Study on Quantitative Assessment of Insulin Response in Impaired Glucose Regulation

Sangavai, G (2010) Study on Quantitative Assessment of Insulin Response in Impaired Glucose Regulation. Masters thesis, College of Pharmacy, Sri Ramakrishna Institute of Paramedical Sciences, Coimbatore.


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The new term ‘pre-diabetes’ or impaired glucose regulation (IGR) was introduced recently and refers to subjects with high fasting plasma glucose (FPG) concentration and normal response to a glucose load (IFG), subjects with abnormal postprandial glucose excursion but normal FPG concentration (IGT), and combination of IGT and IFG. Research on insulin - glucose dynamics is gaining importance particularly in the area of diabetes prevention. Generally fasting & 2-hour postprandial glucose concentrations are considered as reference points for the diagnosis of diabetes & pre-diabetes. American Diabetes Associations (ADA) guidelines rely on measurement of fasting glucose (7.0 mmol/L) and the European & the WHO groups rely on glucose concentration at 2 hours of OGTT (11.1 mmol/L) in the screening and classification of glucose tolerance. However onehour glucose concentration is considered for screening and diagnosis of gestational diabetes in the US. Although fasting plasma glucose (FPG) alone does not always detect people with impaired glucose tolerance (IGT) and the 2-h plasma glucose (PG) does not always identify people with impaired fasting glucose (IFG), both tests are useful in terms of their ability to detect hyperglycemia and the consequences of disordered glucose metabolism. Though both IFG and IGT raise risks for diabetes, some controversies still exist as to the relative contribution of insulin resistance and beta-cell dysfunction in the progression from impaired glucose regulation (IGR) to diabetes. Insulin resistance and impaired insulin secretion concur toward glucose intolerance and diabetes, but it is unclear which defect arises first, which relates more closely to IFG or IGT, and which reflects different alteration in glucose homeostasis. Some reports showed that subjects with IFG had hyperinsulinemia and/or worsening of insulin resistance, and those with IGT had defective secretion in response to glucose loading, while other reports demonstrated a pronounced defect in early insulin secretion in IFG and marked insulin resistance in IGT. Insulin resistance is characterized by a decreased ability of insulin to stimulate the use of glucose by the muscle and adipose tissue, where the suppression of lipase controlled by insulin is impaired. The consequent excessive supply of FFAs further affects glucose transportation in the skeletal muscles, and inhibits insulin activity. In the liver, insulin resistance leads to increased HGP, initially compensated by increased insulin secretion. If the process persists, glucotoxicity may occur, leading to chronic hyperglycemia and clinical diabetes. The OGTT has traditionally been used to classify the status of glucose tolerance for diagnostic purposes: normal glucose tolerance (NGT), IGT and diabetes based on the 2-h PG concentration. The ADA lowered the threshold for IFG from 6.1 mmol / L to 5.6 6.1 mmol / L in order to detect more subjects with pre-diabetes. We carried out oral glucose tolerance test (OGTT-glucose / insulin) with 29 healthy female individuals for exploring parameters associated with impaired glucose regulation. We observed differences in the shape of their OGTT curves. Variations in glucose concentrations at time points 30 min, 60 min (maximum) and 90 min were observed. The fasting and 2-hr glucose concentrations for all the subjects did not differ significantly. We stratified the subjects into three groups by cluster analysis, polynomial (third order) fit and area under curve (glucose) calculations to identify and study the subjects with altered glucose metabolism. We found 1-hr GTT glucose concentration contributed in above studies more than the values of other time points. Few subjects were found to have altered glucose metabolism (IGR Group), possibly unrecognized diabetes. Almost all of the subjects in the IGR group had a family history of diabetes. Based on current WHO/ADA criteria, interpretation all cases would be considered as being normal. Since neither the current WHO nor ADA criteria make allowance for what happens to blood sugar at one hour, the glucose profile of the subjects in the cluster 1 (IGR Group) would be considered as being entirely "normal" in spite of having abnormally shaped GTT curves. We calculated several indices of ß-cell responsivity and insulin sensitivity in order to understand the altered glucose metabolism by comparing the metabolic profiles between groups. We attempted to explore the hyperbolic relationship between insulin release and ß-cell responsivity. We tried to demonstrate the significance of the cutoff value at 60min time point and the area under the curve of glucose (AUCg) during OGTT for discrimination of various degrees of glucose tolerance. The correlation between AUCg and 1-h PG concentrations were found to be high mainly in the impaired glucose regulation group making it useful. It can also be used for identifying individuals with subtypes of pre-diabetes to tailor personalized treatments. One hour OGTT glucose concentrations along with the values of insulin sensitivity indices may help us to understand gestational diabetes mellitus, PCOS and patients of undiagnosed diabetes mellitus with AMI (acute myocardial infarction). Recently, 1-h hyperglycemia (1hPG) during an oral glucose tolerance test (OGTT) with a cut point of 155 mg/dl has been indicated as a further risk factor for type2 diabetes and showed early carotid atherosclerosis. The Honolulu series of studies, showed the one-hour plasma glucose concentration to be an independent risk factor for ischemic heart disease, stroke, and sudden death. They also reported that the vascular risk attached to the one-hour glucose concentration closely followed a gradient pattern with, a direct dose-response relationship. A clearer understanding of the pathophysiologic abnormalities which characterize IGT and IFG provides insights about interventions to slow/halt the progression to type 2 diabetes. • Subjects with IFG, who manifest predominant liver insulin resistance, are most likely to benefit from agents, e.g., metformin, that reduce hepatic insulin resistance. • Subjects with IGT, who predominantly have muscle insulin resistance plus severely impaired insulin secretion, are more likely to respond to agents that improve skeletal muscle insulin resistance, such as PPAR- gamma agonists, in combination with an insulin secretagogue, such as GLP-1 analog. • Both IFG and IGT are characterized by a reduction in earlyphase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion. We conclude that although the number of subjects studied might be considered relatively small and the data preliminary, the elevated plasma glucose at one hour in the presence of an otherwise non-diabetic OGTT profile can be used as a diagnostic point in the detection and classification of glucose intolerance & as a predictor of long term macrovascular complications. Further study on subjects with elevated one-hour glucose concentration is to be done to determine the natural history of the abnormality in relation to the development of diabetic complications. The acute postprandial hyperglycemia at one hour might in itself be a risk factor. Timely effective interventions / measures and screening tests for complications at the time of diagnosis become imperative not only for early detection, but also to prevent progression to end stage disease. Life style changes/interventions utilizing low glycemic, high fibre carbohydrates may be useful in preventing and treating all diseases of insulin resistance. Metformin has been shown to lower the risk of myocardial infarction and all-cause mortality by more than 30% in patients with type2 diabetes and obesity, as well as having a beneficial effect on the lipid profile. Drugs such as ß blockers and high dose thiazides exacerbate insulin resistance unlike ACE inhibitors and β- blockers.

Item Type: Thesis (Masters)
Additional Information: Reg No. 26083653
Uncontrolled Keywords: Quantitative Assessment ; Insulin Response ; Impaired Glucose Regulation.
Subjects: PHARMACY > Pharmaceutical Biotechnology
Depositing User: Ravindran C
Date Deposited: 11 Oct 2017 05:29
Last Modified: 16 May 2018 00:31

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