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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2551
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3854-3860
Copyright © 2007 by The Endocrine Society

The Association of Fasting Insulin Concentrations and Colonic Neoplasms in Acromegaly: A Colonoscopy-Based Study in 210 Patients

Annamaria Colao, Rosario Pivonello, Renata S. Auriemma, Mariano Galdiero, Diego Ferone, Francesco Minuto, Paolo Marzullo and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology (A.C., R.P., R.S.A., M.G., G.L.), Section of Endocrinology, University "Federico II" of Naples, 80131 Naples, Italy; Department of Endocrine and Metabolic Sciences and Center of Excellence for Biomedical Research (D.F., F.M.), University of Genova, 5-16126 Genova, Italy; and Division of General Medicine (P.M.), Ospedale San Giuseppe, Istituto Auxologico Italiano, 28921 Verbania, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular, Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail colao{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Hyperinsulinemia is associated with colon carcinoma in the general population. Patients with acromegaly are considered to be at risk for developing colonic lesions and typically have hyperinsulinemia.

Objective: Our objective was to evaluate the role of fasting insulin levels on the prevalence of colonic adenomatous polyps or adenocarcinoma in acromegaly.

Design: This is an analytical, observational, prospective study.

Patients: A total of 210 patients (111 women, 99 men, age 20–82 yr) undergoing complete colonoscopy at diagnosis of acromegaly were included in this study.

Results: Colonic lesions were found in 81 patients (38.6%), and consisted of hyperplastic polyps in 33 (15.7%), adenomatous polyps in 42 (20.0%), and adenocarcinoma in six patients (2.8%). Polyps were single in 22 cases (27.1%). Fasting insulin levels were significantly lower in patients without lesions (16.0 ± 7.5 mU/liter) than in patients with hyperplastic polyps (22.4 ± 8.8 mU/liter; P < 0.01), adenomatous polyps (38.0 ± 15.9 mU/liter; P < 0.0001), and adenocarcinoma (59.0 ± 30.6 mU/liter; P < 0.0001). Fasting insulin levels were also lower in patients with hyperplastic polyps than in those with adenomatous polyps (P < 0.01). The odds ratio for harboring colonic adenomas was 14.8 (95% confidence interval 4.4–51.2; P < 0.0001) and 8.6 times higher (95% confidence interval 2.8–29.0; P < 0.0001) in patients with fasting insulin levels in the upper tertile [≥27.1 mIU/liter (n = 28)] compared with the lower [≤12.1 mIU/liter (n = 40)] and middle tertiles [>12.1 to <27.1 mIU/liter (n = 74)], respectively.

Conclusion: An increase in fasting insulin levels is associated with an 8.6- to 14.8-fold increased risk of presenting with colonic adenomas in acromegaly.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY AND DIABETES mellitus are associated with an increased incidence of colon cancer, especially in men (1). An analysis of 15 studies (six case-control and nine cohort studies), including 2,593,935 participants, found that diabetes was associated with an increased risk of colorectal cancer when compared with the absence of diabetes. The association of abdominal obesity with colorectal cancer likely depends on hyperinsulinemia. The development of colorectal cancer has been associated with higher fasting glucose (relative risk 1.8) and insulin levels (relative risk 1.6) (2).

Insulin, like IGFs, displays growth-promoting effects and antiapoptotic actions in vitro and in animal models (3, 4, 5, 6), which led to the development of an "insulin hypothesis" for colorectal cancer (6).

Acromegaly is associated with an increased prevalence of colonic polyps, abnormal glucose tolerance, and hyperinsulinemia due to insulin resistance (7). GH and IGF-I excess is associated with an increase in lean mass and decrease in fat mass, but obesity is uncommon in acromegaly. Although it is controversial whether acromegaly increases the risk of developing colorectal carcinoma (8, 9), adenomatous (premalignant) polyps are more frequent in acromegaly than in the general population (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). The possibility that colonic lesions in acromegaly are associated with higher insulin levels has never been explored. Thus, acromegaly represents a unique model of chronically elevated insulin and IGF-I levels associated with glucose abnormalities independent of obesity, which can be used to investigate the role of insulin and IGF-I on the development of colonic lesions.

We investigated the relationship of GH, IGF-I, and insulin levels to colonic lesions in a cohort of consecutive newly diagnosed patients with acromegaly, and found that fasting insulin levels are associated with premalignant and malignant colonic lesions. This finding suggests a new treatment perspective for patients with acromegaly for preventing or delaying the recurrence of colonic lesions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

This is an observational, prospective study to investigate the role of fasting glucose, insulin, GH, and IGF-I levels on the prevalence of colonic adenomatous polyps or adenocarcinoma in newly diagnosed patients with acromegaly. It was conducted in accordance with the Helsinki II Declaration on human experimentation.

Inclusion criteria

Patients with newly diagnosed acromegaly admitted to the Department of Molecular and Clinical Endocrinology and Oncology of the Federico II University of Naples from January 1, 1993, to December 31, 2006, were consecutively enrolled in the study. The diagnosis of acromegaly was defined by somatic characteristics, high-serum GH levels during a 6-h time course and/or not suppressible to less than 1 µg/liter after oral glucose and elevated plasma IGF-I levels for age (21). The presumed duration of acromegaly was assessed by comparing photographs taken over a period of 30 yr, and by interviewing the patients as to the date of onset of acral enlargement and facial disfigurement. The interval between assumed clinical onset and diagnosis ranged from 12–360 months (median 96). A comprehensive clinical history was taken by medical staff to record presenting symptoms and identify risk factors for colorectal cancer, especially a family history of colorectal cancer, colonic polyps, or inflammatory bowel disease. Two patients (1%) had a family history of colorectal cancer. All patients signed an informed consent to approve diagnostic testing and treatment decisions.

Exclusion criteria

Patients were excluded if they were receiving treatment for acromegaly (n = 22), had previously undergone pituitary surgery (n = 17), had a serious medical disorder that could increase the risk associated with colonoscopy (n = 8), or refused colonoscopy (n = 13). To investigate the role of glucose tolerance on the prevalence of colonic lesions, patients with treated or untreated diabetes mellitus at the diagnosis of acromegaly were included in the prevalence analysis. However, data from diabetic patients receiving insulin, metformin, or other agent potentially interfering with circulating insulin levels were excluded from all analyses involving this parameter.

Patients

A total of 210 patients (111 women, 99 men, age 20–82 yr) undergoing complete colonoscopy at the diagnosis of acromegaly were enrolled (Table 1Go). Data from 95 patients (45.2% of the current series) have been previously published (16, 19).


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  		TABLE 1. Profile of patients at diagnosis

 
Study protocol

All patients underwent each of the following:

1. Measurement of height and weight, to calculate the body mass index (BMI) [weight (kilograms)/height (meters)2].

2. Measurement of GH levels as the mean value of at least six samples drawn every 30 min and serum IGF-I levels at time zero of the GH profile.

3. Measurement of glucose and insulin levels at fasting and every 30 min for 2 h after the oral administration of 75 g glucose [oral glucose tolerance test (oGTT)]. Diabetes mellitus was diagnosed when the fasting glucose was above 7 mmol/liter or more than 11 mmol/liter 2 h after the oGTT. Impaired fasting glucose (IFG) was considered when the glucose level was between 5.6 and 6.9 mmol/liter. Glucose tolerance was impaired (IGT) when the glucose level was at least 7.8 and less than 11 mmol/liter 2 h after the oGTT (22). Insulin resistance was determined with the homeostatic model approach (HOMA) (23) by HOMA-resistance (HOMA-R) (%) and HOMA-ß-cell function (HOMA-ß) (%). At diagnosis, 50 patients (23.8%) suffered from diabetes [21 were treated with insulin, 17 with metformin (these cases were excluded from the comparative analysis on HOMA values), and 12 had untreated diabetes], 73 (34.8%) had IFG and/or IGT, and 87 patients (41.4%) had normal glucose tolerance.

4. After careful bowel preparation using a polyethylene glycol-based electrolyte solution, complete colonoscopy was performed with a video colonoscope while the patients were under conscious sedation (16, 19). All colonoscopies were performed by the same board-certified endoscopists who had accumulated extensive endoscopic experience in patients with acromegaly. Location and size of all polyps were determined before removal; visible polyps were removed by snare and recovered. Polyp size was estimated with the use of open biopsy forceps. Small polyps (<5 mm) were removed by cold snare transsection to avoid thermal destruction and provide sufficient material for pathology examination. Polyps underwent classical diathermic resection if larger than 5 mm. Endoscopists were asked to photograph all cecal landmarks and all significant lesions. If the colonoscopic examination could not be completed because of inadequate bowel preparation or failure to reach the cecum, the patient was asked to return for a second procedure. If a complete examination was performed within 1 month of the first attempt, results from both examinations were combined and included in the analysis. All retrieved polypoid lesions were sent to the pathology laboratory for histological evaluation. All lesions were removed and/or biopsied endoscopically and examined histologically by board-certified pathologists, who classified polyps according to the criteria established by the World Health Organization (24) as neoplastic (adenomas and adenocarcinomas) or nonneoplastic (i.e. hyperplastic polyps). Adenomas were classified as tubular, tubulovillous/villous, and serrated, whereas epithelial dysplasia was graded as mild, moderate, or severe (25). Tumor sites were classified as right colon (cecum, ascending, and transverse colon), left colon (descending and sigmoid colon), and rectum (distal 18 cm). Lipomas, lymphoid aggregates, or inflammatory polyps were categorized as normal mucosa.

Assays

Glucose levels were measured with standard methods. Insulin levels were assayed by commercially available ELISA (Diagnostic System Laboratories Inc., Webster, TX). The normal range in normal adults is 2.1–30.8 mIU/liter (to convert to µg/liter: 25 mIU/liter = 1 µg/liter). The sensitivity of the assay was 0.26 mIU/liter. Serum GH levels were measured by immunoradiometric assay (IRMA), using commercially available kits (hGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.05 µg/liter. Serum IGF-I was measured by IRMA after ethanol extraction, using Diagnostic System Laboratories Inc. In our laboratory, the normal IGF-I range in ≤20, 21–30, 31–40, 41–50, 51–60, 61–70, and more than 70-yr-old individuals was 180–625, 118–475, 102–400, 100–306, 95–270, 88–250, and 78–200 µg/liter, respectively, in men, and 151–530, 118–450, 100–390, 96–288, 90–250, 82–200, and 68–188 µg/liter, respectively, in women. The sensitivity of the assay was 0.8 µg/liter. The intraassay coefficients of variation were 3.4, 3.0, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay coefficients of variation were 8.2, 1.5, and 3.7% for low, medium, and high points of the standard curve, respectively. IGF-I data are shown as the upper limit of normal range (ULN), where normal is 1 or greater.

Statistical analysis

Data were analyzed using MedCalc Software for Windows (MedCalc, Mariakerke, Belgium). Data are shown as mean ± SD unless otherwise specified. Significance was set at 5%. The prevalence of hyperplastic or adenomatous polyps or adenocarcinoma was calculated in 210 patients. Continuous variables were tested for differences by the Kruskal-Wallis test, followed by the Dunn’s multiple comparison test among patients with colonic adenomas, carcinomas, hyperplastic polyps, and those who were lesion free (Table 2Go), or among patients with normal glucose tolerance, IFG/IGT, or diabetes mellitus (Table 3Go).


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  		TABLE 2. Profile of the patients according to the type of colonic polyps

 

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  		TABLE 3. Profile of the patients according to the glucose tolerance status

 
The correlation analysis was performed after exclusion of patients with hyperplastic polyps (n = 33; 15.7%), a "reactive" nonpremalignant histotype that is common in Westernized populations, and those with treated diabetes (n = 38), in which the predictive value of fasting insulin might have been potentially altered by pharmacological treatments.

In patients with IFG/IGT or diabetes mellitus, the odds ratio (OR) of adenomatous polyps or adenocarcinoma was plotted against that obtained in patients with normal glucose tolerance. Data are expressed as observed OR, conditional maximum likelihood estimate of OR (CMOR), exact Fisher 95% confidence interval (CI), and two-sided P value (Table 4Go). A similar analysis was also performed according to tertiles of insulin levels by comparing the 43 patients with fasting insulin in the highest tertile with those in the lowest tertile. The entire population for this analysis included 142 patients (Table 4Go).


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  		TABLE 4. Odds ratio of the presence of premalignant and malignant colonic lesions in patients with IFG or IGT (n = 73) or diabetes mellitus (n = 50) compared with those with normal glucose tolerance (n = 87)

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Visualization of the colon up to the cecum was accomplished in all patients. A total of 59 patients (28.1%) underwent a repeat examination within 4 wk to achieve full colon visualization. Colonic lesions were documented in 81 patients (38.6%; Table 2Go). Polyps were hyperplastic in 33 cases (15.7%) and adenomatous in 42 (20%), whereas six patients were diagnosed (2.8%) with an adenocarcinoma. Polyps were single in 22 (27.2%) and multiple in 59 patients (72.8%); 21 patients from this latter group had synchronous polyps (35.6%). Five of the six patients with adenocarcinoma had multiple lesions. In the population as a whole, 309 lesions were resected without any preferential colonic site: 171 (55.3%) were resected from the right colon, 120 (30.8%) from the left colon, and 18 (5.8%) from the rectum. The maximal polyp diameter was smaller in patients with hyperplastic polyps than in the remaining groups. Dysplasia was graded as moderate to severe in 23 of 42 patients with adenomatous polyps (54.8%); three patients had two to three multiple serrated hyperplastic polyps located in the proximal colon (3.7%).

The presence of adenomatous polyps or adenocarcinoma was correlated with patients’ age ({rho} = 0.19; P = 0.021), gender ({rho} =0.21; P = 0.01), insulin levels ({rho} = 0.55; P < 0.0001), HOMA-R ({rho} = 0.54; P < 0.0001), HOMA-ß ({rho} = 0.56; P < 0.0001), and glucose tolerance status ({rho} = 0.43; P < 0.0001). The correlation with insulin levels ({rho} = 0.58; P < 0.0001) and related parameters persisted after correction for BMI, gender, and age.

The endocrine profile according to colonoscopy findings is shown in Table 2Go. Overall, the presence of adenomatous polyps or adenocarcinoma was significantly associated with male gender ({chi}2 7.8; P = 0.005). Patients with no detectable lesions were significantly younger than those with hyperplastic or adenomatous polyps or adenocarcinoma. In patients diagnosed with adenocarcinoma, estimated duration of acromegaly was longer, GH levels were lower, and fasting glucose levels were higher than in the three other groups. In contrast, fasting insulin levels were significantly lower in patients with no detectable lesions than in patients with hyperplastic or adenomatous polyps and adenocarcinoma (Fig. 1Go). Fasting insulin levels were also lower in patients with hyperplastic polyps than in those with adenomatous polyps. Similarly, a lower prevalence of diabetes was documented in patients without lesions or with hyperplastic polyps than in the remaining two groups.


Figure 1
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  		FIG. 1. Fasting insulin levels in the 210 patients according to colonoscopy findings. Only the patients receiving insulin treatment were excluded from this analysis. On the left of individual values in different groups are shown the 25th–75th percentiles. Significance derives from the Kruskal-Wallis test, followed by the Dunn’s test for multiple comparisons.

 
Table 3Go shows the prevalence of colonic lesions based on glucose tolerance status. Patients with diabetes were older and had longer estimated disease duration than those with normal glucose tolerance, IFG, or IGT. Patients with normal glucose tolerance had a lower BMI than those with diabetes. Patients with diabetes had only slightly lower GH levels but higher IGF-I levels for age than those with normal glucose tolerance and those with IFG or IGT. The prevalence of colonic lesions was significantly higher in patients with diabetes than in those with normal glucose tolerance ({chi}2 7.5; P = 0.006) and those with IFG or IGT ({chi}2 4.7; P = 0.031). Conversely, in patients with IFG or IGT, adenomatous polyps were 3.2 times more frequent (1.07–10.71; P = 0.022) than in patients with normal glucose tolerance. In patients with diabetes, adenomatous polyps were 10.6 times more frequent (3.62–36.64; P < 0.0001), and adenocarcinoma was incalculably higher (2.2 to infinity; P = 0.002) than in patients with normal glucose tolerance. The OR for all lesions as well as the single polyp histotype according to glucose tolerance is reported in Table 4Go.

The association between insulin levels and the presence of premalignant colonic lesions was tested in 142 patients who were not receiving antidiabetic drugs potentially interfering with insulin assessment. Serum insulin levels were stratified into tertiles: lower, ≤12.1 mIU/liter (n = 40); middle, more than 12.1 to less than 27.1 mIU/liter (n = 74); and upper, ≥27.1 mIU/liter (n = 28). Only one patient with adenocarcinoma entered the analysis, and, thus, the result for a malignant lesion was not significant (Table 5Go). The patients with fasting insulin levels in the highest tertile had premalignant lesions 14.8 times more frequently than those with insulin levels in the lowest tertile and 8.6 times more than those in the middle tertile.


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  		TABLE 5. Odds ratio of the presence of premalignant and malignant colonic lesions in patients with insulin levels in the III tertile [n = 28 (≥27.1 mIU/liter)] compared with those with insulin levels in the II [n = 74 (>12.1 to <27.1 mIU/liter)] and I tertiles [n = 40 (≤12.1 mIU/liter)]

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most important finding from this study is that glucose tolerance and insulin levels are strongly associated with colonic adenomas and carcinomas in acromegaly. Patients with IFG, IGT, or diabetes have a risk of developing colonic lesions that is 2.4–5.8 times higher than in those with normal glucose tolerance. This effect is likely to be mediated by hyperinsulinemia because patients with fasting insulin levels in the highest tertile had a 14.8 times higher risk of developing adenomatous polyps than those with levels in the lowest tertile.

Gastrointestinal tumors constitute the most frequent malignancies (approximately 27% of all tumors) developing in acromegaly, 18% due to colorectal carcinomas (7). Colon adenomas are regarded as benign glandular dysplastic lesions carrying a high cellular proliferation rate (26). Colon adenomas and carcinomas share some characteristics indicating a temporal link: minute carcinomas are adenomatous in origin, adenomas and carcinomas have morphological homologies, familial adenomatous polyposis predisposes to colon cancer, adenomas and carcinomas often occur in the same area, and adenomas may progress into cancer within 10- to 15-yr onset.

After the first demonstration of an increased occurrence of premalignant colon polyps in acromegaly almost two decades ago by Klein et al. (9), several other reports have shown that acromegalic patients are more prone to develop colon adenomas with rates ranging from 9–38% (7). In contrast, Renehan et al. (8) reported only 14 of 115 patients (12%) with lesions, including three with adenocarcinomas (2.6%). Although the overall prevalence of colonic lesions in the Renehan series (8) is significantly lower than that observed in our series and others, the prevalence of colonic adenocarcinoma was similar. The differences in risk may reflect dissimilarities in the selection of patients, as well as in the gender prevalence, age, and adequate colon visualization. On the basis of the aforementioned studies (7), some observations emerge: 1) acromegaly increases the risk of developing colon adenomas after the age of 50 yr; 2) colonic polyps predominate in male patients; 3) adenomatous polyps may occur from any colon site, but the ascending colon is variably predominant; and 4) colon adenomas are more frequent in patients with disease duration more than 5 yr, three or more skin tags, and a family history of colon polyps, whereas GH and IGF-I levels, years of exposure to elevated GH and IGF-I, and familial colon cancer do not predict the occurrence of colon adenomas. Several of these observations have been confirmed in this series, the largest so far examined. It is particularly interesting to note that most studies, including ours, showed no direct correlation between IGF-I levels and the prevalence of colonic adenomas or carcinomas. This conflicts with experimental evidence that IGF-I has antiapoptotic activity and induces proliferation of colorectal cancer cell lines (3, 4, 5). The role of circulating IGF-I in stimulating tumor growth and metastasis has also been shown in mice carrying liver-specific deficiency of IGF-I, in which both growth and metastatic spread of adenocarcinomas transplanted on the cecum surface were significantly increased after 6-wk ip treatment with IGF-I (27). In acromegaly, the evidence that GH/IGF-I excess does not correlate with the prevalence or severity of colonic lesions can be explained by the concomitant increase in IGF binding protein (IGFBP)-3 levels (28). In addition, although the entire IGF-I axis is increased upon chronic GH stimulation in acromegaly, an increase in free IGF-I has been hypothesized to occur in patients with colon carcinoma due to concomitant reduction of IGFBP-1 and -2 (29, 30).

There are several other endocrine and paracrine factors that can stimulate the development of colonic lesions in acromegaly and have been poorly explored. Similar to IGF-I, insulin stimulates the growth of normal colonic and carcinoma cells in vitro (31). Although colon cancer tissue has both insulin and IGF-I receptors, the mitogenic properties of insulin, in contrast to its glycemic-control properties, may be mediated through IGF-I receptors (32) or possibly hybrid IGF-I and insulin receptors (33, 34). However, mitogenicity occurs at supraphysiological levels of insulin. Insulin increases bioactive IGF-I through various mechanisms. Insulin reduces hepatic secretion of IGFBP-1, which binds IGF-I with high affinity and can inhibit IGF-I actions in vitro (35). Long-term enhancement of insulin secretion also decreases IGFBP-2 (36). Renehan et al. (37, 38) documented a strong correlation between IGF-II and IGFBP-2 levels and colonic adenomas. Moreover, glucose, body weight, C peptide, and insulin levels have predicted colorectal carcinoma (1, 2, 6, 29, 31). Therefore, elevated insulin levels can be the underlying factor responsible for an increase in body weight and visceral fat adiposity with colonic lesions (31). In a recent study of 343 consecutive patients who underwent colonoscopy, Yoshida et al. (39) reported that elevated serum insulin was significantly associated with proximal-only adenomas, both-side hyperplastic polyps, and proximal-only hyperplastic polyps and slightly associated with distal-only adenomas, but not with distal-only hyperplastic polyps.

The predictive role of glucose homeostasis and insulin levels on the risk of colonic neoplasms is unexplored in acromegaly, despite the well-known increased prevalence of IGT and diabetes in this disease. We initiated a prospective analysis of the oncological risk in patients with acromegaly in 1993 and published preliminary results on the prevalence and recurrence of colonic lesions (16, 19). The current observational study was designed to investigate possible relationships among glucose tolerance, insulin levels, and colonic lesions. To this aim, only newly diagnosed patients with acromegaly were enrolled. In line with previous studies (7), the prevalence of diabetes and reduced glucose tolerance was 23.8 and 34.8%, respectively. As expected, patients with IGT or diabetes were older than patients with normal glucose tolerance, indicating that aging may have a role in the increase of colonic lesions in patients with abnormal glucose tolerance.

Importantly, we found that the risk of bearing adenomatous polyps was 3.2 times higher in patients with IFG/IGT and 10.6 times higher in patients with diabetes than in those with normal glucose tolerance. The risk of bearing adenomatous polyps was 14.8 times higher in patients with fasting insulin levels in the highest tertile compared with those in the lowest tertile. All the patients with colon adenocarcinoma in our series had diabetes, and the correlation between the presence of colonic lesions and insulin levels persisted after correction for BMI, age, and gender.

Conclusion

These findings may shed light on the pathophysiological causes of colonic lesions in patients with acromegaly, and indicate that elevated fasting insulin is associated with an increased prevalence of colonic lesions, specifically adenomas and adenocarcinomas independent of a normal BMI. The role played by genetic background remains to be established because family history of colon carcinoma occurred in only 1% of our patients. A potential clinical implication is that improving insulin sensitivity along with controlling GH and IGF-I secretion (19, 20, 40) might be beneficial in delaying or preventing the recurrence of colonic lesions in acromegaly.


   Acknowledgments
 
We thank Dr. Gillian Elisabeth Walker, Laboratory of Molecular Biology, Ospedale San Giuseppe, Istituto Auxologico Italiano, Verbania, Italy, for critically reviewing the manuscript.


   Footnotes
 
This study did not receive any specific grant support. A.C. and G.L. are recipients of grants from the Italian Ministry of University and Research, Regional Government of Campania for Research, for research in neuroendocrine tumors. They also received unrestricted grants from Ferring, Ipsen, Italfarmaco, Novartis, Novo-Nordisk, Pfizer, and Serono for research in neuroendocrinology.

Disclosure Summary: A.C. received lecture fees from Ipsen, Novartis, and Pfizer. R.P., R.S.A., M.G., D.F., and F.M. have nothing to declare. P.M. is a Novartis consultant. G.L. received lecture fees from Ipsen and Novartis.

First Published Online July 24, 2007

Abbreviations: BMI, Body mass index; CI, confidence interval; CMOR, conditional maximum likelihood estimate of OR; HOMA, homeostatic model approach; HOMA-ß, HOMA-ß-cell function; HOMA-R, HOMA-resistance; IFG, impaired fasting glucose; IGFBP, IGF binding protein; IGT, impaired glucose tolerance; IRMA, immunoradiometric assay; oGTT, oral glucose tolerance test; OR, odds ratio; ULN, upper limit of normal range.

Received November 21, 2006.

Accepted July 13, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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