Thresholds of oxidative stress in newly diagnosed diabetic patients on intensive glucose-control therapy.

Rashmi Kulkarni,Jhankar Acharya,Pranay Goel,Saroj Ghaskadbi

doi:10.1371/journal.pone.0100897

Rashmi Kulkarni, Jhankar Acharya + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0100897

Copy DOI

Abstract

Cellular and animal studies suggest that oxidative stress could be the central defect underlying both beta-cell dysfunction and insulin resistance in type 2 diabetes mellitus. A reduction of glycemic stress in diabetic patients on therapy alleviates systemic oxidative stress and improves insulin resistance and beta-cell secretion. Monitoring oxidative stress systematically with glucose can potentially identify an individual's recovery trajectory. To determine a quantitative model of serial changes in oxidative stress, as measured via the antioxidant glutathione, we followed patients newly diagnosed with diabetes over 8 weeks of starting anti-diabetic treatment. We developed a mathematical model which shows recovery is marked with a quantal response. For each individual the model predicts three theoretical quantities: an estimate of maximal glutathione at low stress, a glucose threshold for half-maximal glutathione, and a rate at which recovery progresses. Individual patients are seen to vary considerably in their response to glucose control. Thus, model estimates can potentially be used to determine whether an individual patient's response is better or worse than average in terms of each of these indices; they can therefore be useful in reassessing treatment strategy. We hypothesize that this method can aid the personalization of effective targets of glucose control in anti-diabetic therapy.

Highlights

Fasting plasma glucose (FPG) and glycated hemoglobin (HbA1C) are the central measures of diagnosis of Type 2 diabetes (FPG $ 126 mg/dl (7.0 mmol/L); HbA1C $6.5%) and prediabetic states (FPG 100–125 mg/dl (5.5–6.9 mmol/L); HbA1C 5.7–6.4%)
Metabolic imbalance challenges redox balance and impairs insulin sensitivity as well as insulin secretion, and glucose control ameliorates these conditions as measured through the homeostatic model assessment index, HOMA
Increases in glycolytic flux are expected to lead to increases in reactive oxygen species (ROS) via the TCA cycle, which are at least partially scavenged by glutathione together with other antioxidants; a decrease in glutathione concentration is to be expected with hyperglycemia

Summary

Introduction

Fasting plasma glucose (FPG) and glycated hemoglobin (HbA1C) are the central measures of diagnosis of Type 2 diabetes (FPG $ 126 mg/dl (7.0 mmol/L); HbA1C $6.5%) and prediabetic states (FPG 100–125 mg/dl (5.5–6.9 mmol/L); HbA1C 5.7–6.4%). The clinical management of diabetes focuses on the control of hyperglycemia using a combination of nutritional and pharmacological therapies. Beginning with the current (2013) recommended Standards of Medical Care in Diabetes the ADA recommends a ‘‘patient-centred and personalized care’’ regimen to determine appropriate targets of glycemic control. Beta-cell dysfunction and insulin resistance (IR) together underlie the development of diabetes, there may be differences between their relative contributions in Asian and Westernized populations [2,3]. The development of insulin resistance is the primary event in the metabolic syndrome; with time, if beta-cell failure occurs as well, these results in frank hyperglycemia. Hyperglycemia-induced OS has been clearly indicated in deterioration of beta-cell function [14]; controlling OS either by using antioxidants [15,16] or by overexpressing antioxidant enzymes [17,18] restores beta-cell function

Methods

Results

Conclusion