Adrenergic Mediation of Hypoglycemia-Associated Autonomic Failure.

1.1 MB·English

by  Ramanathan, Ranjani

ORIGINALARTICLE
Adrenergic Mediation of Hypoglycemia-Associated
Autonomic Failure
Ranjani Ramanathan and Philip E. Cryer
OBJECTIVE—We tested the hypothesis that adrenergic activa- causes both the syndrome of defective glucose counter-
tion, cholinergic activation, or both, mediate the effect of recent regulation (by reducing the adrenomedullary epinephrine
antecedenthypoglycemiatoreducethesympathoadrenalresponse response to subsequent hypoglycemia in the setting of
to subsequent hypoglycemia, the key feature of hypoglycemia- absent decrements in insulin and absent increments in
associatedautonomicfailureindiabetes,inhumans. glucagon)andofhypoglycemiaunawareness(byreducing
RESEARCH DESIGN AND METHODS—Seventeen healthy the sympathoadrenal and resulting neurogenic symptom
responses to subsequent hypoglycemia) (1–4). These two
adults were studied on 2 consecutive days on three occasions.
Day 1 involved hyperinsulinemic euglycemic (90 mg/dL 3 1 h), components of HAAF are both associated with a sub-
then hypoglycemic (54 mg/dL 3 2 h) clamps, in the morning stantially increased incidence of hypoglycemia during
and afternoon on all three occasions with 1) saline infusion, intensive therapy for diabetes (1). Perhaps the most com-
2) adrenergic blockade with the nonselective a-adrenergic and pellingevidenceoftheclinicaleffectofHAAFisthefinding,
b-adrenergic antagonists phentolamine and propranolol, or 3) originally in three independent laboratories (5–8), that as
adrenergic blockade plus cholinergic blockade with the musca- little as 2 to 3 weeks of scrupulous avoidance of hypogly-
rinic cholinergicantagonist atropinein random sequence.Day2
cemia reverses hypoglycemia unawareness and improves
involved similar morning euglycemic and hypoglycemic clamps,
theattenuatedepinephrinecomponentofdefectiveglucose
withsaline infusion,onallthreeoccasions.
counterregulation in most affected patients.
RESULTS—Compared with the responses to hypoglycemia The mechanisms of the attenuated sympathoadrenal
during saline infusion on day 1, the plasma epinephrine and response to hypoglycemia, the key feature of the patho-
norepinephrineresponsestohypoglycemiawerereducedonday genesis of HAAF in diabetes (1–8), are unknown (1). Al-
2(351613vs.214622pg/mLforepinephrineand25264vs.
though much of the neuroscience research into this issue
22667pg/mLfornorepinephrineduringthelasthour;bothP,
has focused on the hypothalamus (9), recent translational
0.0001). However, the plasma epinephrine and norepinephrine
researchhasraisedthepossibilitythatacomplexcerebral
responses to hypoglycemia were not reduced on day 2 when
network normally regulates the hypothalamic (and thus
adrenergic or adrenergic plus cholinergic blockade was pro-
ducedduringhypoglycemia onday1. the systemic sympathoadrenal) response to falling plasma
glucose concentrations (10–12) and that an inhibitory
CONCLUSIONS—Adrenergic blockade prevents the effect of
signalmediatedthroughthethalamusmightbeinvolvedin
hypoglycemia to reduce the plasma catecholamine responses to
the pathogenesis of HAAF (12).
subsequent hypoglycemia. Thus, adrenergic activation mediates
Hypoglycemia activates the sympathoadrenal system
the effect of recent antecedent hypoglycemia to reduce the
(1,13,14). This includes the release of catecholamines that
sympathoadrenalresponsetosubsequenthypoglycemia,thekey
feature of hypoglycemia-associated autonomic failure in diabe- interact with a-adrenergic and b-adrenergic receptors—
tes,in humans.Diabetes60:602–606, 2011 norepinephrine from sympathetic postganglionic neurons
and epinephrine and norepinephrine from the adrenal
medullae—andacetylcholinethatinteractswithmuscarinic
I cholinergic receptors—from sympathetic postganglionic
atrogenic hypoglycemia is the limiting factor in the neurons. Hypoglycemia also activates central nervous sys-
glycemic management of diabetes (1). It causes re- tem circuits, including those that involve adrenergic and
current morbidity in most people with type 1 di- cholinergic neurotransmission. There are, of course, an
abetes and in many with type 2 diabetes, and is array of other neurotransmitters released in the peripheral
sometimes fatal, impairs physiologic and behavioral de- and the central nervous systems.
fenses against subsequent hypoglycemia, and generally We used the original model of HAAF (2) and the nonse-
precludes maintenance of euglycemia over a lifetime of lective a-adrenergic and b-adrenergic antagonists phentol-
diabetes. The concept of hypoglycemia-associated auto- amineandpropranololaswellasthemuscariniccholinergic
nomic failure (HAAF) in diabetes posits that recent ante- antagonistatropineindosesshownpreviouslytobeboth
cedent hypoglycemia, as well as prior exercise or sleep, safe and effective (15) to test the hypothesis that ad-
renergic activation, cholinergic activation, or both, me-
diate the effect of recent antecedent hypoglycemia to
FromtheDivisionofEndocrinology,MetabolismandLipidResearch,Wash- reduce the sympathoadrenal response to subsequent hy-
ingtonUniversitySchoolofMedicine,St.Louis,Missouri. poglycemia,thekeyfeatureofHAAFindiabetes(1–8),in
Correspondingauthor:PhilipE.Cryer,[email protected]. humans.
Received27September2010andaccepted8November2010.
DOI:10.2337/db10-1374
Thecontentsofthisarticlearesolelytheresponsibilityoftheauthorsanddo RESEARCHDESIGNANDMETHODS
not necessarily represent the official view of the National Institutes of
This study was approved by the Washington University Human Research
HealthortheAmericanDiabetesAssociation.
(cid:1)2011bytheAmericanDiabetesAssociation.Readersmayusethisarticleas Protection Office and was conducted at the Washington University Clinical
longastheworkisproperlycited,theuseiseducationalandnotforprofit, ResearchUnit(CRU).
and the work is not altered. See http://creativecommons.org/licenses/by Participants.Studyparticipantscomprised17adults(7women,10men),with
-nc-nd/3.0/fordetails. amean(6SD)ageof2965yearsandaBMIof26.564.6kg/m2,whogave
602 DIABETES,VOL.60,FEBRUARY2011 diabetes.diabetesjournals.org
R.RAMANATHANANDP.E.CRYER
their written consent. They were in good health as determined by medical Statisticalmethods.Timeandconditionrelatedvariableswereanalyzedby
history, physical examination, and fasting plasma glucose and creatinine repeatedmeasuresmixedmodelANOVA.ValuesofP,0.05wereconsidered
concentrations,hematocrits,andelectrocardiogramsthatwerewithinnormal to indicate statistically significant differences. Data are expressed as the
referenceranges. mean6SE,exceptwheretheSDisindicated.
Experimental design. Participants were studied on 2 consecutive days on
three occasions, separated by at least 2 weeks, after overnight fasts. In-
travenouscatheterswereinsertedintoahandvein,withthathandkeptina RESULTS
;55°Cplexiglasboxforarterializedvenousbloodsampling,andintoacon-
Plasmaglucoseconcentrations,day1andday2.Plasma
tralateralantecubitalveinforinsulin,glucose,anddruginfusionsandinjections.
Day1involvedhyperinsulinemic(2.0mU/kg/min),euglycemic(90mg/dL glucose concentrations were clamped at euglycemic
[5.0mmol/L]31h),andthenhypoglycemic(54mg/dL[3.0mmol/L]32h) (;90 mg/dL [5.0 mmol/L]) and then hypoglycemic (;54
clampsinthemorningandagainintheafternoononallthreeoccasions.In- mg/dL [3.0 mmol/L]) levels in the morning and again in
travenousinfusionsduringtheseday1glucoseclampswere1)saline,2)the the afternoon—with intravenous infusions of saline,
nonselective a-adrenergic receptor antagonist phentolamine mesylate (70
phentolamine plus propranolol (adrenergic blockade), or
mg/kg,followedby7.0mg/kg/min)andthenonselectiveb-adrenergicantag-
onist propranolol hydrochloride (14 mg/kg, followed by 1.4 mg/kg/min), or phentolamine plus propranolol with injection of atropine
3)phentolaminepluspropranololandthemuscariniccholinergicantagonist (adrenergic plus cholinergic blockade)—on day 1 and on
atropine(1.0mginjectedintravenouslyattheendofeacheuglycemicclamp themorningofday2—withintravenousinfusionofsaline—
and60minintoeachhypoglycemicclamp)inrandomsequence.Thisexper- after saline, phentolamine plus propranolol, or phentol-
imental design is illustrated, with the actual plasma glucose concentration amine plus propranolol with atropine on day 1 on three
data,inFig.1.
separate occasions (Fig. 1). The glucose infusion rates re-
Plasmaglucoseconcentrationsweremeasuredevery5minatthebedside
quiredtomaintaintheclampsweresimilaronalloccasions
(YSI Glucose Analyzer, Yellow Springs Instruments, Yellow Springs, OH) to
guide20%glucoseinfusions.Heartratesandbloodpressures(GEDash3000, (data not shown).
Fairfield,CT)wererecordedat15-minintervals,andtheelectrocardiogramwas Responses on day 1. Compared with those during saline,
monitoredthroughout.Arterializedvenoussamplesfortheadditionalanalytes incrementsinplasmaepinephrine andnorepinephrinecon-
detailedbelowweredrawnat15-minintervalsduringthemorningeuglycemic centrations during hypoglycemia were increased about
andhypoglycemicclampsonbothdays.Thismodelofmorningandafternoon
threefold during adrenergic blockade and during adrener-
hypoglycemia reduces the sympathoadrenal response to hypoglycemia the
followingday(1–4),andthesedosesofphentolamine,propranolol,andatro- gicpluscholinergicblockade(bothP,0.0001;Fig.2).The
pine are safe and hemodynamically, metabolically, and symptomatically ef- finalepinephrinevalueswere352646pg/mL(1,9206251
fective(15). pmol/L), 1,040 6 160 pg/mL (5,680 6 873 pmol/L), and
Day 2 involved identical hyperinsulinemic euglycemic and then hypogly- 1,130 6 193 pg/mL (6,170 6 1,050 pmol/L), respectively.
cemic clamps, with saline infusion, in the morning on all three occasions. The final norepinephrine values were 257 6 19 pg/mL
Arterialized venous samples were again used to measure plasma glucose (1.5260.11nmol/L),809684pg/mL(4.7860.50nmol/L),
concentrations every 5 min and were drawn for the analytes detailed sub-
and 786 6 100 pg/mL (4.65 6 0.59 nmol/L), respectively.
sequentlyevery15min.
Analytic methods. Plasma glucose concentrations were measured with Increments in plasma pancreatic polypeptide concen-
aglucoseoxidasemethod(YSIGlucoseAnalyzer).Plasmainsulin,C-peptide, trations during hypoglycemia were similar during saline
growth hormone, and cortisol concentrations were measured with two site andduringadrenergicblockadebutwerepreventedduring
chemiluminescent assays (Immulite 1000, Siemens Corp., LosAngeles, CA). adrenergic plus cholinergic blockade.The finalpancreatic
Plasmaglucagonandpancreaticpolypeptideconcentrationsweremeasured polypeptidevalueswere356645pg/mL(85611pmol/L),
withLincoradioimmunoassays(Millipore,Temecula,CA).Plasmaepinephrine
374 6 42 pg/mL (89 6 10 pmol/L), and 75 6 9 pg/mL
and norepinephrine concentrations were measured with a single isotope-
derivative(radioenzymatic)method(16). (18 6 2 pmol/L), respectively.
FIG.1.Mean(SEswithinthesymbols)plasmaglucoseconcentrations FIG. 2. Mean (6 SE) plasma epinephrine, norepinephrine, and pan-
areshownduringmorningandafternoonhyperinsulinemiceuglycemic creatic polypeptide concentrations are shown during morning hyper-
and hypoglycemic clamps with intravenous infusions of saline (○), insulinemic euglycemic and hypoglycemic clamps with intravenous
phentolaminepluspropranolol (PTL+PRP,□)orphentolamineplus infusionsofsaline(○),phentolaminepluspropranolol(PTL+PRP,□),
propranololwithinjectionofatropine(PTL+PRP+Atropine,△)on orphentolamine pluspropranololwithatropine(△)onday1.TheP
day1andduringmorninghyperinsulinemiceuglycemicandhypoglyce- values represent comparisons with the values during saline infusion
micclampswithintravenousinfusionofsalineonday2aftersaline(●), (bothP<0.0001)forepinephrineandnorepinephrineandcomparisons
PTL+PRP(■)orPTL+PRP+Atropine(▲)onday1onthreesepa- withvaluesduringphentolaminepluspropranololwithatropine(P<
rateoccasions. 0.0001)forpancreaticpolypeptide.
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ADRENERGICMEDIATIONOFHAAF
Plasma concentrations of infused insulin stabilized at blockade on day 1 (Fig. 4). The epinephrine values during
;95mU/mL(570pmol/L)duringinfusionofsalinebutrose the last hour of hypoglycemia were 359 6 26 pg/mL
to ;120 mU/mL (720 pmol/L) during adrenergic blockade (1,960 6 142 pmol/L) and 375 6 11 pg/mL (2,050 6
andduringadrenergicpluscholinergicblockade(bothP, 60 pmol/L), respectively.
0.0001;Fig.3).Thefinalinsulinvalueswere9668mU/mL Similarly, the increment in the plasma norepinephrine
(576 6 48 pmol/L), 122 6 12 mU/mL (732 6 72 pmol/L), concentrationduringhypoglycemiawasattenuatedonday
and 123 6 9 mU/mL (738 6 54 pmol/L), respectively. 2 compared with that during saline on day 1 (P , 0.0001;
Increments in plasma glucagon concentrations during hy- Fig. 4). The norepinephrine values during the last hour of
poglycemia were similar on all three occasions (Fig. 3). hypoglycemia were 252 6 4 pg/mL (1.49 6 0.02 nmol/L)
The final glucagon values were 98 6 11 pg/mL (28 6 and22667pg/mL(1.3460.04nmol/L),respectively.The
3 pmol/L), 110 6 10 pg/mL (32 6 3 pmol/L), and 104 6 incrementsinplasmanorepinephrineduringhypoglycemia
7 pg/mL (30 6 2 pmol/L), respectively. were not reduced on day 2 after adrenergic blockade
Comparedwiththoseduringsaline,incrementsinplasma or adrenergic plus cholinergic blockade on day 1 (Fig. 4).
growth hormone and cortisol concentrations during hypo- The norepinephrine values during the last hour of hypo-
glycemia were increased during adrenergic blockade and glycemia were 284 6 11 pg/mL (1.68 6 0.06 nmol/L) and
adrenergic plus cholinergic blockade (P , 0.0001 under 256 6 11 pg/mL (1.51 6 0.06 nmol/L), respectively. Com-
bothconditionsforbothhormones;Fig.3).Thefinalgrowth paredwiththatduringsalineonday1,theincrementinthe
hormone values were13.36 2.2 ng/mL (5876 97pmol/L), plasma pancreatic polypeptide concentration during hy-
25.263.2ng/mL(1,1106141pmol/L),and20.762.8ng/mL poglycemia was attenuated by ;50% on day 2 under all
(914 6 124 pmol/L), respectively. The final cortisol values three study conditions (P , 0.0001; Fig. 4). The pancreatic
were 18.461.5mg/dL (508641nmol/L), 22.1 61.4mg/dL polypeptide values during the last hour of hypoglycemia
(610639nmol/L),and23.761.6mg/dL(654644nmol/L), were37366pg/mL(8961pmol/L)onday1and21667
respectively. pg/mL (52 6 2 pmol/L), 214 6 17 pg/mL (51 6 4 pmol/L),
Heart rate responses to hypoglycemia were decreased and239610pg/mL(5762pmol/L),respectively,onday2.
during adrenergic blockade and increased during adren- Plasma concentrations of infused insulin were stable
ergic plus cholinergic blockade compared with those and comparable to those during saline on day 1 during all
during saline (both P , 0.0001; Table 1). Systolic and di- three hyperinsulinemic euglycemic and hypoglycemic
astolic blood pressures were reduced during adrenergic clampsonday2(Fig.5).Comparedwiththatduringsaline
blockadeandduring adrenergicpluscholinergic blockade on day 1, the increments in the plasma glucagon concen-
(both P , 0.0001; Table 1). trationsduringhypoglycemiawerereducedunderallthree
Responses on day 2 compared with those during conditions on day 2 (P = 0.0263, 0.0008 and ,0.0001, re-
saline on day 1. Compared with that during saline on spectively; Fig. 5). The glucagon values during the last
day 1, the increment in the plasma epinephrine concen- hourofhypoglycemiaduringsalineinfusiononday1were
tration during hypoglycemia was attenuated by ;50% on 9961pg/mL(2860pmol/L).Theglucagonvaluesduring
day 2 (P , 0.0001; Fig. 4). The epinephrine values during thelasthourofhypoglycemiaonday2were8963pg/mL
thelasthourofhypoglycemiawere351613pg/mL(19206 (2661pmol/L),8362pg/mL(2461pmol/L),and8662
71 pmol/L) and 214 6 22 pg/mL (1170 6 120 pmol/L), pg/mL(2561pmol/L)aftersaline,adrenergicblockade,and
respectively. In contrast, the increments in plasma epi- adrenergicpluscholinergicblockadeonday1,respectively.
nephrine during hypoglycemia were not reduced on day This was also the case for increments in the plasma
2afteradrenergicblockadeoradrenergicpluscholinergic cortisolconcentrationsduringhypoglycemiaonday2(P=
0.0001, ,0.0001 and 0.0030) (Fig. 5). The cortisol values
duringthelasthourofhypoglycemiaduringsalineinfusion
onday1were17.360.7mg/dL(480619nmol/L).Cortisol
valuesduringthelasthourofhypoglycemiaonday2were
14.2 6 0.6 mg/dL (390 6 17 nmol/L), 13.5 6 1.0 mg/dL
(370628nmol/L),and15.061.1mg/dL(410630nmol/L)
after saline, adrenergic blockade, and adrenergic plus
cholinergic blockade on day 1, respectively. Compared
with that during saline on day 1, the increment in the
plasma growth hormone concentration during hypoglyce-
miawasreducedonday2(P=0.0028;Fig.5).Thegrowth
hormonevaluesduringthelasthourofhypoglycemiawere
12.660.5ng/mL(560622pmol/L)onday1and7.760.2
ng/mL (340 6 9 pmol/L) on day 2. In contrast, growth
hormone values during the last hour of hypoglycemia on
day 2 were not reduced after adrenergic blockade or ad-
renergic plus cholinergic blockade on day 1 210.8 6 0.8
ng/mL (480 6 35 pmol/L) and 14.0 6 1.4 ng/mL (620 6 62
pmol/L), respectively.
FIG. 3. Mean (6 SE) plasma insulin, glucagon, growth hormone, and DISCUSSION
cortisol concentrations are shown during morning hyperinsulinemic
euglycemicandhypoglycemicclampswithintravenousinfusionsofsa- We used a well-documented model of HAAF in diabetes
line (○), phentolamine plus propranolol (□), or phentolamine plus (hypoglycemia attenuates the sympathoadrenal response
pparoripsroannsolwoiltwhitthheatvraolpuiensed(u△ri)ngonsadlainye1,.bTohtehPPv<alu0e.0s0r0e1prfeosrenintscuolimn-, to hypoglycemia the following day) (1–4) and the classic
growthhormone,andcortisol. adrenergic and cholinergic antagonists phentolamine,
604 DIABETES,VOL.60,FEBRUARY2011 diabetes.diabetesjournals.org
R.RAMANATHANANDP.E.CRYER
TABLE1
Heart rate and blood pressure responses on day 1 during clamped hyperinsulinemic euglycemia (0800–0900 h) and hypoglycemia
(0900–1100h)
Saline PTL+PRP PTL+PRP+Atropine
HR sBP dBP HR sBP dBP HR sBP dBP
Clocktime (bpm) (mmHg) (mmHg) (bpm) (mmHg) (mmHg) (bpm) (mmHg) (mmHg)
0745h 6963 12563 7262 6962 12063 6862 6763 11963 6762
0800h 6862 12563 7162 7062 11864 6662 6963 11863 6862
0815h 7062 12463 7063 7162 11763 6362 7163 11463 6462
0830h 7163 12563 7062 7262 11563 6061 6963 11263 6462
0845h 7062 12463 7062 6962 11263 6062 6962 11163 6062
0900h 7162 12463 6862 6862 11363 5861 7764 11263 5962
0915h 7162 12564 6963 6962 11163 5762 9063 11163 6262
0930h 7263 12464 6863 6762 11063 5762 8663 11363 6062
0945h 7463 12364 6563 6762 11063 5562 8263 11063 5862
1000h 7663 12664 6462 6662 10862 5361 8262 10963 5762
1015h 7362 12563 6363 6662 10963 5262 8662 10963 5562
1030h 7362 12264 6163 6362 10563 5261 8462 10663 5362
1045h 7263 12264 6062 6062 10663 5161 8062 10663 5162
1145h 7363 11964 6062 6062 10663 5161 7762 10563 5162
Pvs.saline — — — ,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001
Valuesaremean6SE.dBP,diastolicbloodpressure;HR,heartrate;sBP,systolicbloodpressure;PTL,phentolamine;PRP,propranolol.
propranolol and atropine (13–15) to test the hypothesis sympathoadrenal, primarily adrenomedullary, response to
that adrenergic activation, cholinergic activation, or both, hypoglycemia(17),duringhypoglycemiaonday2.Thus,the
mediate the effect of recent antecedent hypoglycemia to phenomenon that we sought to explore mechanistically—
reduce the sympathoadrenal response to subsequent hy- recent antecedent hypoglycemia reduces the sympatho-
poglycemia, the key feature of HAAF in diabetes (1–8), in adrenal response to subsequent hypoglycemia (1–8)—was
humans. reproduced.
The data indicate that adrenergic mechanisms mediate However, when adrenergic blockade (without or with
theeffectofrecentantecedenthypoglycemiatoreducethe cholinergic blockade) was produced during hypoglycemia
sympathoadrenal response to subsequent hypoglycemia. on day 1, the increments in plasma epinephrine and nor-
Morning and afternoon hypoglycemia with saline infusion epinephrine concentrations during hypoglycemiaon day2
on day 1 led to attenuated increments in plasma epineph- werenotattenuated.Thus,combinedadrenergicblockade
rine and norepinephrine concentrations, markers of the with the nonselective a-adrenergic antagonist phentol-
amine and the nonselective b-adrenergic antagonist pro-
pranololpreventedtheeffectofhypoglycemiatoreducethe
FIG. 4. Mean (6 SE) plasma epinephrine, norepinephrine, and pan-
creatic polypeptide concentrations are shown during morning hyper-
insulinemiceuglycemicandhypoglycemicclampsonday1withsaline
infusion (○) and on day 2 after saline (●), phentolamine plus pro- FIG. 5. Mean (6 SE) plasma insulin, glucagon, growth hormone, and
pranolol(PTL+PRP,■),orphentolaminepluspropranololwithatro- cortisol concentrations are shown during morning hyperinsulinemic
pine (PTL + PRP + Atropine, ▲) during the clamps on day 1. The P euglycemicandhypoglycemicclampsonday1withsalineinfusion(○)
valuesrepresentcomparisonswiththevaluesduringsalineinfusionon andonday2aftersaline(●),phentolaminepluspropranolol(■),or
day1(○),P<0.0001forepinephrineandnorepinephrineonday2(●), phentolaminepluspropranololwithatropine(▲)duringtheclampson
andP<0.0001forpancreaticpolypeptideunderallthreeconditionson day1.ThePvaluesrepresentcomparisonswiththevaluesduringsaline
day2(●,■,and▲). onday1(○);seetextfordetails.
diabetes.diabetesjournals.org DIABETES,VOL.60,FEBRUARY2011 605
ADRENERGICMEDIATIONOFHAAF
sympathoadrenal response to subsequent hypoglycemia. Nordisk in the past year. No other potential conflicts of
The latter is the key feature of HAAF in diabetes (1–8). interest relevant to this article were reported.
The data do not disclose—but do not categorically R.R. and P.E.C. designed the study, R.R. conducted it,
exclude—an additional cholinergic mechanism. The and R.R. and P.E.C. analyzed the data and wrote the
sympathoadrenal response to hypoglycemia on day 2 was manuscript.
similar whether the muscarinic cholinergic antagonist at- Theauthorsacknowledgetheassistanceofthefollowing
ropine was or was not administered with phentolamine WashingtonUniversity staff: Licia Rowe, Laura Karsteter,
and propranolol during hypoglycemia on day 1. Nilima Parikh, Tanya Eden, Shirley Frei, Janice Bathon,
Morning and afternoon hypoglycemia with saline in- Paula Blood, and David Gibson of the Clinical Research
fusion on day 1 also led to attenuated increments in the Unit and of the Core Laboratory for Clinical Studies; the
plasma pancreatic polypeptide concentration, a marker of technicalassistanceofKrishanJethi,MS;andthestatistical
the parasympathetic response to hypoglycemia (18), dur- assistanceofLingChen,PhD,MPH.JanetDedekeprepared
inghypoglycemiaonday2.Incontrasttotheeffectonthe this manuscript.
sympathoadrenal response, adrenergic blockade (without
orwithcholinergicblockade)duringhypoglycemiaonday
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ACKNOWLEDGMENTS
neurogenicsymptomsarelargelytheresultofsympatheticneural,rather
This study was partly supported by National Institutes than adrenomedullary, activation. Am J Physiol Endocrinol Metab 2004;
of Health Grants R37-DK-27085 and UL1-RR-24992 and 287:E32–E41
by a fellowship award from the American Diabetes 18. Schwartz TW. Pancreatic polypeptide: a hormone under vagal control.
Gastroenterology1983;85:1411–1425
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606 DIABETES,VOL.60,FEBRUARY2011 diabetes.diabetesjournals.org