies33,34 were higher than those of the present study. These equivocal and confliction findings can be explained by difference in study populations, study designs, methods to assess insulin resistance and insulin secretion by HOMA-IR (i.e. HOMA1-IR or HOMA2-IR), different cut-off points in categorization of glucose tolerance and ethnic differences. The ethnicity difference statement was supported by findings of previous studies35. Stancakova et al.36 showed in a large cohort study of Finnish men that peripheral insulin resistance started at relatively low plasma glucose levels within normoglycemic range and is the predominant feature of isolated IGT, whereas impairment in early and total insulin release characterizes isolated IFG. Taken together, the present study suggested that insulin resistance along with elevated insulin levels could precipitate the development of prediabetes (IFG, IGT) and T2DM.

The beta cell function as assessed by HOMA2-β, there was no significant change in HOMA2-β in all category subjects when compared to NGT. However, there was significant decline in beta cell function in IFG and DM groups as compared to IGT groups (p<0.01). In the current study, there was a slightly decline in beta cell function as assessed by HOMA2-β cell in subjects with IFG and DM groups with exception of IGT groups. The same patterns of changes in HOMA-β cell were found in other international studies11,36. However, a large reduction in beta cell function in both prediabetes and diabetes had been observed in Japanese and other groups37,38 discussed that individuals with IFG have impairment in both basal and glucose stimulated insulin release, whereas individuals with IGT have increased basal and total insulin release. Festa et al.11 reported that the relationship between glucose and insulin in the basal state reflects the balance between hepatic glucose output and insulin secretion, which is maintained by feedback loop between the liver and beta cells and concluded that the potential limitations of the use of HOMA β include its lack of capture of stimulated state by relying on fasting measures, its insensitivity to a variable β cell glycemic sensitivity. Ning et al.39 discussed that both HOMA-IR and HOMA- β are only surrogate indicators of insulin sensitivity and beta cell function which are mainly based on glucose and insulin levels at the fasting status. They do not directly reflect the capacity of the beta cell to cope with the glucose challenge, and thus may be less associated with IGT. This explanation was applicable to the present finding with high HOMA-ß in IGT group because IGT is characterized by only elevated 2hour glucose level with normal fasting glucose level with elevated insulin levels in compensatory effect to high insulin resistance.

Among the study population, fasting serum C-peptide correlated positively with fasting serum insulin, hs-CRP and HOMA2-IR. Fasting serum hs-CRP also correlated positively with BMI, fasting serum insulin and HOMA2-IR (Table 2). Marx et al.40 had explained that C-peptide might deposit in the vessel wall in patients with insulin resistance and early T2DM and C-peptide deposition is mainly in the subendothelial space and the intima. Higher C-peptide deposition leads to endothelial dysfunction and release of cytokines and chemotactic proteins and expresses adhesion molecules on the endothelial cell surface. Such mechanism supported the present finding that the C-peptide was strongly correlated with hs-CRP. In addition, low grade systemic inflammation is considered an important mechanism leading to obesity, insulin resistance and T2DM. Ford41, Festa et al.42 and Vikram et al.43 reported that there was significantly correlation between inflammatory markers like CRP and fasting insulin as well as BMI. Woperies et al.44 reported that inflammatory modulation may alter insulin signaling in overweight men. Reasner20 also discussed that high insulin level and impaired insulin signaling may contribute to the development of macrovascular complications in T2DM. In healthy individuals, when glucose enters the cell via glucose transporters, it stimulates nitric oxide production. Nitric oxide is a potent vasodilator and improves endothelial function. Persons with insulin resistance have less glucose entering their cells, and therefore less nitric oxide stimulation. As the body makes more insulin to compensate for higher circulating glucose levels, the excess insulin stimulates the MAP kinase pathway. The MAP kinase signaling pathway ultimately promotes inflammation, cell growth/proliferation, and finally, atherosclerosis. The combination of above mechanisms supported the present finding with strong positive correlation of hs-CRP and BMI, fasting insulin, C-peptide, and HOMA-IR indexes.

In the present study, stepwise logistic regression showed that the serum C-peptide, hs-CRP levels and HOMA2-IR were strongly associated with development of diabetes (p< 0.05). Among which, HOMA2-IR (odds ratio, OR = 12.84) was more associated with diabetes than that of serum C-peptide and hs-CRP level and it can be concluded that insulin resistance is the predominant features in the deterioration of the glucose tolerance in the present study. Moreover, one of the great opportunities is to specify the cut off values of HOMA2-IR, fasting serum C-peptide and hs-CRP for predicting diabetes in Myanmar. According to the ROC curve, the cut-off value in predicting T2DM of HOMA2-IR was 1.05 (88%-sensitivity and 84%-specificity), C-peptide was 1.85 ng/ml (82%-sensitivity and 81%-specificity) and hs-CRP was 5.65 mg/L (76%-sensitivity and 70%-specificity) according to ROC curve (Figure 1).

CONCLUSION

The beta cell function deterioration was found in prediabetes and DM group. Within the prediabetic group, IFG subjects had elevated fasting plasma glucose levels because of impaired insulin secretion, whereas the fasting plasma glucose concentrations in IGT subjects were regulated by a compensatory increase in insulin concentration. Therefore the present study supported the notion that Subjects with IFG and IGT differ with respect to beta cell dysfunction. After multivariate analysis, increased in fasting C-peptide or hs-CRP or HOMA-IR index were significantly associated with development of diabetes and they may be regarded as risk factor for diabetes. It was also found out that insulin resistance was a predominant feature in deterioration of the glucose tolerance in Myanmar subjects. Moreover, one of the great opportunities is to specify the cut off values of HOMA2-IR, fasting serum C-peptide and hs-CRP for predicting diabetes in Myanmar. These values suggested that individuals at high risk of developing T2DM can be identified without labor-intensive oral glucose tolerance test and these values can be used as clinical and epidemiological application in Myanmar population.