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Blood glucose and insulin response in patients with senile dementia of the Alzheimer's type
Blood Glucose and Insulin Response in Patients Senile Dementia of the Alzheimer's Type Carol H. Winograd, Daniel H. Jacobson, Jerome R. Minkoff, Cecilia A. Peabody, Brian S. Taylor, Leslie Widrow, and Jerome A. Yesavage
Introduction Some investigators have suggested that hospitalized patients with senile dementia of Alzheimer's type (SDAT) exhibit abnormal fasting glucose and insulin levels and abnormal responses to a glucose challenge, while others report no differences in carbohydrate metabolism between SDAT patients and control~. However, little data exist concerning glucose tolerance among community-dwelling patients with SDAT. We compared community-dwelling SDAT patients and controls using a standard oral glucose tolerance test (OGTr) under controlled dietary conditions. We measured glucose and insulin levels with fasting and in response to a glucose challenge.
Methods The six SDAT patients and six controls were age and sex matched, nondiabetic, communitydwelling, healthy (other than SDAT), normalweight individuals, not taking drugs known to
From the Depamuents of Medicine (CHW, DID. BST. $RML and Psychiatry and Behavioral Medicine (CAP. LW. JAY). S ~ f o f d Universi~ School of Medicine and the Palo Alto Veterans Affairs Medical Cenler (CHW. JRM. LW, JAY). Palo Alto, California. Address reprint requests to Dr. Winograd, ! 82B GRECC, Veterans Affairs Medical Center. 3801 Miranda Avenue, Patio Alto. CA 94304. Received September 7. 1990: revised Man:l~ .... 1991.
Published 1991 by Elsevier Science Publishing Co., inc.
afi~ct glucose tolerance. The SDAT patients, participants at the Stanford N ~ H C | i n ~ Research Center for the S t a y of Senile ~ n t i ' ~ , had "~3b~" A l z b e ~ ' s disease a c c ~ g m NINCDS-AD~A research ~.~a:fia (McKhann et al 1984). Autopsy on two ~tients w ~ s u ~ quently died confim:,ed ~ ~ ' s d~. The SDAT group had at least mild c ~ U v e ~pairmerit [scores >3.0 on the 7-point G I ~ ~ rioration Scale (GDS) (Reisberg et al 1982) <27 on the 30-point Mini-Men~ State Examination (MMSE; Folstein et al 1975)]. The controis scored I>28 on the ~ S E (Table 1). In the month prior to the O(311", ~ subjects had a normal physical e x ~ n a t i o n electrocardiogram. Laboratory data included normal electrolytes, liver, re~ial, ~ thyroid function tests, total cholesterol, c o + r . ~ h ~ count with d:~erential, piateiet count, sedimentation rate, minalysis, and syphilis screen. SDAT patients also had normal red cell and serum folate and fasting serum B~2. All subjects bad a body mass index (BMI) ~ 20% ,~f ideal body wei~3t (Keys et al 1972; et al 1976). Mean BMI did not differ between the two groups. A dietitian instructed aJ| participants and caregivers that subjects should c o n s u ~ at least 300 g of carbohydrate, two servings from both the :neat and milk group, and six servings from both the grain and fruit/vegetable ~ p s during
0(~6-322319b$03.50
Brief Repmu
II~ PSY~TIIY
1991;30:~-$I l
the ~ days pciof to the OGTr. F o l ~ w i ~ an overnight, lO-hr fast in the clinical research contcr, an OGTT was begun at 8 AM. After a standard oral 75-g glucose challenge, blood was drawn in the fasting state and at 30, 60, 120, and 180 rain ~ g h an indwelling cannula for plasma glucose (enzymatic method; Kadish et al 1968) and insulin concentrations (radioimmunoassay; Hales and Randle 1963). Student's two-tailed t test for matched was used to determine significance, comparing values at the initial time point (fasting levels) and the overall response. Overall response was c~ulated as the total integrated area subtended by glucose and insulin concentrations over 180 min.
Discussion
Though the number of subjects was small, we find no significant differences in plasma glucose of I ~ levels while fasting of in response m an OGTT among community-dwelling SDAT ~ e a t s when ~ with controls. These d~a do not ~ the conjecture of abr,ormal ~ y d r a t e metabolism in SDAT pati~ts. In contrast to our findings, Bucht et al (1983) and Adolfsson et al (1980) reported that hospi~ SDAT ~ had a lower fasting blood glucose level than did hospitalized nonSDAT patients. They also found that during an o G T r , patients with SDAT have decreased blood glucose concentrations and elevated serum imulin levels, indicating a changed cmtmhydrate metabolism when compmzd with mmSDAT, hosResults pitaliznd patients and healthy, communityNo statistically siLnificant differences were doc- dwelling elderly controls. In support of our findumented between the SDAT and control ~ p s ings, Fisman et al (1988) reptmed no significant in fasting plasma glucose or insulinconcenlra- differences in fasting glucose and inmlin levels tion (Table 2). The mean glucose and insulin in SDAT patients compared with healthy convalues as well as the incremental areas during trois. Similady, de Leon et al (1988) found no the OGTF did not differ (Figures ! and 2). The differences between SDAT patients and controls overall glucose and insulin response also did not in fasting glucose and insulin after a 12-hr fast. differ significantly between the two groups. The The inconsistent results previously reported average area under the glucose curve for the perhaps have resulted ftmn a pooHy defmed hospatien~ and controls was 394 and 450 mg/dl, pitalized patient population, controls with abrespectively, with an average difference of - 56 normal carb~ydrate metabolism and poor dimg/dl (SEM - __.56, p = 0.37). The average etary and body weight control. Both the Bucht a r e a u n d e r the insuil~ : u r v e f o r [he patients a~d and Fisman studies did not base the diagnosis controls Was 125 a n d 135 ~ U / m i _ re.~zectivelv nf SDAT on ~'~d*~;-..iz~ ,~.,.,.h ..~,--.;o q r l Ilt4~m l i ~ 1 ) o.,a with an average difference of - lO itU/ml (SEM did not clearly docu~::,, the severity of de= -+28, p = 0.73). rnentia. All SDAT patients in our study were .
.
.
.
.
.
.
.
.
.
.
r" .
.
.
.
.
.
J'
vm
~,q~mq~lmm
swim
Table I. Descriptive Characteristics of SDAT Patients and Age-Matched Controls"
Age (yr) Sex (l/M) Bc~-ly mass index (kg/m2) Mini-MentM Status Exam (30 points) Global [kterim'm'on Scale (7 points) mV~ues are the mean _. SEM.
SDAT (n = 6)
Conerol (n = 6)
Diffm~nce
72.2 2/4 24.8 19.0 3.9
70.5 2/4 25.0 29.7
1.7 ± 0.8 -- 0 . 2 ± 2.4 - 1 0 . 7 ± 2.2
p value 0.09 m 0.94 0.004
Brief Repro'Is
~YCH~T~Y
Table 2. Fasting Glucose and Insulin in SDAT Patients and Age-Matched Controls" SDAT Control (a = 6) (n = 6) Difference p valee
Fastingphsm Oecose
95.0
870
8.0 ± 3.9
0°09
absence of diabetes, ~ ~ of medicaliot~ that could affect glucose m e , ~ d s m . ally, they all followed a specL~:~ld~t for 3.~ y s and fasted overnight before t ~ ~ .
prior
SDAT
~ts with either ~ t a l i z e d or ~ ~ y ~m~dl~ dwelling controls. Bucht, Adogfsson, ~ t ~ I0 14 -4 ± 6 054 co|leagues compared SDAT s u ~ to ~ painsulin tients in ~ ~-ute ~ i t a l {Ado~sson ~ a,! | ~ {mtUYml) Bucht et al 1983) who ~ d i a l s assoc~ "Velueslme eh~ ~ ± SEM w/th ~abetes mellims (e.g., cerebrovascular disease,~ gangrene, and ~ failure) comamnity-dwe~ cotarols ~uci~ et al 1983). classified as suffering from "'probable" AIz- The f i ~ d ~ t inclusionof ~ ~ w~ heimer's disease accoMing to NINCDS-ADRDA abnormal carhohy~te metabolism may explain guideliw~s. Although both Bucht et al (1983) the differences reported. Fisman ~ ~ , ~ ~ s with c ~ and Fisman et al (1988) controlled for weight compared h o s p i t a l ~ ~ n t s among the patients, they did not document the nity-living controls. Hospitalization itself may exclusion of subjects not within 20% of their have affected me results ~ ~ phys~al i~mcideal body weight. Additionally, only Fisman fivitycommon among hospitalized patients may and co-workers (1988) controlled for variation reduce glucose tolerance (Fajans 1989). In conpatients ~ cow,trois in diet. Our patients were closely matched for trast, in our study ~ age and sex and selected for normal weight, were ambulatory, con'anuni~welling ~ i d -
180
160
140" .,.=,.
~_. 12o
,y
r u
|
-
0
[ g
6o.
E 40" ""O" 20"
oi
SDAT | n ~ Control ~ = ~
60
120
180
Time ~an) Figure I. Mean _ SEM glucose response during an OGTF in SDAT ~
~
age-~
controls.
Brief Reports
BIOL I~YCHIATRY I ~ ! ;30:~7~ 511
510
60.
t
50-
;3 ..-3
/
40.
8 3o.
20
f
10
0
30
60
120
--0--
SDAT (n=6)
--4P--
Control (nffi6)
180
Time {rain}
Figure 2. Mean ± SEM insulin concentration during an OGTI" in SDAT patients and age-matched controls.
uals with no cow~:orbid copditions known to affect glucose zolcrance. In summary, our small study could not confirm abnormal fasting glucose or insulin levels, or abnormal responses to an O G T r in SDAT patients, and suggests that community-dwelling SDAT patients have normal carbohydrate metabolism. The authors wish to thank Lissy F. Jarvik, M.D., _Ph.D., Lincoln Moses, Ph.D., Sarah L. Poulsen, A.B., and Gerald M. Reaven, M.D. for their critical review and recommendations. This work was supported by the Veterans Affairs and the National Institute of Mental Health grant number MH4004!, of which Dr. Winogradwas the recipient. Daniel Jacobson's work was supported by the Stanford Medical Student Scholars Program.
References
Adol:~so~ ~, "~ Buch~ G, I. i~hr~r F, Winblad B (1980): Hvoog!vce~Aa ia Alzhe!mer's disease. Acta Med -,=.-,t..~. J _
l~.JOU,
Bucht G, Adolfssoa R, Lithner F, Winblad B (1983): Changes in blo~d glucose and insulin secretion in patients with senile dementia of Alzheimer type. Acta Med Stand 213:387-392. de Leon MJ, McRae T, Tsai JR, et ai (1988): Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 2:391-392. Letter. Fajans SJ (1989): Diabetes mellitus: Classification and testing procedures. In DeGroot LJ (ed), Endocrinology. Ph_!ilad~lpbJa: Saun~,~, pp 1~A346 --~ 1356. Fisman M, Gordon B, Feleld V, Helmes E, McDonald T, Dupre J (1988): Metabolic changes in Alzheimer's disease. J Am Geriatr Soc 36:298300. Folstein MF, Folstein SE, McHugh PR (1975): "MiniMen~l State": A practical method for grading the cognitive state o: patients for the clinician. J Psy~ chiorr Res 12:18°-!98. Hales CN, Randle PJ (1963): Lnmnunoassayof insulin wiuh insulin-antibody precipitate. Biochem J 88:137-142. Kadish AH, Litle RL, Sternbcrg JH (!968): A new and rapid method for detem'dnation of glucose by
Brief Reports
measurement of rate of oxygen consumption. C?in C ~ m 14:116-131.
Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL (1972): Indices of relative weight and obesity. J Chronic Dis 25"329-343. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): C|inica] diagnosis of Alzheimer's di~ase: Report of the NINCDSADRDA Work Group under the auspices of the Degarm~nt of Health and Human Ser¢iq:es Task
toOL ~ Y ~ A ~ Y
5| t
Force on A L ? ~ ' s ~ . N e a r ~ , ~.~39944. Reisberg B, Forth SH, de Leon M$, Crook T (! ~2): The Globai D e t e r i ~ o a Scale for assessment of Primary Degenerative Demeaf~. ~ J P~,¢~tr~' 139:1136-1 ]39. Thomas AE, McKay DA, CutL~ MB (19/6): A ograph ~ h ~ g l for a s k i n g body wcigh.~. Am J Clin Nutr 29:302-304.
Introduction Some investigators have suggested that hospitalized patients with senile dementia of Alzheimer's type (SDAT) exhibit abnormal fasting glucose and insulin levels and abnormal responses to a glucose challenge, while others report no differences in carbohydrate metabolism between SDAT patients and control~. However, little data exist concerning glucose tolerance among community-dwelling patients with SDAT. We compared community-dwelling SDAT patients and controls using a standard oral glucose tolerance test (OGTr) under controlled dietary conditions. We measured glucose and insulin levels with fasting and in response to a glucose challenge.
Methods The six SDAT patients and six controls were age and sex matched, nondiabetic, communitydwelling, healthy (other than SDAT), normalweight individuals, not taking drugs known to
From the Depamuents of Medicine (CHW, DID. BST. $RML and Psychiatry and Behavioral Medicine (CAP. LW. JAY). S ~ f o f d Universi~ School of Medicine and the Palo Alto Veterans Affairs Medical Cenler (CHW. JRM. LW, JAY). Palo Alto, California. Address reprint requests to Dr. Winograd, ! 82B GRECC, Veterans Affairs Medical Center. 3801 Miranda Avenue, Patio Alto. CA 94304. Received September 7. 1990: revised Man:l~ .... 1991.
Published 1991 by Elsevier Science Publishing Co., inc.
afi~ct glucose tolerance. The SDAT patients, participants at the Stanford N ~ H C | i n ~ Research Center for the S t a y of Senile ~ n t i ' ~ , had "~3b~" A l z b e ~ ' s disease a c c ~ g m NINCDS-AD~A research ~.~a:fia (McKhann et al 1984). Autopsy on two ~tients w ~ s u ~ quently died confim:,ed ~ ~ ' s d~. The SDAT group had at least mild c ~ U v e ~pairmerit [scores >3.0 on the 7-point G I ~ ~ rioration Scale (GDS) (Reisberg et al 1982) <27 on the 30-point Mini-Men~ State Examination (MMSE; Folstein et al 1975)]. The controis scored I>28 on the ~ S E (Table 1). In the month prior to the O(311", ~ subjects had a normal physical e x ~ n a t i o n electrocardiogram. Laboratory data included normal electrolytes, liver, re~ial, ~ thyroid function tests, total cholesterol, c o + r . ~ h ~ count with d:~erential, piateiet count, sedimentation rate, minalysis, and syphilis screen. SDAT patients also had normal red cell and serum folate and fasting serum B~2. All subjects bad a body mass index (BMI) ~ 20% ,~f ideal body wei~3t (Keys et al 1972; et al 1976). Mean BMI did not differ between the two groups. A dietitian instructed aJ| participants and caregivers that subjects should c o n s u ~ at least 300 g of carbohydrate, two servings from both the :neat and milk group, and six servings from both the grain and fruit/vegetable ~ p s during
0(~6-322319b$03.50
Brief Repmu
II~ PSY~TIIY
1991;30:~-$I l
the ~ days pciof to the OGTr. F o l ~ w i ~ an overnight, lO-hr fast in the clinical research contcr, an OGTT was begun at 8 AM. After a standard oral 75-g glucose challenge, blood was drawn in the fasting state and at 30, 60, 120, and 180 rain ~ g h an indwelling cannula for plasma glucose (enzymatic method; Kadish et al 1968) and insulin concentrations (radioimmunoassay; Hales and Randle 1963). Student's two-tailed t test for matched was used to determine significance, comparing values at the initial time point (fasting levels) and the overall response. Overall response was c~ulated as the total integrated area subtended by glucose and insulin concentrations over 180 min.
Discussion
Though the number of subjects was small, we find no significant differences in plasma glucose of I ~ levels while fasting of in response m an OGTT among community-dwelling SDAT ~ e a t s when ~ with controls. These d~a do not ~ the conjecture of abr,ormal ~ y d r a t e metabolism in SDAT pati~ts. In contrast to our findings, Bucht et al (1983) and Adolfsson et al (1980) reported that hospi~ SDAT ~ had a lower fasting blood glucose level than did hospitalized nonSDAT patients. They also found that during an o G T r , patients with SDAT have decreased blood glucose concentrations and elevated serum imulin levels, indicating a changed cmtmhydrate metabolism when compmzd with mmSDAT, hosResults pitaliznd patients and healthy, communityNo statistically siLnificant differences were doc- dwelling elderly controls. In support of our findumented between the SDAT and control ~ p s ings, Fisman et al (1988) reptmed no significant in fasting plasma glucose or insulinconcenlra- differences in fasting glucose and inmlin levels tion (Table 2). The mean glucose and insulin in SDAT patients compared with healthy convalues as well as the incremental areas during trois. Similady, de Leon et al (1988) found no the OGTF did not differ (Figures ! and 2). The differences between SDAT patients and controls overall glucose and insulin response also did not in fasting glucose and insulin after a 12-hr fast. differ significantly between the two groups. The The inconsistent results previously reported average area under the glucose curve for the perhaps have resulted ftmn a pooHy defmed hospatien~ and controls was 394 and 450 mg/dl, pitalized patient population, controls with abrespectively, with an average difference of - 56 normal carb~ydrate metabolism and poor dimg/dl (SEM - __.56, p = 0.37). The average etary and body weight control. Both the Bucht a r e a u n d e r the insuil~ : u r v e f o r [he patients a~d and Fisman studies did not base the diagnosis controls Was 125 a n d 135 ~ U / m i _ re.~zectivelv nf SDAT on ~'~d*~;-..iz~ ,~.,.,.h ..~,--.;o q r l Ilt4~m l i ~ 1 ) o.,a with an average difference of - lO itU/ml (SEM did not clearly docu~::,, the severity of de= -+28, p = 0.73). rnentia. All SDAT patients in our study were .
.
.
.
.
.
.
.
.
.
.
r" .
.
.
.
.
.
J'
vm
~,q~mq~lmm
swim
Table I. Descriptive Characteristics of SDAT Patients and Age-Matched Controls"
Age (yr) Sex (l/M) Bc~-ly mass index (kg/m2) Mini-MentM Status Exam (30 points) Global [kterim'm'on Scale (7 points) mV~ues are the mean _. SEM.
SDAT (n = 6)
Conerol (n = 6)
Diffm~nce
72.2 2/4 24.8 19.0 3.9
70.5 2/4 25.0 29.7
1.7 ± 0.8 -- 0 . 2 ± 2.4 - 1 0 . 7 ± 2.2
p value 0.09 m 0.94 0.004
Brief Repro'Is
~YCH~T~Y
Table 2. Fasting Glucose and Insulin in SDAT Patients and Age-Matched Controls" SDAT Control (a = 6) (n = 6) Difference p valee
Fastingphsm Oecose
95.0
870
8.0 ± 3.9
0°09
absence of diabetes, ~ ~ of medicaliot~ that could affect glucose m e , ~ d s m . ally, they all followed a specL~:~ld~t for 3.~ y s and fasted overnight before t ~ ~ .
prior
SDAT
~ts with either ~ t a l i z e d or ~ ~ y ~m~dl~ dwelling controls. Bucht, Adogfsson, ~ t ~ I0 14 -4 ± 6 054 co|leagues compared SDAT s u ~ to ~ painsulin tients in ~ ~-ute ~ i t a l {Ado~sson ~ a,! | ~ {mtUYml) Bucht et al 1983) who ~ d i a l s assoc~ "Velueslme eh~ ~ ± SEM w/th ~abetes mellims (e.g., cerebrovascular disease,~ gangrene, and ~ failure) comamnity-dwe~ cotarols ~uci~ et al 1983). classified as suffering from "'probable" AIz- The f i ~ d ~ t inclusionof ~ ~ w~ heimer's disease accoMing to NINCDS-ADRDA abnormal carhohy~te metabolism may explain guideliw~s. Although both Bucht et al (1983) the differences reported. Fisman ~ ~ , ~ ~ s with c ~ and Fisman et al (1988) controlled for weight compared h o s p i t a l ~ ~ n t s among the patients, they did not document the nity-living controls. Hospitalization itself may exclusion of subjects not within 20% of their have affected me results ~ ~ phys~al i~mcideal body weight. Additionally, only Fisman fivitycommon among hospitalized patients may and co-workers (1988) controlled for variation reduce glucose tolerance (Fajans 1989). In conpatients ~ cow,trois in diet. Our patients were closely matched for trast, in our study ~ age and sex and selected for normal weight, were ambulatory, con'anuni~welling ~ i d -
180
160
140" .,.=,.
~_. 12o
,y
r u
|
-
0
[ g
6o.
E 40" ""O" 20"
oi
SDAT | n ~ Control ~ = ~
60
120
180
Time ~an) Figure I. Mean _ SEM glucose response during an OGTF in SDAT ~
~
age-~
controls.
Brief Reports
BIOL I~YCHIATRY I ~ ! ;30:~7~ 511
510
60.
t
50-
;3 ..-3
/
40.
8 3o.
20
f
10
0
30
60
120
--0--
SDAT (n=6)
--4P--
Control (nffi6)
180
Time {rain}
Figure 2. Mean ± SEM insulin concentration during an OGTI" in SDAT patients and age-matched controls.
uals with no cow~:orbid copditions known to affect glucose zolcrance. In summary, our small study could not confirm abnormal fasting glucose or insulin levels, or abnormal responses to an O G T r in SDAT patients, and suggests that community-dwelling SDAT patients have normal carbohydrate metabolism. The authors wish to thank Lissy F. Jarvik, M.D., _Ph.D., Lincoln Moses, Ph.D., Sarah L. Poulsen, A.B., and Gerald M. Reaven, M.D. for their critical review and recommendations. This work was supported by the Veterans Affairs and the National Institute of Mental Health grant number MH4004!, of which Dr. Winogradwas the recipient. Daniel Jacobson's work was supported by the Stanford Medical Student Scholars Program.
References
Adol:~so~ ~, "~ Buch~ G, I. i~hr~r F, Winblad B (1980): Hvoog!vce~Aa ia Alzhe!mer's disease. Acta Med -,=.-,t..~. J _
l~.JOU,
Bucht G, Adolfssoa R, Lithner F, Winblad B (1983): Changes in blo~d glucose and insulin secretion in patients with senile dementia of Alzheimer type. Acta Med Stand 213:387-392. de Leon MJ, McRae T, Tsai JR, et ai (1988): Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 2:391-392. Letter. Fajans SJ (1989): Diabetes mellitus: Classification and testing procedures. In DeGroot LJ (ed), Endocrinology. Ph_!ilad~lpbJa: Saun~,~, pp 1~A346 --~ 1356. Fisman M, Gordon B, Feleld V, Helmes E, McDonald T, Dupre J (1988): Metabolic changes in Alzheimer's disease. J Am Geriatr Soc 36:298300. Folstein MF, Folstein SE, McHugh PR (1975): "MiniMen~l State": A practical method for grading the cognitive state o: patients for the clinician. J Psy~ chiorr Res 12:18°-!98. Hales CN, Randle PJ (1963): Lnmnunoassayof insulin wiuh insulin-antibody precipitate. Biochem J 88:137-142. Kadish AH, Litle RL, Sternbcrg JH (!968): A new and rapid method for detem'dnation of glucose by
Brief Reports
measurement of rate of oxygen consumption. C?in C ~ m 14:116-131.
Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL (1972): Indices of relative weight and obesity. J Chronic Dis 25"329-343. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): C|inica] diagnosis of Alzheimer's di~ase: Report of the NINCDSADRDA Work Group under the auspices of the Degarm~nt of Health and Human Ser¢iq:es Task
toOL ~ Y ~ A ~ Y
5| t
Force on A L ? ~ ' s ~ . N e a r ~ , ~.~39944. Reisberg B, Forth SH, de Leon M$, Crook T (! ~2): The Globai D e t e r i ~ o a Scale for assessment of Primary Degenerative Demeaf~. ~ J P~,¢~tr~' 139:1136-1 ]39. Thomas AE, McKay DA, CutL~ MB (19/6): A ograph ~ h ~ g l for a s k i n g body wcigh.~. Am J Clin Nutr 29:302-304.