Philip E. Cryer, MD: SeminalContributions to theUnderstanding of HypoglycemiaandGlucoseCounterregulation andthe Discovery of HAAF (CryerSyndrome)

Diabetes Care 2015;38:2193–2199 | DOI: 10.2337/dc15-0533

Optimized glycemic control preventsand slows the progression of long-termcomplications inpatientswith type 1andtype 2 diabetes. In healthy individuals,a decrease in plasma glucose below thephysiological range triggers defensivecounterregulatory responses that re-store euglycemia. Many individualswith diabetes harbor defects in theirdefenses against hypoglycemia, makingiatrogenic hypoglycemia the Achillesheel of glycemic control. This Profile inProgress focuses on the seminal contri-butions of Philip E. Cryer, MD, to ourunderstanding of hypoglycemia andglucose counterregulation, particularlyhis discovery of the syndrome ofhypoglycemia-associated autonomicfailure (HAAF).

Early Promise Fulfilled

Philip E. Cryer was born in 1940 in ElPaso, IL, where his father was a countrydoctor. The founding of the AmericanDiabetes Association (ADA) in the sameyear was an interesting coincidence,given his later career path in diabetesresearch and his leadership role in theADA. An outstanding student, Cryer wasvaledictorian of his high school class in

1958andaPhi Beta Kappagraduate (1962)of NorthwesternUniversity in Evanston, IL.He obtained his MD (Alpha Omega Alpha)from the same institution in 1965, with“highest distinction.” Cryer received clini-cal and research training in endocrinology

and metabolism under the direction ofDrs. William H. Daughaday and David M.Kipnis at Barnes Hospital/WashingtonUniversity School of Medicine in St. Louis(St. Louis, MO). After his completion ofendocrinology training in 1969, he

Philip E. Cryer, as a mature professor and as a U.S. Naval officer.

Division of Endocrinology, Diabetes and Metabolism, The University of Tennessee Health Science Center, Memphis, TN

Corresponding author: Samuel Dagogo-Jack, sdj@uthsc.edu.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered.

Samuel Dagogo-Jack

Diabetes Care Volume 38, December 2015 2193

PROFILES

INPROGRESS

served in theU.S. Navy at theNavalMed-ical Research Institute in Bethesda, MD,until 1971. After that, he returned toBarnes Hospital/Washington UniversitySchool of Medicine in St. Louis, wherehe has spent his entire career.

Cryer rose to leadership positions atthe Washington University School ofMedicine. He was director of the Divi-sion of Endocrinology, Diabetes andMetabolism (1985–2002), director ofthe General Clinical Research Center(GCRC) for decades, and associate direc-tor of the Diabetes Research Center(2002–2014), among other roles. To hisgreat credit, he led the GCRC through sixsuccessful competitive renewal applica-tions to the National Institutes of Healthover a period spanning 33 years. Cryerwas named the Irene E. and Michael M.Karl Professor of Endocrinology andMetabolism in Medicine at WashingtonUniversity in St. Louis in 1995, a positionhe held until he became emeritus in2014. Despite the numerous demandson his time, Cryer’s major focus hasbeen on patient-oriented, translationalresearch. His research training in thelate 1960s included experiences inboth clinical research and then–state-of-the-art basic research. His first re-search publication, with Dr. Daughaday,was on the regulation of growth hor-mone secretion (1); his second article(with Drs. Jarett and Kipnis), titled “Nu-cleotide Inhibition of Adenyl CyclaseActivity in Fat Cell Membranes” (2), an-tedated the discovery of G proteins.Cryer’s independent research work co-alesced around the sympathoadrenal

system, glucose counterregulation, andhypoglycemia in general. In a careerspanning more than four decades, Cryerhas contributed three single-authoredbooks, 94 book chapters, and 374 pub-lished articles to the medical literature.

Sympathoadrenal System andGlucose Counterregulation

In the 1970s, Cryer developed a sensi-tive single-isotope derivative (radioen-zymatic) assay for catecholamines (3).The advantages of that assay over theoriginal double-isotope derivativemethod of Engelman et al. (4) includedthe use of smaller sample volumes andmethodological simplicity. By dispens-ing with the need for internal standards(without compromising accuracy or pre-cision), the Cryer assay also had an edgeover the single-isotope derivativemethod of Passon and Peuler (5). Withthat tool, Cryer launched pioneeringstudies on the physiology and patho-physiologyof thehumansympathoadrenalsystem (6), as well as mechanistic studieson themetabolic actions of epinephrine inhumans (7–10). The achievement of pre-cision and efficiency in themeasurementof catecholamines and other hormonesenabled Cryer and his colleagues tochronicle the temporal pattern in the se-cretion of the glucose counterregulatoryhormones during insulin-induced hypo-glycemia. Those early studies set thestage for the discovery of the physiologyof “glucose counterregulation,” a then-novel term that appeared as a runningtitle of the 1976 publication authored byAlanGarber, Cryer, Julio Santiago,MoreyHaymond, Anthony Pagliara, and DavidKipnis (11).

Hierarchy of CounterregulatoryResponses

Subsequent work led by John Gerich andCryer (12–15) discovered the principlesof counterregulatory physiology by clar-ifying the hierarchy of changes in neuro-endocrine hormones, symptoms, andcognitive function in response to decre-ments in blood glucose. In pivotal stud-ies reported in 1979, Gerich and Cryer(12), along with their colleagues Jona-than Davis, Mara Lorenzi, Robert Rizza,Nancy Bohannon, John Karam, StephenLewis, Roy Kaplan, and Thomas Schultz,investigated themechanisms for recoveryof plasma glucose from insulin-inducedhypoglycemia in healthy subjects and

Cryer,WashingtonUniversity School ofMedicinein St. Louis (Washington Magazine, Fall 2002,p. 48).

Family portrait taken circa June 1997. Seated (center): Cryer and Carolyn Havlin-Cryer. Fromleft: Mary Gudermuth Cryer (wife of Philip Clifford Cryer), Justine Laurel Cryer Dugan, PhilipClifford Cryer, Anthony Victor Havlin, Krista Victoria Havlin, and Rebecca Elizabeth HavlinEberhart.

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individuals who had undergone bilateraladrenalectomy. The study protocol in-cluded somatostatin infusion to inhibitglucagon and growth hormone secre-tion, with and without separate infusionof either hormone, to better understandthe hierarchy of counterregulatory hor-mones. Those studies generated thenow axiomatic knowledge that glucagonand epinephrine play critical roles, whilethe immediate contributions of growthhormoneand cortisol are less critical, in thehierarchy of counterregulatory responsesto acute insulin-induced hypoglycemia.The findings extended previous observa-tions by Robert Brodows, F. Xavier Pi-Sunyer, and Robert Campbell (16) thatdemonstrated the neurohormonal controlof counterregulatory responses during2-deoxy-glucose–induced glucoprivationin healthy subjects andpatientswith spinalcord transection.

Hypoglycemia Unawareness

Elucidation of the hierarchy of counter-regulatory responses soon was followedby the discovery (by Geremia Bolli, Ger-ich, Cryer, and colleagues) that thesephysiological defenses against hypoglyce-mia were compromised in people withtype 1 diabetes (17,18). Those discover-ies provided a conceptual framework forunderstanding hypoglycemia unaware-ness as the clinical expression of defec-tive glucose counterregulation in peoplewith diabetes. Probing the cause of theloss of glucagon response to hypoglyce-mia, insightful work from Cryer’s groupsuggested that b-cell failure (and thusinability to modulate intraislet insulinlevels) may be a mechanism for theaglucagonemic response to hypoglyce-mia (19,20). The neurogenic symptomsof hypoglycemia trigger a behavioralresponse (carbohydrate consumption)to abort hypoglycemia and restoreeuglycemia. Patients with hypoglycemiaunawareness do not perceive neuro-genic warning symptoms and thus areat risk for severe hypoglycemia, neuro-glycopenia, coma, seizure, and evendeath. It had been generally believedthat the neurogenic symptoms of hypo-glycemia were of adrenomedullary ori-gin (hence the term “adrenergic”).However, given the assessment of neu-rogenic symptoms, norepinephrine ki-netics, and hemodynamic changesunder clamped euglycemic and steppedhypoglycemic conditions in healthy

subjects and adrenalectomized pa-tients, Cryer convincingly showed thatthe neurogenic symptoms of hypogly-cemia are indeed largely the result ofsympathetic neural, rather than adre-nomedullary, activation (21). The clin-ical importance of these observationsfrom studies championed by Cryer andcolleagues is underscored by the dem-onstration that the combination of hy-poglycemia unawareness and defectiveglucose counterregulation confers a 25-fold increased risk for severe hypogly-cemia (22,23).

Hypoglycemia BegetsHypoglycemia: Early Clues to aSyndrome

The benefits of glycemic control wereclearly demonstrated in the DiabetesControl and Complications Trial (DCCT)(24), but the risk of iatrogenic hypogly-cemia did not escape notice (24–26).The overall rates of severe hypoglyce-mia (including coma and seizure) were61.2 per 100 patient-years versus 18.7per 100 patient-years in the intensiveand conventional treatment groups, re-spectively (25,26). DCCT participantswho experienced severe hypoglycemiawere at increased risk of subsequentepisodes. Indeed, approximately one-third of the patients in each groupexperienced a second episode withinthe 4 months following the first episodeof severe hypoglycemia (25,26). Analysisof several risk factors revealed that thenumber of prior episodes of hypoglyce-mia was the strongest predictor of therisk of future hypoglycemia (25,26). Ele-gant work in the late 1980s by RobertSherwin and colleagues (27,28) (nota-bly, Stephanie Amiel, Don Simonson,and William Tamborlane) linked strictglycemic control to impaired glucosecounterregulation/hypoglycemia un-awareness; however, a causal linkbetween the latter and antecedenthypoglycemia had not been establishedat that time.

Indeed, conventional wisdom of thatera had (mis)attributed the cause of hy-poglycemia unawareness to diabetic au-tonomic neuropathy, until a convincingstudy in 1990 debunked that conclusion(29). Using an extensive battery of testsfor autonomic function, Ryder et al.(29) observed that 12 patients withdiabetes with hypoglycemia unaware-ness and 7 patients with defective

glucose counterregulation showed “lit-tle evidence of autonomic neuropathy.”If not autonomic neuropathy, then whatwas the cause of impaired counterregu-lation and hypoglycemia unawareness?Extrapolating from their data, the extantliterature (27,28,30), and clinical obser-vations of pseudohypoglycemic symp-toms in some normoglycemic (or evenhyperglycemic) patients, Ryder et al.(29) speculated that “frequent hypogly-caemia might cause a downward reset-ting” of putative hypothalamic sites “toexplain the hypoglycaemic counterregu-latory defect.” From about the late1980s onward, Cryer’s investigative ef-forts concentrated on the specific role ofhypoglycemia in the etiology of hypogly-cemia. Those efforts culminated in hismaximd“hypoglycemia begets hypo-glycemia,”quod erat demonstrandum!In 1991, Simon Heller and Cryer (31)demonstrated that a single episode ofhypoglycemia in the afternoon impairedthe hormonal, neurogenic, and neuro-glycopenic symptom responses to sub-sequent hypoglycemia the followingmorning in healthy volunteers. Thosefindings were subsequently replicatedin patients with type 1 diabetes whowere carefully selected for the absenceof autonomic neuropathy (32).

Hypoglycemia-AssociatedAutonomic Failure

Cryer coined the term hypoglycemia-associated autonomic failure (HAAF)in a review article in 1992 (33) and sub-sequently used it as the title of the de-scription of the syndrome in a 1993publication (32). As originally proposed(32,33), the concept of HAAF in diabetesposits that recent antecedent hypogly-cemia causes both defective glucosecounterregulation and hypoglycemiaunawareness during subsequent hypo-glycemia, thus creating a vicious cycleof recurrent hypoglycemia (Fig. 1) (34).The syndrome of HAAF was demon-strated in subjects without diabetes(31), in patients with type 1 diabetes(32), and in those with advancedtype 2 diabetes (35). Rodent models ofHAAF soon appeared (36), and additionalfeatures (including decreased baroreflexsensitivity and muscle sympathetic nerveactivity) were described following recentantecedent hypoglycemia in humans(37). An important question is whetherHAAF is adaptive or maladaptive. Clearly,

care.diabetesjournals.org Dagogo-Jack 2195

the vicious cycle of severe iatrogenic hy-poglycemia triggered by HAAF is malad-aptive. However, HAAF appears toprotect against brain damage (38) andfatal cardiac arrhythmias (39) from sub-sequent severe hypoglycemia in rats,findings that raise the possibility of anadaptive response, somewhat akin to is-chemic preconditioning (40). Recurrenthypoglycemia and HAAF also increasedgene expression of GAD and levels of theinhibitory neurotransmitterg-aminobutyricacid (GABA) in rat neurons (41).Although recent antecedent hypogly-

cemia was pivotal in the initial descrip-tion of HAAF, prior exercise (42) andsleep (43) were demonstrated to inducesimilar syndromes, thereby linking de-fective glucose counterregulation tothe well-known increased vulnerabilityto hypoglycemia after exercise and dur-ing sleep. Indeed, the demonstration ofsleep-induced HAAF by Salomon Ba-narer and Cryer (43) helps explain thepredilection of most episodes of severehypoglycemia for nocturnal hours (25).Although insulin action is highest atnighttime (44), that factor alone oughtnot pose a particular hazard for hypogly-cemia if counterregulatory functionwere intact. Cryer often stresses thatHAAF is pathophysiologically distinct fromclassic diabetic autonomic neuropathydastructural disorder characterized bynerve fiber loss. The veracity of that as-sertion is underscored by the discoveryby Fanelli et al. (45), Amiel and col-leagues (46), and Cryer and colleagues

(47,48) that components of the HAAFsyndrome are reversible in as little as2–3 weeks of scrupulous avoidance ofiatrogenic hypoglycemia. It is now stan-dard clinical practice to recommendcautious relaxation of glycemic controland strict avoidance of hypoglycemiaas a therapeutic strategy in patientswith recurrent hypoglycemia and HAAF(49,50). Seldom has a research findingfound its way so quickly into clinicalpractice.

A search of the medical literatureshowed just one article with specific refer-ence to HAAF in 1992; the term has sinceappeared in the title, subtitle, or text ofseveral thousand articles (Fig. 2). Twenty-five years ago, few would have imaginedthat an episode of hypoglycemia couldelicit such a panoply of neuroendocrine,electrophysiological, cardiovascular, geno-mic, biochemical, neurocognitive, andbehavioral responses! Cryer opened a Pan-dora’s box: his healthy infatuation with themechanisms of hypoglycemia stretched afield far beyond its traditional boundaries,opening up new vistas for inquiry anddiscovery. Unraveling the intricacies ofthis new physiology is an ongoing effortin numerous laboratories. To begin with,we do not yet have a unifying mecha-nism for the myriad manifestations ofHAAF. Several groups, including Cryer’s,have been testing a number of interest-ing potential mechanisms of HAAF (41,51–55). These studies suggest possiblecontributions from glucocorticoids (52),inhibitory thalamic centers (53), altered

gene expression in GABAergic neurons(41), and excitotoxicity pathways (55),among others, as possible mechanismsunderlying the syndrome of HAAF. Thefield opened up by Cryer and a coterieof dedicated hypoglycemia researchersno doubt will continue to intrigue andattract creative minds well into thefuture.

Case for a New Taxonomy

As originally proposed by Cryer, HAAF ischaracterized by a clinical or subclinicalevent (recent antecedent hypoglycemia),biochemical features (defective glucosecounterregulation, evidenced by attenu-ated glucagon and epinephrine re-sponses), and subjective manifestations(absent or impaired awareness of neuro-genic symptoms, arising from attenuatedsympathetic neural responses to hypogly-cemia) (32,33,51,54). Subsequent reportshave identified additional features asso-ciated with recent antecedent hypogly-cemia, including decreased baroreflexsensitivity andmuscle sympathetic nerveactivity in humans (37). Furthermore,HAAF is associated with neurocognitive/antiarrhythmogenic preconditioning(38,39) and increased GABAergic (41)tone in rodents. The etiology of the syn-drome itself has expanded to includeexercise (42) and sleep (43); thus, induc-tion of HAAF is no longer restricted tothe stimulus of recent antecedent hypo-glycemia. Although his disquisitive re-views (51,54) now recognize the diversecauses of HAAF (51,54), Cryer would admit

Figure 1—Schematic representation of theconcept of HAAF. Adapted with permissionfrom Awoniyi et al. (34). T1DM, type 1 di-abetes mellitus; T2DM, type 2 diabetesmellitus.

Figure 2—Publications with HAAF in the title, subtitle, or text, 1992–2014 (source: Google Scholar).

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that, semantically, HAAF has becomesomewhat of a misnomer for a func-tional autonomic disorder that is in-ducible by nonhypoglycemic stimuli.The taxonomic mismatch is likely towiden in the future, as additional in-ducers of HAAF are recognized. Perhapsit is time to consider “Cryer syndrome”as a descriptor for the foundationalconstruct of a reversible autonomicdisorder characterized by defectiveglucose counterregulation, hypoglyce-mia unawareness, and increased riskfor severe hypoglycemia that is in-duced by antecedent hypoglycemia,prior exercise, sleep, or other putativefactors.Admittedly, the use of eponyms in

medicine is in decline, after havingpeaked in the 1950s (56). Yet, eponymsdo have certain advantages, includingsuccinct communication, nosologic syn-thesis, and diagnostic parsimony. Con-sider the example of Cushing syndrome:Affected patients could present withweight gain, bruising, striae, osteoporo-sis, facial plethora, depression, diabetes,hypertension, and hirsutism, amongother features. The underlying etiologycould be an adrenal tumor, a pituitarytumor, exogenous glucocorticoid expo-sure, or ectopic ACTH or CRH secretion.Yet, the term Cushing syndrome is imme-diately informative and directs clinical be-havior along established paths. Adoptionof Cryer syndrome could deliver a similarparsimonious taxonomy for a complexdisorder of diverse etiologies character-ized by functional autonomic failure andmyriad neuroendocrine, physiological,behavioral, and clinical manifestations.As already noted, the features of Cryersyndrome are reversible (45–48), makingit a clinically relevant and treatable syn-drome. Pragmatically, a patient with di-abetes with a history of severe orrecurrent hypoglycemia and hypoglyce-mia unawareness can be presumed tohave Cryer syndrome. Given the imprac-ticality of routine documentation of de-fective counterregulation in the clinic, ahistory of hypoglycemia unawarenesscan be used as a surrogate for defectiveglucose counterregulation in the settingof recurrent antecedent hypoglycemia.Fortunately, self-reported hypoglyce-mia awareness status is reliable, as evi-denced by assessment of symptomscores during stepped hypoglycemiaclamp (47).

One drawback is that eponyms can befraught with rancorous priority dis-putes. Witness the eponym in Gravesdisease, which has been variouslysubstituted with the names of Parry,Basedow, March, Parsons, Flajani, Beg-bie, and others (57,58). Although Parryfirst described the condition in 1825,10 years before Graves and Basedow(57,58), Robert Graves was the first toconvincingly link the major diagnosticfeatures of goiter, palpitations, and ex-ophthalmos. The triumph of Graves overother eponyms illustrates Sir FrancisDarwin’s dictum that “in science thecredit goes to the man who convincesthe world, not to the man to whomthe idea first occurred” (59).

Back to Cryer

Cryer has had a global impact on the di-abetes field through his direct work andthe work of the more than 40 fellows hehas mentored. The many honors he hasreceived in recognition of his contribu-tions include the Banting Medal for Dis-tinguished Scientific Achievement andthe Albert Renold Award (for mentor-ship), both from the ADA; the ClaudeBernardMedal from the European Asso-ciation for the Study of Diabetes; theKellion Award from the Australian Dia-betes Society; the Rorer Clinical Investi-gator Award from the EndocrineSociety; the David Rumbaugh ScientificAward from JDRF; and an honorary doc-torate from the University of Copenha-gen, among others. Cryer is the onlyperson in the 75-year history of theADA to receive its Banting Medal for sci-entific achievement, serve as editor ofits prestigious journal Diabetes, and beelected president of the Association.An advocate for people with diabetes,Cryer frequently reminds his profes-sional colleagues that “hypoglycemia isthe limiting factor in the glycemic man-agement of diabetes.” That was thetheme of his Banting Lecture (1994)and his Claude Bernard Lecture (2001).Cryer consistently acknowledges thecontributions of collaborators andtrainees and expresses high regard andgratitude for their collaboration.

Formerly married to Susan ShipmanCryer, Cryer married Carolyn Havlin-Cryer in 1994. Their blended family in-cludes five childrendPhilip CliffordCryer, Justine Laurel Cryer Dugan, AnthonyVictor Havlin, Krista Victoria Havlin, and

Rebecca Elizabeth Havlin Eberhartdandsix grandchildrendKacy Elizabeth Cryer,Benjamin Philip Cryer, Matthew PhilipDugan, Emma Inez Dugan, Mollie BreanneHavlin, and Max Havlin Eberhart. At thetime of his retirement fromWashingtonUniversity in St. Louis in 2014, Cryer wasgreatly honored by the decision of theWilliam and Elaine Wolff Family, includ-ing their son Gary Wolff, to endow thePhilip E. and Carolyn E. Cryer Professorof Endocrinology and MetabolismChair at Washington University inSt. Louis.

Albeit as a listener and no longer a per-former, Cryer is a fan of the tight, four-part harmony of barbershop quartetsinging, a classic American art form; heeven knows the meaning of the acronymSPEBSQSA! He also enjoys nonmedicalreading, mostly of histories and biogra-phies, and counts the American writerand humorist Mark Twain (Samuel Clem-ens, 1835–1910) and the British mathe-matician, philosopher, and social criticBertrand Russell (1872–1970) among hisfavorite authors. Indeed, Cryer frequentlyprefaces his lectures with a quote fromRussell’s The Conquest of Happiness, firstpublished in 1930: “One of the symptomsof an approaching nervous breakdown isthe belief that one’s work is terribly im-portant” (60).

Summary

In closing, work championed by Cryer andothers clearly established the legitimacyof a syndrome of functional autonomic fail-ure, defective glucose counterregulation,hypoglycemia unawareness, and increasedrisk for recurrent severe hypoglycemia. Thesyndrome is inducible by recent antecedenthypoglycemia, prior exercise, or sleep.Finding a parsimonious descriptor forsuch amultifarious syndrome that capturesthe foundational construct and current(and potentially future) diverse etiologieshas become a challenge in medical taxon-omy. The proposed termCryer syndrome isanapt, succinct, andattributively congruentsolution.

Acknowledgments. S.D.-J. was a research fel-low in metabolism in Dr. Cryer’s group from1990 to 1992 and subsequently served as a fac-ulty member in the Division of Endocrinology,Diabetes and Metabolism at the WashingtonUniversity School of Medicine in St. Louis from1992 to 2000.

care.diabetesjournals.org Dagogo-Jack 2197

Funding. S.D.-J. is supported, in part, by grantsfrom the National Institutes of Health (R01DK067269, DK62203, and DK48411).

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