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Original Research |

Diagnostic Accuracy of an “Amended” Insulin–Glucose Ratio for the Biochemical Diagnosis of Insulinomas

Michael A. Nauck, MD; and Juris J. Meier, MD
[+] Article and Author Information

From Diabeteszentrum Bad Lauterberg, Harz, and Ruhr-Universität Bochum, Bochum, Germany.

Disclaimer: The authors take full responsibility for the content of the manuscript.

Acknowledgment: The authors thank Dr. Christiane Qualmann (Rotenburg [Wümme], Germany), Dr. M. Christiane Saddig (Insulinom- und GEP-Tumor-Zentrum Neuss-Düsseldorf, Germany), and Dr. Jochen Post (Nettetal, Germany) for their help in retrieving clinical and laboratory data from hospital charts; Professor Dr. Achim A.R. Starke (Insulinom- und GEP-Tumor-Zentrum Neuss-Düsseldorf) and the late Professor Dr. Michael Berger (Heinrich Heine University Düsseldorf, Düsseldorf, Germany) for contributing data from patients who were diagnosed and had surgery at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; and Professor Dr. Hans Jürgen Peiper (Department of Surgery, Georg-August University, Göttingen, Germany) and Professor Dr. Hans-Dietrich Röher (Department of Surgery, Heinrich Heine University Düsseldorf, Düsseldorf, Germany) for the surgical care of the patients with insulinoma described in this manuscript and for allowing access to respective clinical and histologic data.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0539.

Reproducible Research Statement: Study protocol and statistical code: Not available. Data set: Available for collaborative analyses upon negotiation and agreement with Dr. Nauck (e-mail, nauck@diabeteszentrum.de).

Requests for Single Reprints: Michael Nauck, MD, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany; e-mail, nauck@diabeteszentrum.de.

Current Author Addresses: Dr. Nauck: Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany.

Dr. Meier: Medizinische Klinik I, Abteilung für Diabetologie und Gasrointestinale Endokrinologie, St. Josef-Hospital, Klinikum der Ruhr-Universität, Gudrunstraße 56, 44891 Bochum, Germany.

Author Contributions: Conception and design: M.A. Nauck.

Analysis and interpretation of the data: M.A. Nauck, J.J. Meier.

Drafting of the article: M.A. Nauck, J.J. Meier.

Critical revision of the article for important intellectual content: M.A. Nauck, J.J. Meier.

Final approval of the article: M.A. Nauck, J.J. Meier.

Statistical expertise: M.A. Nauck, J.J. Meier.

Administrative, technical, or logistic support: J.J. Meier.

Collection and assembly of data: M.A. Nauck, J.J. Meier.


Ann Intern Med. 2012;157(11):767-775. doi:10.7326/0003-4819-157-11-201212040-00004
Text Size: A A A

Background: Recent biochemical diagnostic guidelines for insulinomas require demonstration of hypoglycemia with inappropriately elevated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in patients without insulinomas. Use of an “amended” insulin–glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia may improve diagnostic accuracy.

Objective: To compare the diagnostic accuracy of current diagnostic guideline criteria with the amended insulin–glucose ratio in patients with a suspected insulinoma.

Design: Retrospective cohort study.

Setting: 2 specialized university departments in Germany.

Patients: 114 patients with suspected hypoglycemia over 10 years having diagnostic prolonged fasts.

Measurements: Glucose, insulin, C-peptide, and the amended insulin–glucose ratio were measured during and at discontinuation of prolonged fasts.

Results: Of 114 patients who were evaluated, 49 had surgical resection of histologically confirmed insulinomas. Insulinoma was excluded in 65 patients; follow-up for a mean of 10 years (range, 0 to 16 years) showed no progressively severe hypoglycemic events or diagnoses of insulinoma. Patients with insulinoma had lower glucose levels and higher insulin and C-peptide levels overall than did control patients at the end of prolonged fasts, but there was considerable overlap. The amended insulin–glucose ratio correctly identified 48 of 49 patients with insulinoma and excluded the diagnosis in 64 of 65 control patients, resulting in positive and negative predictive values of 0.98 (95% CI, 0.89 to 1.00) and 0.99 (CI, 0.92 to 1.00), respectively, compared with 0.75 (CI, 0.63 to 0.85) and 0.98 (CI, 0.89 to 1.00), respectively, for glucose, insulin, and C-peptide concentration criteria.

Limitation: The study had a retrospective design, no proinsulin concentrations were available, and a nonspecific insulin immunoassay (crossreactive with proinsulin) was used.

Conclusion: The amended insulin–glucose ratio showed improved diagnostic accuracy over established criteria that use glucose, insulin, and C-peptide concentrations.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

All diagnosed insulinomas were confirmed by surgery and histologic evaluation. Amended insulin–glucose ratios of at least 53.6 (pmol/L)/(mmol/L) were considered abnormally high (12).

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.

Proportion of patients with insulinoma, control patients, and patients who had successful surgical removal of the insulinoma tolerating prolonged fasts for as long as 48 h (top) or maintaining a plasma glucose level of at least 3.1 mmol/L (≥55 mg/dL) (bottom).

Analysis was performed using the Kaplan–Meier method and the Mantel–Cox log-rank test.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Plasma values at discontinuation of prolonged fasts.

Plasma concentrations of glucose (A), insulin (B), and C-peptide (C); insulin–glucose ratios (D); and “amended” insulin–glucose ratios (insulin [pmol/L]/[glucose {mmol/L} − 1.7 mmol/L]) (E) are shown, as well as insulin (F) and C-peptide (G) values plotted versus plasma glucose value measured at the time of discontinuation of prolonged fasts in patients with insulinoma (circles: benign insulinomas; squares: malignant insulinomas), control patients (triangles), and patients with insulinoma who were restudied after successful tumor removal (diamonds). P values indicate results of analysis of variance (comparison between patients with insulinoma and control patients; patients after successful surgery were not included in this analysis). In A, the dotted line indicates a glucose concentration of 3.1 mmol/L (55 mg/dL) (one of the criteria advocated by the Endocrine Society), and the dashed line indicates a glucose concentration of 2.4 mmol/L (43 mg/dL), below which prolonged fasts were discontinued in this study. In D and E, dotted lines indicate the upper normal limits as published previously (910, 12). In F and G, the dotted lines were drawn to best separate patients with and without insulinoma. To convert glucose values from mmol/L to mg/dL, divide by 0.0555. To convert C-peptide values from nmol/L to ng/mL, divide by 0.331.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Glucose concentrations during prolonged fasts over 48 h or until discontinuation.

Patients with insulinoma are shown in the top panel and control patients are shown in the middle panel separated by sex (mean [95% CI]). The proportion of female and male control patients with a glucose concentration less than 3.1 mmol/L (<55 mg/dL) is shown in the bottom panel. In the top panel, individual glucose concentrations over time are shown, highlighting the first glucose concentration less than 3.1 mmol/L (<55 mg/dL) (open circles) and the glucose concentration at the time of discontinuation of prolonged fasts (solid circles). In the middle panel, solid lines are means, and dotted lines are 95% CIs; statistical analysis was performed using repeated-measures analysis of variance, and asterisks indicate significant differences (by analysis of variance) between female and male control patients at single time points. To convert glucose values from mmol/L to mg/dL, divide by 0.0555. A = female vs. male control patients; B = changes over time; AB = interaction.

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Comment On: Nauck MA, Meier JJ. Diagnostic accuracy of an “amended” insulin-glucose ratio for the biochemical diagnosis of insulinomas. Ann Intern Med 2012; 157:767-775.
Posted on December 27, 2012
Philip E. Cryer, Lloyd Axelrod, Ashley B. Grossman, Simon R. Heller, Elizabeth R. Seaquist, F. John Service
The Endocrine Society Task Force on the Evaluation and Management of Adult Hypoglycemic Disorders
Conflict of Interest: These were provided with the published Guideline (ref. 2). Disclosures for the past three years: Dr. Cryer, consultant for Novo Nordisk, MannKind Corp., Marcadia Biotech, Bristol-Myers Squibb/AstraZeneca and MerckDr. Axelrod, noneDr. Grossman, noneDr. Heller, consultant for Johnson & Johnson, Lilly, Merck, Novo NordiskDr. Seaquist, consultant for AMG Medical, Sanofi-AventisDr. Service, none

Nauck and Meier (1) reported their diagnostic use of an amended insulin-glucose ratio, based on the assumption that the insulin concentration is normally zero only at a plasma glucose concentration of 1.7 mmol/L (30 mg/dL), in the diagnosis of insulinoma, and contrasted that experience with the recommendations of the Endocrine Society Clinical Practice Guideline on the evaluation and management of adult hypoglycemic disorders (2). Measurements of insulin secretion were not reported in the 1971 manuscript cited by Nauck and Meier. In fact, plasma C-peptide concentrations, and the insulin secretion rates calculated from those concentrations, fall to values not significantly different from zero at mean clamped plasma glucose concentrations of 3.6 mmol/L (65 mg/dL) or lower (3), as do C-peptide concentrations when plasma glucose concentrations are lowered to 3.6 mmol/l (65 mg/dL) (4), in healthy humans in contrast to patients with insulinoma. Thus, the diagnostic plasma glucose cut-off of <3.0 mmol/L (<55 mg/dL) recommended in the Guideline (provided Whipple’s triad is, or had been, documented) (2) is reasonable. Using the criteria recommended in the Guideline (2) and the corresponding contemporary assays for the diagnosis of insulinoma, at fasting serum glucose concentrations <3.3 mmol/L (60 mg/dL) the diagnostic sensitivities were 93% for insulin, 100% for C-peptide and 100% for proinsulin (5). Specificities (95%, 60% and 68% respectively) were higher at glucose levels <2.8 mol/L (50 mg/dL) (100%, 78% and 78% respectively) (5). Importantly, Nauck and Meier (1) acknowledge that they used a nonspecific insulin assay that cross reacts with proinsulin and its degradation products, and contrast its performance with Guideline diagnostic criteria (2) based on measurements with a specific insulin assay. Indeed, Nauck and Meier caution that when one uses a specific insulin assay it is necessary to also measure proinsulin, as is recommended in the Guideline. They acknowledge (1) that their amended insulin-glucose ratio did not perform better when applied to the data of Vezzosi, et al. who used insulin, and C-peptide, specific assays devoid of significant cross-reactivity with proinsulin that are representative of contemporary clinical assays.Author ResponsibilityThe first author attests that all authors participated in the decision to publish this comment and in its development.

References

1. Nauck MA, Meier JJ. Diagnostic accuracy of an “amended” insulin-glucose ratio for the biochemical diagnosis of insulinomas. Ann Intern Med. 2012;157:767-75.

2. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94:709-28.

3. Heller SR, Cryer PE. Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans. Am J Physiol Endocrinol Metab. 1991;261:E41-8.

4. Breckenridge SM, Raju B, Arbelaez AM, Patterson BW, Cooperberg BA, Cryer PE. Basal insulin, glucagon, and growth hormone replacement. Am J Physiol Endocrinol Metab. 2007;293:E1303-10.

5. Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, Andrews JC, Lloyd RV, Service FJ. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab. 2009;94:1069-73.

Author's Response
Posted on January 10, 2013
Michael A Nauck, MD
Diabeteszentrum Bad Lauterberg
Conflict of Interest: None Declared

Nauck M.A., Meier J.J., response to the commentary by Cryer P.E. et al. on: Nauck MA, Meier JJ. Diagnostic accuracy of an “amended” insulin-glucose ratio for the biochemical diagnosis of insulinomas. Ann Intern Med 2012; 157:767-775.

We thank Cryer et al. representing the The Endocrine Society Task Force on the Evaluation and Management of Adult Hypoglycemic Disorders for their clarifications regarding our manuscript focusing on the value of the “amended” insulin/glucose ratio for diagnosing and ruling out insulinomas. We would like to make clear that the assumption that the insulin secretion ceases at a plasma glucose concentration of 1.7 mmol/L (30 mg/dL) (1) probably does not represent the true concentration-response relationship in human subjects in vivo (2), but this consideration was the basis for suggesting the “amended” insulin/glucose ratio for diagnostic purposes. Cryer et al. correctly point out, that the diagnostic sensitivity of this ratio for the diagnosis of an insulinoma was not superior to conventional criteria as suggested by the Endocrine Society. However, our findings suggest that the “amended” insulin/glucose ratio may be more reliable in ruling out a suspected insulinoma in patients presenting with typical symptoms. Cryer et al. derive the normal pattern of C-peptide concentrations in the presence of low glucose concentrations from hyperinsulinemic hypoglycemic clamp experiments performed in healthy subjects. We have taken results from a similar hyperinsulinemic hypoglycemic clamp study from our group (3) and expressed them in relation to the ambient glucose levels in the same format that we had used for the controls at the end of their 48 h prolonged fasts (Figure).

Figure to be published in an upcoming print version of comment.

Individual C-peptide concentrations at the end of 48 h prolonged fasts in control subjects (black dots), in whom an insulinoma was ruled out, plotted against the plasma glucose concentrations measured at the same time, as reported in our manuscript (A) and C-peptide concentrations during hyperinsulinemic, stepped hypoglycaemic clamp experiments aiming at plateaus of 4.3, 3.7, 3.0 and 2.3 mmol/l plotted against ambient capillary plasma glucose concentrations in healthy volunteers (grey circles) (B) taken from a published study (3). Dotted lines connect values belonging to the same subject. Grey dots in panel A represent insulinoma patients cured by pancreatic resection studied after surgery.

The degree of suppression of C-peptide in the healthy subjects recruited for this study was much higher than in the control patients, in whom an insulinoma was ruled out, for any degree of hypoglycemia. Reasons may be concomitant hyperinsulinemia having an additional suppressive influence on ß-cell secretion (4), and the insulin-induced suppression of free fatty acids, which at higher concentrations may acutely stimulate insulin secretion(5). This indicates that the C-peptide concentration pattern in our control patients with a suspected hypoglycemic disorder may behave differently from that in healthy volunteers, and suggests that for clinical purposes, the diagnostic accuracy should not be derived from tests performed in perfectly healthy individuals. It is therefore a particular strength of our study that exactly those subjects who were referred with the suspicion of an insulinoma, which could not be confirmed by conventional work-up, were taken to define our diagnostic criteria.

References

1. Turner RC, Oakley NW, Nabarro JD. Control of basal insulin secretion, with special reference to the diagnosis of insulinomas. Br Med J. 1971;2:132-5.

2. Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987;79:777-81.

3. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239-46.

4. DeFronzo RA, Binder C, Wahren J, Felig P, Ferrannini E, Faber OK. Sensitivity of insulin secretion to feedback inhibition by hyperinsulinaemia. Acta Endocrinol (Copenh). 1981;98:81-6.

5. Boden G. Free fatty acids and insulin secretion in humans. Curr Diab Rep. 2005;5:167-70.

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