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

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.

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.