Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology

The rapid rise in prevalence of type 2 diabetes mellitus (T2DM) has been driven by changes in environmental factors – primarily increased caloric intake and reduced energy expenditure – resulting in reduced whole body insulin sensitivity (often termed insulin resistance). Insulin resistance has been proposed to be a major driver of progression to T2DM. However, of 38 individual susceptibility loci for T2DM recently identified by genome wide association studies, by far the majority code for proteins involved in β-cell function. In this review, we discuss the possible reasons for the paucity of insulin resistance genes and ask whether the new genetic susceptibility data should focus attention on β-cell targets in the development of therapies for T2DM.     

One-Hour Plasma Glucose Identifies Insulin Resistance and ��-Cell Dysfunction in Individuals With Normal Glucose Tolerance: Cross-sectional data from the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study

OBJECTIVE

Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype.

RESEARCH DESIGN AND METHODS

A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study.

RESULTS

One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), β-cell glucose sensitivity (r = −0.46), and β-cell rate sensitivity (r = −0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose ≤8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower β-cell glucose sensitivity (P < 0.001), β-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, β-cell glucose sensitivity, β-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002).

CONCLUSIONS

Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced β-cell glucose sensitivity, and reduced β-cell rate sensitivity.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are states of carbohydrate metabolism intermediate between normal glucose tolerance (NGT) and type 2 diabetes, which represent two partially overlapping conditions with distinct metabolic characteristics (1,2). In IFG, there is marked hepatic insulin resistance with near-normal muscle insulin sensitivity, whereas this pattern is reversed in IGT (2). Although both conditions are characterized by reduced early-phase insulin secretion, there is an additional impairment of late-phase insulin secretion in IGT. Accordingly, individuals with IGT have a rapid early (30 min) rise in plasma glucose during an oral glucose tolerance test (OGTT) which continues to rise until 60 min (1-h plasma glucose) and thereafter remains ≥7.8 mmol/l (140 mg/dl) at 120 min (2-h plasma glucose).As longitudinal studies have demonstrated that 40% of patients who develop type 2 diabetes after 10 years have NGT at baseline (1), there may be additional information beyond conventional IFG/IGT categories that may better discriminate future progression to type 2 diabetes (3). We have noted a subset of individuals with NGT who have early glucose excursions during an OGTT as high as those observed in individuals with IGT. However, because plasma glucose concentrations decline adequately by 2 h, due to preservation of late-phase insulin secretion, these individuals do not have, by current definitions, any form of disordered carbohydrate metabolism (4). Data from the San Antonio Study have shown that β-cell glucose sensitivity and insulin sensitivity contribute to values of 2-h plasma glucose independently of each other (5); thus, we hypothesized that individuals with NGT with 1-h plasma glucose levels as high as in those with IGT might represent an intermediate phenotype of abnormal carbohydrate metabolism with either impaired insulin sensitivity or β-cell glucose sensitivity, who are potentially at increased risk of progression to type 2 diabetes.To investigate this hypothesis we analyzed cross-sectional data from the European Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study (6), examining the metabolic phenotype of individuals with NGT who had high 1-h plasma glucose excursions. We aimed to identify a new glucose tolerance subgroup who might benefit from targeted lifestyle advice and/or pharmacological intervention.     

The Impact of 3-D Models versus Animations on Perceptions of Osteoporosis and Treatment Motivation: A Randomised Trial

Background

Osteoporosis is a degenerative bone disorder that disproportionately affects older women worldwide. Raising awareness regarding osteoporosis within this demographic is significant for health promotion. Initial evidence suggests that visualisations of illness and treatment can improve illness perceptions, increase treatment motivations and even promote health behaviours. We are yet to understand whether different visualisation mediums vary in their impact on perceptions and motivations.

Purpose

We investigated whether physical models or virtual animations had a greater impact on changing perceptions of osteoporosis and treatment motivation in an at-risk population of older women.

Methods

A total of 128 women aged 50 and over were randomly assigned to view a brief presentation about osteoporosis using either 3-D printed bone models or electronic tablet animations. Illness perceptions, medication beliefs and motivations were measured at baseline and post-presentation. Mixed ANOVAs were used to identify significant changes over time between groups.

Results

There were no significant interaction effects, revealing that neither medium had a greater impact on beliefs over time. Significant main effects of time revealed that from baseline to post-presentation, both mediums increased consequence beliefs, personal and treatment control, understanding of osteoporosis, motivations to take treatment if needed and medication necessity beliefs. Timeline beliefs and medication concerns decreased over time for both groups.

Conclusions

Both 3-D models and animations of osteoporosis are equally effective in changing beliefs and treatment motivation in an at-risk population. Visualisation devices are brief, cost-effective, have high acceptability and have considerable clinical applicability to promote awareness and prevention.