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Published in final edited form as: Clin Endocrinol (Oxf). 2012 Feb;76(2):212–219. doi: 10.1111/j.1365-2265.2011.04159.x

A Concerted Decline in Insulin Secretion and Action occurs across the Spectrum of Fasting and Post-Challenge Glucose Concentrations

Airani Sathananthan 1,*, Chiara Dalla Man 2,*, Alan R Zinsmeister 3, Michael Camilleri 4, Richard J Rodeheffer 5, Gianna Toffolo 2, Claudio Cobelli 2, Robert A Rizza 1, Adrian Vella 1
PMCID: PMC3983528  NIHMSID: NIHMS569220  PMID: 21707690

Abstract

Aims/hypothesis:

Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the pre-diabetic range of fasting glucose.

Methods:

We studied a cohort of 173 individuals with a fasting glucose concentration < 7.0mmol/L after an overnight fast using a 75g oral glucose tolerance test (OGTT). Insulin action (Si) was estimated using the oral glucose minimal model and β-cell responsitivity indices (ϕ) were estimated by using the oral C-peptide minimal model. The Disposition Index (DI) for each individual was calculated. The relationship of DI, ϕ and Si with fasting and post-challenge glucose, as well as other covariates, were explored using a generalized linear regression model.

Results:

In this cross-sectional study, Si and DI were inversely related to fasting glucose concentrations. On the other hand, ϕ was unrelated to fasting glucose concentrations. Si, ϕ and DI were all inversely related to area-above-basal glucose concentrations after glucose challenge. Multiple parameters including body composition and gender contributed to the variability of Si and DI at a given fasting or post-challenge glucose concentration.

Conclusions/Interpretation:

Defects in insulin secretion and action interact with body composition and gender to influence post-challenge glucose concentrations. There is considerable heterogeneity of insulin secretion and action for a given fasting glucose likely because of patient subsets with isolated IFG and normal glucose tolerance.

Keywords: Insulin Secretion, Insulin Action, Impaired Fasting Glucose, Disposition Index, Hepatic Extraction, Pre-diabetes

INTRODUCTION

The states of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) place affected individuals at higher risk of progression to overt type 2 diabetes 1, 2 and are associated with an increased incidence of cardiovascular disease 3. Understanding the defects that lead to these pre-diabetic states may help better predict individual risk of diabetes as well as increase understanding of diabetes pathogenesis thereby leading to targeted strategies for prevention and treatment. For example, in Olmsted County, MN ~ 40% of people with a fasting glucose in the 6.9 – 7.0 mmol/l range progress to overt diabetes within a 10 year period 4. While this is higher than the rate of progression (5%) in those with a fasting glucose < 5.3 mmol/l (over a 10 year period), the reasons underlying the heterogeneity of progression to diabetes in people with IFG remain uncertain.

The presence of IGT may be a better predictor of future diabetes risk than IFG, either because the response to an oral glucose challenge is more representative of carbohydrate homeostasis in a given individual, or IFG and IGT represents two distinct phenotypes 5. Indeed prior studies have suggested the existence of subjects with isolated IFG who have normal glucose tolerance and β-cell function 6, 7. In healthy individuals, glucose concentrations are closely regulated by insulin in a feedback-control system whereby insulin is secreted in response to rising glucose concentrations and inhibited when glucose concentrations fall. The integrity of this system depends on the ability of insulin to suppress glucose production and stimulate glucose uptake (insulin action) and the ability of the beta cell to secrete insulin in response to glucose (β-cell responsivity). Both of these processes are impaired in type 2 diabetes 8, and in IFG 9-12. However, the relative importance of these processes to the development of diabetes has been uncertain. Cross-sectional data has suggested that defects in insulin action ultimately lead to the development of diabetes - insulin secretion increases to adapt to progressively impaired insulin action up to a point beyond which this compensatory response fails and diabetes develops – the so-called ‘Starling Curve of the pancreas’13.

Measurements of insulin secretion that utilize peripheral insulin concentrations correlate weakly with acute insulin response 14 in part because insulin appearing in the systemic circulation has already undergone hepatic extraction 15. Moreover, hepatic insulin extraction may be altered by factors such as obesity 16, 17, ethnicity 18,or β-cell function 19 which confound interpretation of such measures in cross-sectional studies. In an attempt to relate insulin secretion to the prevailing insulin action, Bergman et al. developed the concept of Disposition Index (DI) to embody the (hyperbolic) relationship between the 2 parameters20. However, the assumptions that underlie the calculation of DI have been challenged by some authors suggesting that the relationship between insulin secretion and action differs across differing states of glucose tolerance 21. However, this contention is based on the measurement of insulin secretion and of insulin action on different days under differing conditions which may not be relevant to physiologic stimuli such as meal ingestion 22, 23.

Previously, we had combined the oral c-peptide and insulin minimal models to compare insulin secretion and action in people with normal fasting glucose/glucose tolerance and IFG, in response to a labeled mixed meal. In subjects with IFG and IGT, postprandial hyperglycemia was associated with decreases in both insulin secretion and action. These data implied that hyperglycemia resulted when defects in insulin action could not be adequately compensated by increases in insulin secretion 7. However, those studies involved a relatively small number of subjects and hepatic insulin extraction was not directly measured. The present experiments sought to clarify the relative contributions of alterations in insulin secretion and action to postprandial hyperglycemia and to specifically determine if there was a threshold wherein insulin secretion follows the ‘pancreatic Starling Curve’ i.e. it ceases to increase and then decreases, leading to hyperglycemia. In order to do so, we measured insulin secretion, hepatic extraction and insulin action in response to a 75 gram glucose challenge in a large number of subjects across the spectrum of fasting glucose and glucose tolerance 24, 25. Multivariate analyses were undertaken to identify covariates that might affect these parameters in non-diabetic individuals.

METHODS

Subjects

After approval by the Mayo Institutional Review Board, subjects who previously participated in a population-based, cross-sectional study 26 were contacted by means of a letter and invited to participate. Subjects with a prior diagnosis of diabetes or a fasting glucose ≥ 126mg/dL (>7mmol/l) at the time of screening were excluded, as were those taking medications that could affect glucose metabolism. A total of 173 subjects (92 women, 81 men) gave informed written consent to participate in the study. All subjects were in good health and were at a stable weight and did not engage in regular vigorous exercise. All subjects were instructed to follow a weight-maintenance diet containing 55% carbohydrate, 30% fat and 15% protein for at least three days prior to the study. Despite a fasting glucose < 7mmol/l at the time of screening, one subject presented with a fasting glucose of 7.4mmol/l on the day of study.

Experimental Design

Body composition was measured using dual-energy X-ray absorptiometry (DPX scanner; Lunar, Madison, WI) at the time of screening. Participating subjects were admitted to the Mayo Clinic Clinical Research Unit at 0630 after an overnight fast. An 18-gauge cannula was inserted in a retrograde fashion into a dorsal hand vein of the non-dominant arm. The hand was placed in a heated box (55°C) to enable sampling of arterialized venous blood. At 0700 (time 0), subjects ingested 75g of glucose over a period of five minutes. Blood was drawn for glucose and hormone measurements at 0, 10, 20, 30, 60, 90 and 120 minutes.

Analytical techniques

Arterialized plasma samples were placed in ice, centrifuged at 4°C, separated, and stored at −20°C until assay. Plasma glucose concentrations were measured using a glucose oxidase method (Analox Instruments Inc., Lunenburg, MA). Plasma insulin concentrations were measured using a chemiluminescence assay with reagents obtained from Beckman (Access Assay, Beckman, Chaska, MN). Plasma C-peptide concentrations were measured by radioimmunoassay (Linco Research, St. Louis, MO).

Calculations

Net insulin sensitivity (Si), which measures the overall effect of insulin to stimulate glucose disposal and suppress endogenous glucose production was estimated from plasma insulin and glucose concentrations using the unlabeled oral minimal model 24. Beta Cell responsivity indexes were estimated from the plasma glucose and C-peptide concentrations observed during the experiment by using the oral C-peptide minimal model, incorporating age-associated changes in C-peptide kinetics as measured by Van Cauter et al. 27. The model assumes that insulin secretion is comprised of a static and dynamic component. The parameter ϕdynamic, defines the dynamic responsivity index and is proportional to the rate of increase of glucose concentrations. ϕstatic represents the provision of new insulin to the releasable pool. An index of total beta-cell responsivity to glucose (ϕ) is derived from both indices. Disposition indices (DI) were subsequently calculated from ϕ and Si as reviewed previously 23.

Statistical analysis

The aim of the analyses was to examine the relationship between glucose and DITotal. This was achieved by evaluating various generalized linear regression models for predicting DITotal using plasma glucose concentrations and other relevant covariates. Locally Weighted Robust Scatterplot Smoothing (LOWESS) splines were fitted to scatter plot data to provide guidance on the terms to include in the regression models (See Appendix). The distribution of DI was positively skewed and the generalized linear regression models for predicting DI assumed a gamma distribution for DI. The models employed an identity link function incorporating gender (1=Males, 0=Females) and baseline plasma glucose (Glucose0) in all models.

Several models which included BMI or percent body fat, plasma glucose at 120 minutes (Glucose120), post-challenge glucose excursion expressed as area above baseline (AAB) – calculated using the trapezoidal rule - were also examined (GlucoseAAB). The overall fit of the model for predicting DI was assessed by computing the (Pearson linear) correlation (r) between the observed DI and the model-predicted disposition index – DIPredicted. A similar correlation was computed between the (observed) measured Si and a predicted measure of insulin action - Si-Predicted - calculated by dividing DIPredicted by ϕ. The associations between several covariates and insulin secretion (ϕ), insulin action (Si), and DI were also summarized via Spearman correlation coefficients (Rs).

We subsequently used repeated cross validation to evaluate the models. To do so, a “development” subset (66% of the total cohort) was randomly selected stratified by gender and the distribution of DI (categorized using quartiles) with the remaining 34% kept as a “validation” subset. The generalized linear regression model parameters were estimated using the development subset and then applied to the data in the validation subset. This was repeated 100 times. The distribution of correlation coefficients (e.g. between observed DIvalues and DI Predicted values in the validation subset) was then summarized (median [range]). All other data are presented as means ± SEM unless otherwise noted.

RESULTS

Subject were initially categorized by fasting and 120 minute glucose values (NFG = normal fasting glucose i.e. < 5.56 mmol/l, NGT = normal glucose tolerance < 7.78 mmol/l, IFG = impaired fasting glucose > 5.56 mmol/l < 7.0 mmol/l, IGT = impaired glucose tolerance > 7.78 mmol/l < 11.1 mmol/l, DM = > 11.1 mmol/l). The mean fasting glucose for NFG/NGT, IFG/NGT, NFG/IGT, IFG/IGT and IFG/DM was 5.24 ± 0.04, 5.92 ± 0.06, 5.28 ± 0.04, 5.94 ± 0.04 and 6.29 ± 0.13 mmol/l respectively. Similarly, the mean 120minute glucose value for NFG/NGT, IFG/NGT, NFG/IGT, IFG/IGT and IFG/DM was 6.87 ± 0.10, 6.45 ± 0.18, 9.45 ± 0.20, 8.94 ± 0.13 and 13.16 ± 0.31 mmol/l respectively.

Insulin action (Si), insulin secretion (ϕ) and Disposition Indices (DI) across a categorical classification of pre-diabetes (Figure 1 and Table 1)

Figure 1.

Figure 1

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Insulin action (top panel), insulin secretion (middle panel) and disposition index (lower panel) across groups classified by fasting glucose and glucose tolerance status. NFG = Normal Fasting Glucose i.e. < 5.56 mmol/l, IFG = Impaired Fasting Glucose i.e. > 5.56 and < 7.0 mmol/l. NGT = Normal Glucose Tolerance i.e. 2-hour post OGTT glucose < 7.78 mmol/l, IGT = Impaired Glucose Tolerance > 7.78 and < 11.1 mmol/l, DM = Diabetes Mellitus > 11.1 mmol/l.

Table 1.

Subject characteristics and indices of insulin secretion and action according to fasting and 120 minute glucose values (NFG = normal fasting glucose i.e. < 5.56 mmol/l, NGT = normal glucose tolerance < 7.78 mmol/l, IFG = impaired fasting glucose > 5.56 mmol/l < 7.0 mmol/l, IGT = impaired glucose tolerance > 7.78 mmol/l < 11.1 mmol/l, DM = > 11.1 mmol/l). Data represent Mean ± SEM. P* = p-value calculated by ANOVA. P# = p-value calculated by t-test in comparison to NFG / NGT.

NFG /
NGT		 IFG / NGT NFG / IGT IFG / IGT IFG / DM P*
n 41 17 46 53 16
Gender (M / F) 19 / 22 10 / 7 14 / 32 30 / 23 8 / 8
Age (years) 64.1 ± 1.0 62.1 ± 2.0 68.2 ± 1.1 67.3 ± 1.0 68.4 ± 1.7 < 0.01
P# 0.31 0.008 0.03 0.03
BMI (kg/m2) 26.0 ± 0.7 28.4 ± 0.8 25.9 ± 0.6 29.0 ± 0.7 28.0 ± 0.9 < 0.01
P# 0.04 0.94 0.003 0.10
Body Fat (%) 38.4 ± 1.6 40.3 ± 2.4 41.0 ± 1.3 41.9 ± 1.2 43.3 ± 2.4 0.33
ϕd(10−9) 670 ± 73 559 ± 77 502 ± 37 605 ± 37 377 ± 61 0.02
P# 0.38 0.04 0.41 0.02
ϕs (10−9 min−1) 48 ± 2 57 ± 7 42 ± 3 51 ± 3 38 ± 3 0.02
P# 0.12 0.13 0.52 0.01
ϕ (10−9 min−1) 55.6 ± 2.8 63.8 ± 7.5 46.5 ± 3.4 56.6 ± 3.1 40.8 ± 2.7 < 0.01
P# 0.21 0.05 0.82 0.003
Si (10 −4
dl/kg/min/μU/ml) 		20.6 ± 2.3 18.4 ± 2.2 10.8 ± 1.0 8.7 ± 1.0 3.1 ± 0.8 < 0.01
P# 0.57 1.3 × 10−4 1.9 × 10−6 2.3 × 10−5
DI(10−14 dl/kg/min−2
per pmol/l) 		1709 ± 172 1920 ± 321 804 ± 98 682 ± 63 211 ± 50 < 0.01
P# 0.53 1.0 × 10−5 2.2 × 10−8 1.7 × 10−6
Hepatic Extraction
(%) 		42.5 ± 2 47.0 ± 4 48.7 ± 2 38.3 ± 3 40.0 ± 4 0.02
P# 0.24 0.03 0.25 0.52
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Although insulin action (Si) was associated overall with subgroup status, subjects with isolated IFG did not differ significantly form NFG / NGT subjects. However, Si was significantly impaired in subjects with IGT. (figure 1, upper panel). Insulin secretion (ϕ) differed from NFG / NGT subjects in NFG / IGT and IFG / DM subjects (figure 1, middle panel). However, when ϕ was expressed as function of Si as a Disposition Index (DI) this differed from that observed in NFG / NGT subjects in all subjects with IGT(figure 1, lower panel).

Relationship of insulin action (Si), insulin secretion (ϕ) and Disposition Indices (DI) with fasting and postprandial glucose concentrations (Figure2)

Figure 2.

Figure 2

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Relationship of Insulin action (top panel), insulin secretion (middle panel) and disposition index (lower panel) with fasting glucose concentrations - Glucose0 = Plasma glucose at 0 minutes (left) and area-above-basal after oral glucose challenge - GlucoseAAB (right). The inset panels represent the rank transformed values of Si, ϕ and DI plotted against fasting and area above basal glucose values.

Insulin action (Si) was inversely related (Rs = −0.37, p<0.001) to fasting glucose concentrations and (figure 2, left upper panel). Similarly, Si was inversely related (Rs = −0.58, p<0.001) to area above basal glucose concentrations (right upper panel).

Insulin secretion (ϕ) did not exhibit a relationship (Rs = 0.10, p=0.20) with fasting glucose (left middle panel). In contrast, Insulin secretion (ϕ) was inversely related (Rs = −0.36, p<0.001) to area above basal glucose concentrations (right, middle panel).

However, when ϕ was expressed as function of Si as the Disposition Index (DI) an inverse relationship with both fasting glucose (Rs =−0.32, p<0.001) and glucose area above basal (Rs= −0.73, p<0.001) were observed (left and right lower panel respectively).

Relationship of Insulin action (Si) with % Body Fat and gender (Figure 3)

Figure 3.

Figure 3

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Relationship of measured Si with % Body Fat in males (●) and females (○).The regression line for males (dashed) and females (solid) are included.

Insulin action (Si) was inversely related to % body fat in both females (Rs = −0.48) and males (Rs = −0.18). However, for a given % Body Fat, females exhibit a decreased Si compared to males.

Relationship of Disposition Index adjusted for covariates with fasting and postprandial glucose concentrations (Figure 4)

Figure 4.

Figure 4

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Relationship of Disposition index, adjusted for gender, %body fat and GlucoseAAB, with fasting glucose concentrations (top panel), and relationship of Disposition index, adjusted for gender, %body fat and Glucose0, and area-above-basal after oral glucose challenge (bottom panel).

The (independent) relationship of DI with fasting glucose (r = −0.06, p=0.45), adjusted for gender, %body fat and GlucoseAAB - is shown in Figure 4 (upper panel), and the corresponding (independent) relationship of DI with GlucoseAAB (r = −0.73, p<0.001), again adjusted for gender, %body fat and Glucose0, is shown in Figure 4 (lower panel).

Relationship of Disposition Index to Hepatic Extraction of insulin (Figure 5)

Figure 5.

Figure 5

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Relationship of Hepatic Extraction of secreted insulin (HE) with Disposition Index.

Hepatic Extraction (HE) was calculated as previously described 25 and exhibited a direct relationship with DI (Rs= 0.39, p<0.001). Higher hepatic extraction of secreted insulin was observed at higher values of DI. Incorporating hepatic extraction in the generalized linear regression model (See Appendix) indicated hepatic extraction was a significant predictor (p<0.001), but the overall correlation of observed DI vs. DIPredicted only increased to 0.87 (from 0.86) and thus did not appreciably improve the prediction of DI shown in Appendix Figure 2.

DISCUSSION

In this cross-sectional sample of non-diabetic individuals, when insulin secretion (ϕ) is expressed as a function of insulin action (Si), the resulting disposition index (DI) is inversely related to both fasting and post-challenge glucose concentrations. This supports the prior observation that both defects in insulin secretion and action contribute to the development of diabetes 7. In this study population, there does not appear to be a specific threshold of fasting and post-challenge glucose concentration associated with decreased insulin secretion and action, whether this is expressed as DI or the constituent indices (ϕ, Si) are examined separately. Of note, for a given % Body Fat, females exhibit a decreased Si compared to males, illustrating the importance of gender as a covariate in determining insulin secretion and action.

Despite adjusting for covariates, there is considerable inter-individual variation in Disposition Index especially at the lower end of fasting blood glucose concentrations. An obvious explanation is that individuals with NFG may have normal or impaired glucose tolerance and individuals with IFG may have normal, impaired glucose tolerance or 2-hour glucose concentrations in the diabetic range. This variation cannot be wholly accounted for by age, gender, weight and body composition and it remains to be ascertained whether other unmeasured covariates can contribute to the observed variability of DI. Genetic association studies have implicated multiple genes in the pathogenesis of type 2 diabetes 28 as well as loci that affect fasting glucose concentrations independently of glucose tolerance or diabetes risk 28, 29. Taken together with the current and prior observations 7, 10 that people with isolated IFG have normal β-cell function this reinforces the notion that IFG and IGT may have distinct pathophysiology 5, with isolated IFG explained by altered set-point regulation of fasting glucose.

As a group, individuals characterized solely by the presence of IFG have defects in insulin secretion and insulin action 9-12. However, more recently, in a cohort of 3,450 individuals with NGT, glucose concentrations one hour after glucose challenge were a better predictor of diabetes risk than fasting concentrations, underlining the heterogeneity of glucose tolerance, β-cell function and diabetes risk in people with IFG 30. Indeed in the present data, when DI was adjusted for covariates such as age, weight, post-challenge glucose and gender, there was no relationship with fasting glucose concentrations. The indices of insulin secretion, unlike those of insulin action, were unrelated to fasting glucose concentrations, although inappropriate for the prevailing insulin action.

In contrast, Abdul-Ghani 31 and Utzschneider 32 reported that disposition indices (insulin secretion expressed as a function of insulin action) measured respectively with an oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were decreased in individuals with IFG. Defects in insulin secretion, rather than action were the primary cause of decrease in DI. In support of these findings, Ritzel et al. reported a curvilinear relationship between β-cell volume (measured from autopsy specimen) and fasting blood glucose concentration, suggesting that small decreases in β-cell numbers may have large adverse effects on glucose concentrations 33.There are, however, limitations to be taken into account when interpreting these studies. Abdul-Ghani et al. utilized a measure of insulin secretion that is weakly correlated with acute insulin response and did not comment on the relationship of insulin action to fasting glucose concentrations 14. Utzschneider et al. measured insulin secretion following an intravenous bolus of glucose; the studies could not determine whether individuals with IFG also had impaired glucose tolerance (IGT) 32. The autopsy data discussed above was obtained from obese subjects (Body Mass Index (BMI) > 27 kg/m2) in whom no data on individual glucose tolerance was available 33.It is also important to appreciate that insulin secretion as measured by the oral C-peptide minimal model is dependent on the nature of the stimulus. The response to an intravenous glucose tolerance test (IVGTT) likely tests different compartments of the insulin secretory process as compared to more physiologic oral challenges, hence the relatively poor correlation of ϕdynamic with 1st phase insulin secretion (ϕ1) and that of ϕstatic with the 2nd phase of insulin secretion (ϕ2) measured by IVGTT 22, 23. This distinction needs to be borne in mind when comparing DI across studies 23.

Of note, hepatic extraction of insulin increased as disposition indices rose. Although this was not an important covariate in DI (see appendix), it underscores the unreliability of peripheral measures of insulin secretion (i.e. based on insulin concentrations) since peripheral insulin concentrations variably reflect portal insulin concentrations (as derived from peripheral C-peptide concentrations). Reliance on peripheral insulin concentrations as a surrogate of insulin secretion in individuals with widely differing degrees of glucose tolerance (and therefore hepatic extraction) likely introduces a systematic error in such a comparison. This phenomenon has been observed previously where hepatic extraction in the basal state as well as during glucose infusion rises in proportion to insulin secretory-burst mass 19, likely due to insulin-receptor binding kinetics 34. This would be in keeping with the suggestion that insulin secretory pulses are necessary for the maintenance of hepatocyte insulin receptors 35 and the observation that insulin pulsatility 36 and hepatic insulin extraction 37 are decreased in type 2 diabetes.

In conclusion, our study of insulin secretion and action and their relationship to impaired fasting glucose and impaired glucose tolerance demonstrates that the relationship is not characterized by a defined threshold but is continuous across the entire spectrum. Moreover, fasting glucose concentrations may be a poor marker for the presence or absence of β-cell dysfunction in individuals with IFG. The observation of a parallel decline in insulin secretion and action across the spectrum of pre-diabetes in our study suggests the inter-relatedness of these processes. The failure of insulin secretion to compensate for defective insulin action seems to be apparent even in patients with mild hyperglycemia and declines in concert with decreasing insulin action. Future interventional studies using an acute intervention that alters one parameter e.g. insulin action will be necessary to dissect the relationship between insulin secretion and insulin action across the spectrum of prediabetes.

Supplementary Material

Appendix

ACKNOWLEDGMENTS

Grant Support: The authors acknowledge the support of the Mayo Clinic CTSA grant (RR24150), Minnesota Obesity Center grant (DK50456), the Mayo Clinic CR20 program (grant to Dr Vella); Dr. Vella is supported by DK78646, Dr. Rizza by DK29953, and Dr Camilleri DK 67071. The original cohort development for the Olmsted County Heart Function Study was funded by HL-55502.

Abbreviations

AAB

Area Above Basal

BMI

Body Mass Index

DI

Disposition Index

DM

Diabetes Mellitus

IFG

Impaired Fasting Glucose

IGT

Impaired Glucose Tolerance

IVGTT

Intravenous Glucose Tolerance Test

LOWESS

Locally Weighted Robust Scatterplot Smoothing

OGTT

Oral Glucose Tolerance Test

Footnotes

DUALITY OF INTEREST

The authors have no relevant conflict of interest to disclose.

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Appendix
NIHMS569220-supplement-Appendix.doc (689.5KB, doc)

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