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Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline
Philip E. Cryer, Lloyd Axelrod, Ashley B. Grossman, Simon R. Heller, Victor M. Montori, Elizabeth R. Seaquist, and F. John Service
Washington University School of Medicine (P.E.C.), St. Louis,Missouri 63110; Massachusetts General Hospital and Harvard Medical School (L.A.), Boston, Massachusetts 02114; Barts and the London School of Medicine, Queen Mary University of London (A.B.G.), London E1 2AD, United Kingdom; University of Sheffield (S.R.H.), Sheffield S10 2TN, United Kingdom; University of Minnesota (E.R.S.), Minneapolis, Minnesota 55455; and Mayo Clinic (V.M.M., F.J.S.), Rochester,Minnesota 55905

Objective: The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. Evidence: Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (QEEE), low (QQEE), moderate (QQQE), or high (QQQQ).Conclusions: We recommend evaluation and management of hypoglycemia only in patients in whom Whipple’s triad—symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy.First, pursue clinical clues to potential hypoglycemic etiologies— drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin,C-peptide, proinsulin, -hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction—addressing the issue of hypoglycemia, applying the principles of intensive glycemictherapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations—in persons with diabetes. (J Clin Endocrinol Metab 94: 709 –728, 2009)

Summary of Recommendations
1.0 Workup for a hypoglycemic disorder 1.1 We recommend evaluation and management of hypoglycemia only in patients in whom Whipple’s triad—symptoms,signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented (1QQQQ).
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2008-1410 Received July 2, 2008. Accepted December 8, 2008. First Published OnlineDecember 16, 2008

2.0 Evaluation and management of hypoglycemia in persons without diabetes mellitus 2.1 Compared with a much less thorough workup, we recommend the following strategy in patients with hypoglycemia without diabetes mellitus (1QQQE): • Review the history, physical findings, and all available laboratory data seeking clues to specific disorders— drugs,
Abbreviations: CSII,Continuous sc insulin infusion; HAAF, hypoglycemia-associated autonomic failure; HbA1C, hemoglobin A1C; MDI, multiple daily insulin injection; MEN-1, multiple endocrine neoplasia, type 1; MRI, magnetic resonance imaging; NIPHS, noninsulinoma pancreatogenous hypoglycemia syndrome; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

J Clin Endocrinol Metab, March 2009, 94(3):709 –728...