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Diabetologia 8, 3r (1972) 169 by Springer-Verlag~1972 Day-to-Day Variation of Continuously Monitored Glycaemia: A Further Measure of Diabetic Instability*

G.D. Molnar, W.F. Taylor, M.M. Ho

Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U. S. A.

Received: April 25, 1972, accepted: June 22, 1972

Summary. Differences between paired blood glucose values during two successive 24-h periods of continuous blood glucose analysis were investigated during 22 studies in seven unstable diabetics, three stable diabetics, and three normaI subjects. The absolute means (without regard to sign) of daily differences (MODD) were high in unstable diabetics (36.6 to 158.1 mg/100 ml), intermediate in

stable diabetics (10.2 to 35.1 rag/100 ml), and low in normals (6.2 to 8.2 mg/100 ml). MODD was a measure of

the blood glucose changes resulting from day-to-day

variation in response to therapy that was kept as constant as possible. When therapy was deliberately intensified

through the use of four daily injections of short-acting insulin, MODD decreased in five of six such experiments. In two diabetics retested at intervals of 5 to 7 months without change in insulin regimen, MODD values re- mained similar. MODD quantifies another characteristic of blood glucose behaviour, the between-day variability; this is an important complement of the mean amplitude of

glyeaemic excursions (MAGE, a measure of within-day variability) and of the mean blood glucose concentration,

MBG (the overall level of glycaemia during the variability measurements). Variation quotidienne de la glyedmie enregistrde en eon- tinu: une mesure suppldmentaire de l'instabilitd diabdtique

Rdsumd. L'analyse continue de la glyc@mie pendant deux p@riodes suecessives de 24 heures a permis d'dtablir la diff@rence entre les valeurs coupl4es du glucose sanguin pour chaque p6riode, au cours de 22 dtudes chez 7 diabd- tiques instables, 3 diabdtiques stables et 3 sujets normaux. Chez les diab@tiques instables, la moyenne absolue des diff@rences quotidiennes (MADQ) dtait 61evde (36.6 158.1 mg/1O0 nil), interm@diaire chez les diab6tiques stables (10.2 k 35.1 mg/1OO ml) et basse ehez les sujets

normaux (6.2 ~ 8.2 mg/1OO ml). La MADQ mesurait les ehangements de la glyegmie dus aux variations quoti- diennes de la r@onse au traitement, lequel trait aussi constant que possible. Duns six exp6riences, l'augmenta- tion intentionnelle du traitement, par l'injection d'insuline rapide 4 lois par jour, provoqua une diminution de la MADQ k cinq reprises. Chez deux diabdtiques 6tudids ~ in- tervalles de 5 ~ 7 mois, sans changement de traitement, la

MADQ est rest@e semblable. La MADQ earact6rise aussi la variabilit@ quotidienne de la glyedmie, eompl~ment important .k l'amplitude moyenne des

variations du glu- cose sangum pendant la journ@e (AMVG) et ~ la glye6mie moyenne (GSM) au tours de la m6me p6riode. Tag-zu-Tag-Schwankungen des kontinuierlich gemesse- hen Blutzuekers: ein weiteres Marl f~r die Lab~liti~t des Diabetes

Zusammenfassung. Es wurden die Differenzen zwi- schen den beiden einander zugeordneten Blutzucker- werten w/ihrend zwei aufeinanderfolgender 24-Stunden Perioden einer kontinuierliehen Blutzuckeranalyse bei 22 Untersuehungen an sieben labilen Diabetikern, drei stabilen Diabetikern und drei Normalpersonen unter- sucht. Der absolute Durchsehnittswert der tgglichen Differenzen (MODD) (ohne das Vorzeiehen zu beachten) war bei den labilen Diabetikern hoch (36.6 bis 158.1 rag/ 100 ml), weniger hoch bei den stabilen Diabetikern (10.2 bis 35.1 mg/100 ml) und niedrig bei den Normalen (6.2 bis

8.2 mg/100 nil). Der Mittelwert der ti~gliehen Unterschie-

de (MODD) war ein Mat? der Anderungen der Blutglueose- konzentration auf Grund yon Tag-zu-Tag-Schwankungen als Folge der Therapie, die so konstant wie m6glieh ge- halten wurde. Wenn die Therapie betrgchtlieh intensiviert wurde, indem vier t/igliehe Insulininjektionen eines kurz- wirkenden Insulins gegeben wurden, verminderte sieh der Mittelwert bei 5 yon 6 Untersuehungen. Bei zwei Dia- betikern, die naeh 5 bis 7 Monaten ohne Ver/~nderungen der Insulinbehandlung wieder untersueht wurden, blieben die MODD-Werte/~hnlich. Sic sind ein Mal3 einer weiteren Eigenschaft des Blutzuekerverhaltens, n/~mlich der

Sehwankungen yon Tag zu Tag. Dies ist eine wiehtige Ergi~nzung zu den Messungen tier durchschnittlichen

Amplitude der Blutzuckerkurve (MAGE, ein Mal~ der

Sehwankungen innerhalb eines Tages) und der durch- sehnittlichen Blutzuckerkonzentration, MBG (dureh- schnittlieher Blutzuekerspiegel wghrend der Messung der

Blutzuckerschwankungen).

Key words: Blood glucose variability, Continuous blood glucose analysis, Insulin therapy, Unstable dia- betes.

After 50 years of the therapeutic use of insulin,

restoring normal blood glucose homoeostasis in diabetic patients has not been achieved [1, 2]. This is parti- cularly so in diabetics who are most lacking in endo- genous insulin [3]. If progress is to be made in therapy

* This investigation was supported in part by Re- search Grant AM-I0152 from the National Institutes of

]-[ealth, Public Health Service, and by a grant from the

Endieott-Bohn Foundation.

toward normal blood glucose homoeostasis achieve- ment, the causes of the differences between normal and deranged behaviour must be identified and measured [4]. In an effort to determine why current "optimal" diabetic therapy fails to achieve blood glucose normal- ization in more than just a general [5] or an indirect way [6], we have performed studies with continuous monitoring of blood glucose and have attempted to identify and measure the differences between diabetic

Vo[. 8, No. 5, 1972 G.D. Molnar et al. : Day-to-Day Variation of Continuously Monitored Glycaemia 343 and normal blood patterns [1, 2]. A previous report

dealt with higher mean levels of glycaemia and the wider blood glucose fluctuations of diabetics [2]. This report identifies and quantifies the greater day-to-day variability of diabetics. Recently, we have described, as a measure of blood glucose regulatory stability, the mean amplitude of glycaemic excursions (MAGE) during continuous blood glucose monitoring of ambulatory, fed subjects under standardized living conditions [2]. In that work, we were concerned mainly with within-day blood glucose swings, although day-to-day changes also were ex- amined. We observed that some diabetic patients with wide within-day blood glucose swings (high MAGE values) had relatively more consistent blood glucose patterns from day to day than did others with similar

MAGE values. Conversely, some patients With lower

IVIAGE values had less consistent blood glucose patterns from day to day. Evidently, MAGE and the diurnal mean blood glucose level do not identify or quantify the day-to-day component of blood glucose variation. Others also have considered day-to-day blood glucose variation [5, 7--9] in attempting to quantify diabetic instability, but on the basis of intermittent blood glucose determinations and generally under less highly standardized conditions.

We report herein our findings concerning the mean

of daily blood glucose differences (MODD) of paired blood glucose values on successive days. As anticipated in a previous report [4], this new parameter seems to be a useful additional quantification of blood glucose regulatory stability, along with MAGE and the diurnal mean blood glucose level. Methods Our methods of study, which combined prolonged metabolic investigations with 48-hour-long continuous blood glucose monitoring, as well as the clinical features of the subjects we investigated, have been described in detail [1, 10]. Two programs of clinically optimal therapy with insulin were developed and used for the unstable diabetics [1]. One was the once or twice daily injection of intermediate-acting insulin, with or without short-acting insulin, from the same syringe. The other was the four times daily injection of short-acting insulin. The time schedule of insulin injections, meals, exercise, and sleep was consistent throughout the studies (Fig. 1 through 4). The diet provided major meals of equal calories and equal com- position (by weight and analysis) of carbohydrate, of protein and fat content within each day and between days [1]. The exercise consisted of a 1-hour walk in the third postprandial hour. The subjects were train- ed to walk at a similar pace during each exercise period [1]. The analytic methods, including the con- tinuous automated blood glucose monitoring, also

have been reported [1, 11]. A quantification of blood glucose regulatory stability (or diabetic instability)

also has been reported [2]. In the present study, both previously reported and additional data ~ were examined as follows. Blood glucose values at 5-minute intervals (taken from the \ 150 100
50)
0 150
100
50
0 150
100
50
0

1700 Su B L Sk D

~ E ~ E ~ E E l I l t

I [ ; I I I I r r t I I 1 NI *8.2

1"80 r I I [ r I I I r I I I r r *44

149 178

I r I I I I I r I I I ~'22

2100 0100 ~ 0500 0900 1500 1700 2100

Clock time

Fig. 1. Blood glucose curves of three normal subjects dur- ing 48 h of continuous blood glucose analysis. Solid line = first 24 h ; interrupted line = second 24 h ; B = break- fast ; L = lunch; Sk = snack; D = dinner ; Su = supper; E = exercise for 1 h. * = MODD, mg/100 ml; t = mean blood glucose mg/100 ml; = MAGE, mg/100 ml B L Sk D Su B

~ E ~ E~ ~ E ~ l E

R5 L44 R5 L44

RSL44 RsL,~4 200 {./-..,, 149

,50 ~oo \ 50 i 1

0 ! i i ' ' r L17 ~"1 67 ,g L17 --

200 LI", ~ ....... L17 ,; I

0 | ] I r I ~ I I I , ~ ,v *79

0700 1100 1500 1900 2500 0500 0700 1100

Clock lime

Fig. 2. Blood glucose curves of two stable diabetics during 48 h of continuous blood glucose analysis. Treatment was predominantly with intermediate-acting insulin injected once daily. 1% = regular insulin; L = lente insulin. The first 24 h dose is in solid letters and numbers; the second 24 h dose is in dotted letters and numbers. Other symbols as in Fig. 1 continuous record) were matched with the corre-

sponding values 24 h later, and the absolute differen-

ces (without regard to sign) of the matched pairs were 1 Three studies not previously reported (one each in patients D1, D2, and D4) are included in this report). niabetologia, Vol. 8 24

344 G.D. Molnar et al. : Day-to-Day Variation of Continuously Monitored Glycaemia Diabetologia B Sk D Su B t E El' i E t t E t I I t

Ro SL7 UL13 R8 SL7 UL13 R8 SL7 UL13 R8 SL7 UL13 450 400

350150 ~~.

500
250
200
. .00 / '.,, f ........... . ........ \ / ',<,.,,./ ..., ,158.1 ~' 50 "" f196 i , , i , r i i r I i r I_D4 .154

74SL14UL22-- R4 SLI4UL22

350-R4 SL14 UL22 ....... R4 SLt4 UL22

% 250 2OO 150

IO0 .4t.1 50 D~ t149

0 r 1 i __,, , I ~ i I _~ I I I *t49 0700 1100 1500 1900 2500 0500 0700 1100

Clock lime

Fig. 3. Blood glucose curves of t~o unstable diabetics obtained during" 48 h gf continuous blood glucose analysis, SL = semilente insulin. Insulin was injected once daily. Symbols as in Figs. 1 and 9, B I.s Sk D Su B

{' E ~ E ~ i E ~ I' ~-

R12 ~ R8 i RI6 ~ SL14 R12 {

R15 R9 R16 SL14 R~5 3oo -~, { {/,,, § {

250
200
"~ 150 ~b 100
k48.5 \ 5O D7 r141 I__ H19 0 ! [ I I P [ I I [ I I [ I

12-- R9 R7 SLIO RIO 500 RIO ..... R8 R9 SL12 A RIO

2oo; r,.,, @ 150

100
~39.7 50 *152

0 r , i" i Vl r ~ T" i T i i , i D2 .184

0700 1100 1500 1900 2300 0500 0700 1100

Clock lime

Fig. 4. Blood glucose curves of two unstable diabetics obtained during 48 h of continuous blood glucose analysis. Treatment was with short-acting insulin injected four times daily. Symbols as in Fig. i through 3 determined. The mean of these differences (MODD)

and their dispersion about the mean were calculated. 2

2 We are aware of anMogous measures of between-day blood glucose variability by Izzo and Crump [7] and by Hedner and Nord4n [9] involving the variance of measure- ments between days. We chose our measure because of its simplicity. Analyses were also carried out by using the method of Hedner and Nordgn [9]; results were similar to those using our method. Nonparametric rank-sum tests and Student's "t"

test were used to test hypotheses as deemed appro- priate. Results Relevant clinical and analytic data are summarized in Table 1. Daily insulin dosage and differences, during successive 24-h periods, in paired blood glucose values (MODD) are shown in Table 2. The Figures illustrate typical pairs of consecutive

24-h continuous blood glucose records. Fig. 1 shows the

patterns for three normal subjects (N1, N2, and N3); all three subjects had low values for MODD and for the other parameters noted in Table 1. Fig. 2 shows blood glucose patterns for two stable diabetics; one (D10) had a low MODD value and the other (Dll) had an intermediate MODD value, despite similar MAGE and mean blood glucose values (Table 1). Fig. 3 shows blood glucose patterns for two unstable diabetics who were treated with intermediate-acting insulin regimens; in one (D4), the MODD value was high, and in the other (D8), it was intermediate. Their MAGE values were similar although their mean blood glucose values were different. Figure 4 shows blood glucose patterns for two other unstable diabetics, during treatment with short-acting insulin regimens. The higher MODD value is associated with the lower 3~AGE value (D7), and the lower MODD value is associated with the higher MAGE value (D2) ; the mean blood glucose values were similar.

The values of MODD varied significantly among the

three groups of subjects (P<0.001; Kruskal-Wallis test). They were significantly higher for unstable dia- betics than for the other two groups (P < 0.01).

To determine whether changes in MODD values

occurred merely as the result of day-to-day changes in insulin dosage (Table 2), the data from studies without day-to-day dosage changes were reexamined. There still was a highly significant difference (by rank-sum test) in MODD between unstable diabeticsquotesdbs_dbs11.pdfusesText_17