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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1834-1838
Copyright © 1997 by The Endocrine Society

Clinical Studies

Alterations in the Glucose-Stimulated Insulin Secretory Dose-Response Curve and in Insulin Clearance in Nondiabetic Insulin-Resistant Individuals

Clare N. O. Jones, Dee Pei, Patricia Staris, Kenneth S. Polonsky, Y. D.-Ida Chen and Gerald M. Reaven

Departments of Medicine, Stanford University School of Medicine, Stanford, California 94305; University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637; and Shaman Pharmaceuticals, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: G. M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Plasma glucose and insulin responses to a graded iv infusion of glucose were compared in two groups of glucose-tolerant women divided on the basis of their insulin sensitivity. Resistance to insulin-mediated glucose disposal was measured using the insulin suppression test, and the women studied were chosen to represent the highest and lowest quartiles of insulin resistance seen in the normal population. The sensitivity of the pancreatic ß-cell to glucose was assessed by measuring the glucose, insulin, and C peptide concentrations in response to continuous graded iv infusions of glucose at rates of 1, 2, 3, 4, 6, and 8 mg/kg·min for 40 min each. In addition, insulin secretion rates in response to the graded glucose infusion, calculated over each sampling period, were derived from deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance. Although plasma glucose concentrations were only slightly higher throughout the glucose infusion, the insulin concentrations were approximately doubled in the insulin-resistant subjects. When expressed as a function of the molar increments in plasma glucose achieved during the glucose infusion studies, the insulin-resistant women had a 90% higher (684 ± 55 vs. 360 ± 36 pmol/L·mmol/L; P < 0.001) total integrated plasma insulin response as the glucose concentration was increased from 5 to 9 mmol/L. However, the total integrated insulin secretory rate was only increased by 37% (1494 ± 133 vs. 1093 ± 125 pmol/mmol/L·min; P < 0.05) in the insulin-resistant group. This discrepancy suggested that insulin clearance was lower in the insulin-resistant subjects, and the calculation of this value, as the ratio of the total secretion of insulin to the area under the plasma insulin curve, was significantly lower in the insulin-resistant group (1.25 ± 0.05 vs. 1.87 ± 0.16 L/min·m2; P < 0.005). These results show that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as a decrease in insulin clearance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PREVIOUS STUDIES have demonstrated a highly significant relationship in normoglycemic individuals between resistance to insulin-mediated glucose disposal and the plasma insulin response to oral glucose (1, 2, 3). Although the plasma glucose concentration is increased in normal individuals proportionate to the degree of resistance to insulin-mediated glucose disposal, the plasma insulin response to oral glucose is increased out of proportion to the coexisting plasma glucose concentration (1, 2, 3). Thus, the pancreatic ß-cell appears to adapt to and compensate for the chronic state of insulin resistance by secreting more insulin in response to a given increment in plasma glucose than would be the case in an insulin-sensitive individual. In this study we have used the graded glucose infusion protocol devised by Polonsky and associates (4, 5) to test the hypothesis that the increase in the insulin secretory response that is observed in insulin-resistant subjects is due at least in part to a shift to the left in the glucose-stimulated insulin secretory dose-response curve.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The experimental population consisted of 20 nonobese, nondiabetic, healthy women, less than 60 yr of age, recruited from the San Francisco Bay area by advertisements in local newspapers and selected from a larger group of volunteers on the basis of their degrees of insulin resistance. They were in good general health on the basis of history, physical examination, complete blood count, routine biochemical screening, and electrocardiogram. There was a family history of noninsulin-dependent diabetes in a first degree relative in 4 of the insulin-sensitive and 5 of the insulin-resistant women. The insulin-sensitive group contained 1 woman of Asian origin, 1 Latina, and 9 non-Hispanic whites, whereas the insulin-resistant group contained 1 Asian, 2 Latinas, and 6 non-Hispanic whites. None of the women had a history of gestational diabetes or obesity. This project was approved by the Stanford human subjects committee, and all women gave informed consent.

After an overnight fast, blood was drawn for measurement of plasma glucose (6) and insulin (7) concentrations before and 30, 60, 120, and 180 min after the ingestion of a 75-g oral glucose challenge. Only volunteer subjects with a normal glucose tolerance test by the National Diabetes Data Group criteria were included in the study (8).

Resistance to insulin-mediated glucose disposal was estimated by a modification (9) of the original insulin suppression test (IST) (10). After an overnight fast, iv catheters were placed in a superficial antecubital vein in each arm. One arm was used for a continuous 180-min infusion of glucose (240 mg/m2·min), somatostatin (5 µg/min), and insulin (25 mU/m2·min). Venous blood samples for glucose and insulin determinations were obtained from the contralateral arm every 30 min (to 150 min) and then every 10 min for the last 30 min of the infusion. The mean of these last 4 values was used to calculate the steady state plasma glucose (SSPG) and insulin (SSPI) concentrations. Under these experimental conditions, endogenous insulin secretion was suppressed by somatostatin, and the SSPI concentration achieved was comparable in all individuals. The SSPG provided a measure of insulin-mediated glucose disposal: the higher the SSPG, the more insulin resistant the individual. Volunteers with a SSPG concentration above 9 mmol/L were classified as being insulin resistant, whereas those with values below 5 mmol/L were classified as being insulin sensitive. This differentiation corresponds to the upper and lower quartiles, respectively, of SSPG values observed in nondiabetic individuals studied by our research group (3). On the basis of these criteria, 9 insulin-resistant and 11 insulin-sensitive women were selected for further study. These 2 groups were matched for age (44 ± 4 vs. 40 ± 2 yr) and body mass index (24.6 ± 1.1 vs. 23.3 ± 0.8 kg/m2).

Pancreatic ß-cell function was quantified by determining the insulin and C peptide responses to graded iv infusions of glucose (4, 5). After an overnight fast, iv catheters were placed in a superficial antecubital vein in each arm. One arm was used for the infusion of 20% glucose at a rate 1 mg/kg·min, followed by infusions of 2, 3, 4, 6, and 8 mg/kg·min. Each infusion rate was administered for a period of 40 min. Venous blood samples for glucose, insulin, and C peptide determinations were obtained from the contralateral arm at fasting and then 10, 20, 30, and 40 min into each glucose infusion period.

Insulin secretion rates over each sampling period were derived by deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance estimated for each subject, taking into account body surface area and age (11, 12). For each subject, the mean glucose and insulin levels during each stage of the graded glucose infusion were used to plot a graph of the insulin-glucose dose-response curve. To compare each subject’s plasma insulin response at the same plasma glucose level, the best-fit quadratic curve (least squares fit using Microsoft Deltagraph, Seattle, WA) was drawn through the data. The insulin concentration at molar increments of plasma glucose beginning at 5 mmol/L can then be obtained by interpolation. The same technique applied to the insulin secretion rate yields a plot of the insulin secretion rate at molar increments of plasma glucose.

Values for continuous variables are expressed as the mean ± SE. The SSPG and SSPI values were compared using two-tailed unpaired Student’s t tests. The areas under the glucose and insulin curves after the oral glucose challenge were calculated using the trapezoidal method, and statistical analysis was performed using two-tailed unpaired Student’s t tests. Differences between the glucose and insulin concentrations after the oral glucose challenge and the insulin secretory response to iv glucose in the two groups were compared by two-way ANOVA, using SAS software (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The SSPG and SSPI of the two groups during the IST are shown in Fig. 1Go. The SSPG values were over 3 times higher in the insulin-resistant women, with no overlap between the two groups (10.95 ± 0.61 vs. 3.42 ± 0.14 mmol/L; P < 0.001). SSPI values were also somewhat higher in the insulin-resistant individuals (280 ± 15 vs. 220 ± 13 pmol/L; P < 0.005) despite the fact that a similar amount of insulin was infused in both groups.



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  		Figure 1. SSPG (A) and SSPI (B) concentrations at the end of the IST in the insulin-resistant ({blacksquare}) and insulin-sensitive ( ) groups.

 
Plasma glucose and insulin concentrations before and after the oral glucose challenge are shown in Fig. 2Go. Although all volunteers had normal glucose tolerance, the total area under the glucose response curve was 25% greater in the insulin-resistant women (21.5 ± 0.35 vs. 16.3 ± 0.67 mmol/L·h; P < 0.001). However, the plasma insulin response to oral glucose was more than twice as high in the insulin-resistant group (1115 ± 160 vs. 544 ± 60 pmol/L·h; P < 0 01).



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  		Figure 2. Plasma glucose (A) and insulin (B) concentrations before and after a 75-g oral glucose challenge in the insulin-resistant (···•···) and insulin-sensitive (—•—) groups.

 
The mean plasma glucose, insulin, and C peptide concentrations achieved at each stage of the graded glucose infusion shown in Fig. 3Go indicate that the insulin-resistant women had a slightly higher plasma glucose (averaging ~0.7 mmol/L higher) at any given glucose infusion rate (P = 0.06, by two-way ANOVA). Despite the relative similarity in plasma glucose concentrations, plasma insulin concentrations at the end of each glucose infusion rate were more than twice as high in the insulin-resistant subjects (P < 0.001, by two-way ANOVA). The relative increase in the plasma C peptide concentrations was less marked, being approximately 70% higher in the insulin-resistant women (P < 0.001, by two-way ANOVA).



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  		Figure 3. Plasma glucose (A), insulin (B), and C peptide (C) concentrations at each stage of the graded glucose infusion in the insulin-resistant (···•···) and insulin-sensitive (—•—) groups. Note that the x-axis is drawn to be linear with increasing glucose infusion rate rather than with time.

 
Figure 4Go shows plasma insulin concentrations and insulin secretion rates at molar increments in plasma glucose. The insulin-resistant subjects had higher plasma insulin concentrations and insulin secretion rates as the plasma glucose concentration was increased above 5 mmol/L, and in both cases, the increases were statistically significant (P < 0.001, by ANOVA). The magnitude of these differences can be evaluated by comparing the total integrated responses as the plasma glucose concentration was increased from 5 to 9 mmol/L. In the case of plasma insulin (Fig. 4Go, left panel), there was an approximately 90% increase in the total integrated response of the insulin-resistant individuals (684 ± 55 vs. 360 ± 36 pmol/L·mmol/L; P < 0.001, by t test), whereas the increase in the insulin secretion rate was approximately half as great in these subjects (1494 ± 133 vs. 1093 ± 125 pmol/mmol/L·min; P < 0.05, by t test).



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  		Figure 4. Plasma insulin concentrations (A) and insulin secretion rates (B) in response to molar increments in the plasma glucose concentration during the graded glucose infusion in the insulin-resistant (···•···) and insulin-sensitive (—•—) groups.

 
The observation that the increase in the plasma insulin concentration was relatively greater than the increase in the insulin secretion rate suggested that the insulin-resistant subjects also had a decrease in the rate of insulin clearance, a possibility supported by the fact that they also had higher SSPI concentrations (see Fig. 1Go). One way to estimate insulin clearance during the graded glucose infusions is to calculate the ratio of the total production of insulin to the area under the peripheral insulin curve (13). This nonsteady state estimate of endogenous (end) insulin metabolic clearance rate (MCR) was significantly lower in the insulin-resistant subjects (MCRend adjusted for body surface area: resistant vs. sensitive, 1.25 ± 0.05 vs. 1.87 ± 0.16 L/min·m2; P < 0.005). It is also possible to estimate insulin clearance during the steady state conditions of the insulin suppression test. In this instance, the insulin clearance will equal the rate of infusion of insulin divided by the SSPI concentration. This calculation also indicated that exogenous (ex) insulin clearance of the insulin-resistant subjects was significantly lower (steady state MCRex, 0.54 ± 0.02 vs. 0.64 ± 0.03 L/min·m2; P < 0.02). Although both methods for calculating insulin clearance indicate that the process was significantly reduced in the insulin-resistant subjects, the quantitative relationships were not the same. This is to be expected because the first calculates the clearance of endogenously produced insulin secreted into the portal circulation and thus exposed to extensive first pass metabolism by the liver before reaching the systemic circulation. The second represents the clearance of exogenously infused insulin when endogenous secretion is suppressed by somatostatin, a situation in which the portal and arterial concentrations of insulin are identical, and clearance by the liver and other peripheral tissues (largely the kidneys) occurs in parallel. The two are related in the following way: MCRend = MCRex/(1 - Eh), where Eh indicates the hepatic extraction ratio (14). As the hepatic extraction ratio is approximately 60% at physiological insulin concentrations (15), we would expect endogenous insulin clearance to be approximately 2.5 times the exogenous clearance; our results agree fairly well with this. Thus, regardless of the method employed, there appears to be a defect in the removal of insulin from plasma in insulin-resistant subjects.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results in Fig. 2Go show that the plasma insulin response to an oral glucose load is increased relatively more than the coexisting plasma glucose concentration in insulin-resistant compared to insulin-sensitive subjects. However, the contribution of ß-cell sensitivity to glucose is difficult to analyze in this situation because the glycemic stimulus to the ß-cells is not matched, and other factors, such as variable gastric emptying and unquantified neural and enteric stimuli, will complicate the interpretation. The graded glucose infusion allows comparison of the insulin secretory responses at matched plasma glucose concentrations and in response to a slowly rising plasma glucose level within the physiological range. Using this technique, it is clear that the insulin secretory response is significantly higher in insulin-resistant subjects. As such, these data support the view that an adaptive response occurs in the ß-cells of insulin-resistant subjects, permitting them to maintain normal glucose tolerance by responding in an accentuated manner to a glucose challenge. Consistent with the idea of an adaptive response on the part of the ß-cell to variations in insulin-mediated glucose disposal is the situation in exercise-trained subjects, in whom a decrease in the insulin response to both oral and iv glucose appears to represent an adaptation to their enhanced insulin sensitivity (16, 17, 18).

The results presented also demonstrated a decrease in insulin clearance in insulin-resistant women when determined both under the steady state condition of exogenous infusion of insulin during the IST and during the nonsteady state endogenous production of insulin in the grade glucose infusion. The fact that the estimated decrease in clearance was greater when based on the endogenous vs. the exogenous approach (33% vs. 15%) may also be due to incomplete suppression of the ß-cell by somatostatin. As we did not measure C peptide levels during the IST, we cannot resolve this issue for certain, although past experience with the same infusion rate of somatostatin suggests that C peptide levels are indeed satisfactorily suppressed (9). In any event, the fact that insulin clearance was decreased in insulin-resistant individuals when estimated by either approach is consistent with previous demonstrations of a decrease in insulin clearance in two different ethnic groups at high risk for future diabetes [Mexican-Americans (19) and African-Americans (20)], in nondiabetic off-spring of patients with noninsulin-dependent diabetes (21), and in obesity (22).

In conclusion, it is apparent from the results presented that the plasma insulin response to a glucose challenge is a complex function not only of the coexisting plasma glucose concentration, but of both the ß-cell sensitivity to glucose and the rate of insulin clearance, which, in turn, are related to the degree of resistance to insulin-mediated glucose disposal. Both the enhanced ß-cell sensitivity to glucose and the reduced insulin clearance of insulin-resistant subjects may be viewed as an adaptive response, permitting them to maintain normal glucose tolerance in response to a glucose challenge. Although it is tempting to regard this as an autoregulatory mechanism, a cross-sectional study such as this cannot dissect which abnormality is primary and which is an adaptation to it. Finally, two important caveats must be made concerning our results. In the first place, the technique used to calculate insulin secretion used a model containing parameters for C peptide kinetics that were estimated for each subject rather than measured individually. However, this approach should give estimates of insulin secretion rates that differ by only 10–12% for each individual and 1–2% for group means from those obtained with individual parameters, even in a sample heterogeneous in terms of insulin resistance (12). Secondly, insulin secretion was measured at the end of each 40 min of a stepped glucose infusion, and it is possible that longer infusion periods will lead to different estimates of the ß-cell secretory response to incremental increases in plasma glucose. On the other hand, unless the dynamics of insulin secretion and clearance changed disproportionately in one of the two experimental groups, the qualitative nature of our findings would not be confounded. Thus, we believe it likely that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as from a decrease in insulin clearance.

Received September 23, 1996.

Revised February 3, 1997.

Accepted February 19, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals