Diabetologia 9 Springer-Verlag 1991

Transcription

1 Diabetlgia (1991) 34: X A Diabetlgia 9 Springer-Verlag 1991 The dawn phenmenn in Type 1 (insulin-dependent) diabetes mellitus: magnitude, frequency, variability, and dependency n glucse cunterregnlatin and insulin sensitivity G. Perriell, R De Fe, E. Trlne, C. Fanelli, E Santeusani, R Brunetti and G. B. BUi Istitut di Patlgia Medica e Metdlgia Clinica, dell' Universita' degli Studi, Perugia, Italy Summary. In 114 subjects with Type 1 (insulin-dependent) diabetes mellitus the ncturnalinsulin requirements t maintain euglycaemia were assessed by means f i. v. insulin infusin by a Harvard pump. The insulin requirements decreased after midnight t a nadir f mu- kg- ~- rain- ~ at hurs. Thereafter, the insulin requirements increased t a peak f mu.kg -1.rain -1 at hurs (p < 0.05). The dawn phenmenn (increase in insulin requirements by mre than 20% after hurs lasting fr at least 90 rain) was present in 101 ut f the 114 diabetic subjects, and its magnitude (% increase in insulin requirements between hurs vs that between hurs) was % and crrelated inversely with the duratin f diabetes (r = , p < 0.001), but nt with age. The ncturnal insulin requirements and the dawn phenmenn were highly reprducible n three separate nights. In additin, glycaemic cntrl, state f cunterregulatin t hypglycaemia and insulin sensitivity all influenced the magnitude f the dawn phenmenn as fllws. In a subgrup f 84 subjects with Type I diabetes, the multiple crrelatin analysis shwed that nt nly duratin f diabetes (t = -9.76, p < ), but als % HbA1 significantly influenced the magnitude f the dawn phenmenn (t = 2.03, p < 0.05). After 5-9 mnths f intensive therapy, the magnitude f the dawn phenmenn decreased frm 24 ~+ 2% t % (p < 0.05) in seven Type i diabetic subjects with initially pr glycaemic cntrl, whereas it increased frm % t % (p < 0.05) in five Type i diabetic subjects in whm glycaemic cntrl had deterirated fr 2 weeks. In 18 Type 1 diabetic subjects the magnitude f the dawn phenmenn crrelated with the indices f adequate glucse cunterregulatin, namely plasma glucse cncentratin at the hypglycaemic nadir (r = ) and the rate f plasma glucse recvery frm hypglycaemia (r=-0.74) (bth p < 0.01). Finally, in 10 diabetic subjects in whm insulin sensitivity was examined by the euglycaemic glucse clamp technique, there was a crrelatin between the residual rate f hepatic glucse prductin (r = 0.78,p < 0.005) as well as between the rate f peripheral glucse utilizatin and the magnitude f the dawn phenmenn (r = , p < 0.025). In cnclusin, the dawn phenmenn is a very frequent event in Type 1 diabetes; its magnitude (-20%) is much lwer than that indicated by previus Bistatr studies; it is highly reprducible frm day t day; it is influenced by the duratin f diabetes, glycaemic cntrl, state f the cunterregulatin system t hypglycaemia and insulin sensitivity. Key wrds: Dawn phenmenn, Type 1 (insulin-dependent) diabetes mellitus, insulin-sensitivity, glucse cunterregulatin, glucse turnver, grwth hrmne. The dawn phenmenn is a transient increase in insulin requirements which may ccur between and hurs in peple with Type 1 (insulin-dependent) diabetes mellitus [1-3], Type 2 (nn-insulin-dependent) diabetes mellitus [4-8], and in nn-diabetic individuals [8-10]. In subjects with Type i diabetes, if the increase in insulin requirement after hurs is nt met, hyperglycaemia develps [11, 12]. In Type i diabetes, cnsiderable evidence indicates that the dawn phenmenn is the result f a transient decrease in sensitivity t insulin, bth at hepatic and extrahepatic level [13], induced by ncturnal secretin f grwth hrmne [13-16] rather than increased clearance f insulin [3, 8, 10, 13, 17,18]. Despite the number f studies published ver the last few years [19], it is surprising that several clinical aspects f the dawn phenmenn in Type i diabetes have nt yet been clarified. Fr example, it is nt knwn t what extent the insulin requirements increase at dawn cmpared t the early night hurs; hw frequent is the dawn phenmenn amng peple with Type 1 diabetes, and hw reprducible it is when examined n different ccasins in the same diabetic individuals. In additin, it is nt knwn

2 22 whether factrs such as glycaemic cntrl, state f the cunterreguiatin system t hypglycaemia and insulin sensitivity, influence the dawn phenmenn. Clearly, all this infrmatin is crucial fr a ratinal strategy f intensive insulin therapy fr the ncturnal hurs f subjects with Type 1 diabetes, which aims at pre-breakfast nearnrmglycaemia while aviding ncturnal hypglycaemia [20, 21]. The present series f studies were undertaken t assess: (1)the magnitude; (2)the frequency f the dawn phenmenn in a large ppulatin f peple with Type 1 diabetes; (3) hw reprducible is the dawn phenmenn in the same diabetic individuals; (4) the influence f factrs such as glycaemic cntrl, state f the cunterregulatin system t hypglycaemia and insulin sensitivity n the dawn phenmenn. Subjects and methds Subjects Between 1980 and 1988, 114 subjects with Type i diabetes (68 men, 46 wmen) were studied after fuliy infrmed cnsent was btained. The subjects aged years (31 +2 years, mean + SEM), had a duratin f diabetes f years ( years). With the exceptin f 11 subjects with duratin f diabetes < i year, wh had detectable, althugh subnrmal plasma C-peptide cncentratins, the remaining 103 subjects had n residual endgenus insulin secretin as assessed by the plasma C-peptide respnse t intravenus glucagn [22]. Their percent HbAlc [23] was 8.64 _+ 0.56% (nrmal range %) and the bdy mass index (BMI) was kg/m 2. All subjects were n a therapeutic regimen f tw r three daily injectins f insulin (mixture f regular and intermediate-acting insulin at breakfast and dinner; r regular insulin at breakfast and lunch, and a mixture f regular and intermediateacting insulin at dinner), with the exceptin f nine subjects wh were treated with fur daily insulin injectins (regular insulin at each meal, and intermediate-acting insulin at bedtime). The subjects were healthy apart frm their diabetes and did nt present clinically vert diabetic cmplicatins. Nne f the subjects at the time f the study were given any ther drug treatment apart frm insulin. Study design T assess the magnitude and the frequency f the dawn phenmenn, the vernight insulin requirements were assessed retrspectively in all 114 diabetic subjects, the majrity f whm had participated in previusly reprted studies [3, 24-31]. Intermediate-acting insulin was withdrawn fr at least 48 h prir t the studies and the subjects were injected with regular insulin at breakfast, lunch, dinner, bedtime, and at hurs based n capillary bld glucse cncentratin. On the day f the study, the last s. c. injectin f regular insulin was given at lunch. Thereafter, between hurs the subjects rested in bed, and a 18-gauge catheter-needle was placed int a superficial frearm vein fr infusin f regular insulin (diluted t a final cncentratin f -3.5 p.ml/1 in 0.9% NaC1 slutin cntaining 0.5% human albumin, Immun S. p. A., Pisa, Italy) by means f a syringe pump (Harvard Apparatus, Suth Natick, Mass, USA). A 21-gauge butterfly needlewas inserted retrgradely int a drsal vein f the cntralateral hand which was kept warm in a thermregulated plexiglass bx at 65 ~ t ensure arterializatin f venus bld [32]. This line was used fr intermittent bld sampling and bedside measurement f plasma glucse cncentratin every min. G. Perriell et al.: Dawn phenmenn in Type 1 diabetes Between hurs the subjects cnsumed a standard meal (725 kcal, 45% carbhydrate, 30% fat, 25% prtein). Insulin was infused at variable rates t prevent an increase in the plasma glucse cncentratin abve 10 mml/l fr the first 2 h after the meal. Thereafter, between and hurs the next mrning, the plasma glucse cncentratin was maintained between 4.5 and 5.5 retl/1 by infusing insulin accrding t a previusly described algrithm [3]. Adjustments in the insulin infusin rate were made every min. T assess the intraindividual variability f the dawn phenmenn, 29 diabetic subjects [26-28] were restudied n tw additinal ccasins, separated by 6-30 days, and the ncturnal insulin requirements were reassessed as described abve. T assess the effects f glycaemic cntrl n the dawn phenmenn, first, the crrelatin between the % HbAI and the increase in insulin requirements at dawn was examined in 84 diabetic subjects in whm glycsylated haemglbin had always been measured with the same technique [33]. Secnd, 13 subjects with initially pr glycemic cntrl were studied befre and after either imprvement (fr 5-9 mnths, n = 7) r n change (fr 6-8 mnths, n = 6) in glycaemic cntrl [29], whereas, in five patients with initially gd cntrl during intensive insulin therapy, the ncturnal insulin requirements were studied befre and tw weeks after deliberate deteriratin f their bld glucse cntrl, as previusly reprted [29]. T assess the effects f the state f the cunterregulatin system n the dawn phenmenn, the increase in insulin requirements at dawn and the indices f adequate cunterregulatin, namely plasma glucse nadir and pst-nadir plasma glucse recvery rate in a standardized insulin-infusin test, were analysed in 18 subjects with Type 1 diabetes [28]. T assess the effect f insulin sensitivity n the dawn phenmenn, insulin sensitivity was studied in 10 subjects by means f the euglycaemic-hyperinsulinaemic glucse clamp technique [34] after assessing their ncturnal insulin requirements and nrmalizing plasma glucse cncentratin ver the previus 12 h, as recently described [13]. The clinical features f these 10 subjects [7 men, 3 wmen, age years (29 _+ 2 years), diabetes duratin years ( ), BMI 21-25kg/m 2 ( kg/m2), %HbAlc % ( %)] did nt differ significantly frm thse f the remaining 104 subjects f this study. In the clamp studies, hyperinsulinaemia was induced by tw sequential steps, 2 h each, f insulin infusin at the rate f 0.25 mu. kg-1. min-~ and l mu-kg-l-min -I, respectively. A primed (18gCi) cntinuus (0.18 gci/min) infusin f 3-3H-glucse (New England Nuclear, Bstn, Mass, USA) was started at -3 h (between and hurs) and cntinued until the end f the clamp studies (between and hurs) t measure the rate f endgenus (hepatic) glucse prductin. Methds Plasma glucse was measured by the glucse xidase methd (Beckman Glucse Analyzer, Beckman Instruments, Fullertn, Calif., USA). Glucse specific activity [35] and plasma free insulin [36] were determined by previusly decribed methds. Plyethyleneglycl precipitatin f plasma insulin antibdies was perfrmed sn after drawing bld, as previusly described [31]. Calculatins, definitin f the dawn phenmenn and its magnitude. Plasma glucse cncentratin and vernight insulin requirements were analysed as the mean values ver 20 min perids. In these studies, the dawn phenmenn was defined as an increase by mre than 20% in the insulin infusin rates required t maintain euglycaemia after hurs and lasting fr at least 90 rain. This definitin was adpted because in previus studies in which the dawn phenmenn was prevented by suppressin f ncturnal spikes f grwth hrmne secretin [13], the ncturnal insulin infusin rates required t maintain euglycaemia after hurs increased by less than 10% as cmpared t the insulin infusin rates befre

3 G. Perriell et al.: Dawn phenmenn in Type 1 diabetes hurs. The magnitude f the dawn phenmenn was defined as the percent increase in the insulin requirements ccurring between and hurs as cmpared t thse ccurring between and hurs. Glucse turnver. Rates f glucse prductin and utilizatin at baseline during the first 2 h f the euglycaemic-hyperinsulinaemic clamp studies (insulin infusin rate 0.25 mu-kg-~-min-~) were calculated with the use f the nn-steady-state equatins f D e B d et al. [37] and were "smthed" accrding t the methd f Miles et al. [38]. During thelast 2 h f the euglycaemic-hyperinsulinaemic clamp experiments at the insulin infusin rate f i mu.kg -a,min -1, the calculated rate f hepatic glucse prductin yielded negative numbers [39]. Thus, it was assumed that in this secnd part f the damp, the hepatic glucse prductin was fully suppressed [40] and that therefre the rate f exgenus cld glucse infusin equalled the whle bdy glucse utilizatin. Cnsequently, in the secnd part f the clamp studies at high insulin infusin rate, the rate f cld glucse infusin and nt the istpically calculated glucse turnver, was cnsidered as the real rate f peripheral glucse utilizatin, as previusly reprted [13]. Statistical analysis Data are given as mean _+SEM and were evaluated by analysis f variance crrected fr repeated measures, and where apprpriate, tw-tailed, paired t-test. Regressins were calculated by multiple regressin analysis [41]. Statistical analysis was perfrmed using CSS 2.1 sftware (Statsft, Inc., Tulsa, Okla, USA). Results Overnight insulin requirements in Type 1 diabetes (Fig. 1) The insulin infusin rate required t maintain euglycaemia decreased cntinuusly after midnight frm mu.kg -~.min -~ t a nadir value f 0.102_ mu. kg -~. rain -~ at hurs9 Thereafter, insulin requirements increased prgressively by 30% t a peak f _+0.06 mu.kg -~.min -~ at hurs (p < 0.05 vs the nadir value f hurs), and remained increased until hurs ( mu. kg- t. min-~, p < 0.05 vs the nadir value at hurs). As a result f e ~ e e~ e :::i::: eeeee eeee e e < n=9 e Magnitude f dawn phenmenn (rank distributin) n=18 n=37 n=lo n=lo c r- E 24 g 18 gl. cj "O 12 ~S ) "O 6 'E 03 Fig. 2. Distributin f the magnitude f the dawn phenmenn (percent increase in the mean insulin requirements between and hurs as cmpared t thse ccurring between and hurs) in the 114 subjects with Type I diabetes divided int grups accrding t intervals f 5% difference sin f insulin at variable rate, plasma glucse cncentratins remained cnstant frm midnight t hurs ( mmi/1). After which they increased by 10% between and hurs despite the increase in insulin infusin rate ( mml/1,p < 0.05 vs the midnight hurs value) (Fig. i). Frequency, timing and magnitude f the dawn phenmenn (Figs. 2, 3) The dawn phenmenn was present in 101 ut the 114 subjects (89%) and it started at hurs (range hurs) and lasted fr h ( h) with a magnitude f % (6-31%). The subjects were divided int grups accrding t a 5% difference in the magnitude f the dawn phenmenn 0 ~g 23 i ~ 5.5 ~-~E. 2"Tc 0.16[ I.V, Feedback insulin infusin IHarvard pump) ~ 30 E 25 -~ 20 9 ~ :.:'.... "7 "". ": "" "". 9 :. ~ :.....;.::. '-~ ~ 'Y 0.12 [ c "E E 0.10 L L Time (h) Fig.1. Ncturnal insulin requirements t maintain euglycaemia in 114 subjects with Type i (insulin-dependent) diabetes mellitus infused with intravenus insulin at variable rate by means f a Harvard pump. Tp panel-plasma glucse; lwer panel-insulin infusin rate (mean _+ SEM) ~ 15 0/ 10 c- ~ zr 5 9 ~. Duratin f diabetes (years) Fig.3. Scatter plt f duratin f diabetes and the magnitude f the dawn phenmenn (defined in the legend t Fig.2) in the 114 subjects with Type 1 diabetes. Fr multiple regressin analysis see text

4 24 G. Perriell et al.: Dawn phenmenn in Type i diabetes I.V, Feedback insulin infusin (Harvard pump) ~ E 4.5 2% 0.16[ ~ > "s I l J I I "--- m x 0.12 L --.- E 0.10 L 22'. ~: :00 s'. 08'.00 Time (h) Fig.4. Reprducibility f vernight insulin requirements and dawn phenmenn in 29 subjects with Type 1 diabetes studies n three separate ccasins (A study 1, 9 study 2, 9 study 3) (Fig. 2). Cmpared t 37 subjects in whm the magnitude f the dawn phenmenn ranged between 16 and 20%, the magnitude in 50subjects was greater than 20%, whereas it was less than 16% in the remaining 27 subjects. The 50 subjects with the greatest magnitude f dawn phenmenn (24 _+ 0.3%) had a shrter duratin f diabetes ( vs years), less ptimal glycaemic cntrl (HbAI, vs %, bth p < 0.05), but their age was nt significantly different frm that the rest f the subjects. The scatter plt f duratin f diabetes and magnitude f dawn phenmenn is shwn in Fig- tn _~ g 0.150[ C ~: 9 I I I ::3 ~";" 9 5._ / cr E > I/1 D 0 L O.- E -g g ~176 I 0 L g 30[ _ Zg,, OJ "'~..ic E ~ Night Fig.5. Reprducibihty f the dawn phenmenn. The insulin requirements were superimpsable n three different nights, when analysed as verall insulin infusin rates frm midnight t hurs (tp panel), as well as in the perids frm t hurs (pen bar) and frm t hurs (shaded bar) (centre panel), and finally when calculated as percent increases in the insulin requirements between and hurs as cmpared t thse ccurring between and hurs (magnitude f the dawn phenmenn, bttm panel) (*p < 0.05) (~ ~i~ I I, i I i I I c Time (h) Fig, 6. Cefficients f variatins f mean hurly plasma glucse cncentratin and insulin infusin rates t maintain euglycaemia in 29 subjects with Type 1 diabetes studied n three different nights (mean + SEM) ure 3. Using the crrelatin analysis, n effects f age (r = , p < 0.05), but a strng effect f duratin f diabetes n the magnitude f the dawn phenmenn was fund (r = ,p < 0.001). Intraindividual variability f the dawn phenmenn (Figs. 4-6) In the experiments in which the same 29 subjects were studied n three different nights, their insulin requirements were virtually superimpsable frm study t study, as was the plasma glucse cncentratin (Fig. 4). In these studies the verall ncturnal insulin requirements were n different n the three separate nights ( mU.kg-l.min -1, mU.kg -1. min- 1, and mu-kg- 1. min- t, nights 1, 2 and 3, respectively, p = NS) (Fig. 5, tp panel). In additin, the increases in insulin requirements ccurring between and hurs cmpared t thse ccurring between and hurs was highly reprducible n the three different nights f the studies (Fig. 5, center and bttm panels). Finally, the lw variability f the ncturnal insulin requirements and the dawn phenmenn is als indicated by the cefficient f variatin f mean hurly plasma glucse cncentratin and insulin infusin rates, which in individual subjects never exceeded 10% (Fig. 6). Effect f glycaemic cntrl n the dawn phenmenn (Figs. 7, 8) In Figure 7 the magnitude f the dawn phenmenn and % HbA1 are shwn as scatter plts in 84 diabetic subjects in whm I-IbA~ was always determined with the same methd [33]. The multiple regressin analysis perfrmed t examine the effects f duratin f diabetes, % HbA1 (glycaemic cntrl), and age (independent variables) n the magnitude f the dawn phenmenn (dependent variable), shwed a highly significant multiple R (0.76,

5 G. Perriell et al.: Dawn phenmenn in Type 1 diabetes 0 E 32 E.c 24.c _ x~ 0) xj c 8 9 t ~ J % HbA I Fig. 7. Scatter plt f the percent HbA1, and the magnitude f dawn phenmenn (see legend t Fig. 2 fr definitin) in 84 subjects with Type i diabetes in whm the HbA~ had always been measured with the same methd [33] F(3.80) = 36.52, p <0.0001) with the fllwing cefficients: intercept = 17.93, B1 = , B2 = 0.36, B3 = Althugh the highest cntributin t multiple R was due t duratin f diabetes (t = , p < ), % HbA~ als cntributed significantly (t= 2.03, p < 0.05) t the final estimates, whereas age did nt cntribute significantly t the mdel. Thus, the prer the glycaemic cntrl, the greater the dawn phenmenn. In the seven diabetic subjects wh were initially in pr glycaemic cntrl, institutin f intensive insulin therapy fr 5-9 mnths imprved glycaemic cntrl (HbA~ fell frm % t 7:9 _+ 0.2%,p < 0.001) and resulted in a decrease in the magnitude f the dawn phenmenn frm 24 _+ 2% t % (p < 0.05). On the ther hand, in the six subjects in whm intensive insulin therapy was nt instituted and glycaemic cntrl remained similarly pr befre and after 6-8 mnths f bservatin (HbA~ % and! %, respective- ly, p = NS), the magnitude f the dawn phenmenn did nt change (27 + 3% and 25 +_ 2%, respectively, p = NS). Finally, in the five diabetic subjects wh were switched frm intensive t nn-intensive insulin therapy fr tw weeks, HbA1 increased frm % t % [22] and als the magnitude f the dawn phenmenn (frm % t %) (bth p < 0.05). Thus, imprvement in glycaemic cntrl attenuated, and deteriratin exaggerated the magnitude f the dawn phenmenn, respectively, whereas unchanged glycaemic cntrl had n effect (Fig. 8). Effects f the state f the cunterregulatry system t hypglycaemia n the dawn phenmenn In the 18 diabetic subjects studied, the magnitude f the dawn phenmenn was crrelated inversely with the indices f adequate glucse cunterregulatin [28], namely plasma glucse cncentratin at hypglycaemic nadir (r = ) and the rate f pst-nadir plasma glucse recvery frm hypglycaemia (r = ) (bth p < 0.01). Thus, the mre adequate the cunterregulatry respnse t hypglycaemia, the mre prnunced the dawn phenmenn and vice-versa. Effect f insulin sensitivity n the dawn phenmenn (Fig. 9) In the 10 diabetic subjects in whm insulin sensitivity was examined by means f the euglycaemic-hyperinsuhnaemic glucse clamp, there was a crrelatin between the residual rate f hepatic glucse prductin (calculated during the first 2 h f the clamp studies at the plasma free insulin cncentratin f pr9 and the magni- f- 3O 25 ~g 20 g g 0 g , 15 0 Fig.8. Effect f imprved [upper panel, 7 subjects with Type I diabetes, befre (pen bar) and 5-9 mnths after gd glycaemic cntrl (shaded bar)], unchanged [centre panel, 6 subjects with Type 1 diabetes, befre (pen bar) and 6-8 mnths after unchanged glycaemic cntrl (shaded bar)] r deterirated glycaemic cntrl [lwer panel, 5 subjects with Type i diabetes, befre (pen bar) and 2 weeks after pr glycaemic cntrl (shaded bar)], n the magnitude f the dawn phenmenn (see legend t Fig. 2 fr definitin (*p < 0.05) 0) r- "O 0J ze 10 O Q- 0 a b (#tl 9 kg q. min-1) Fig.9 a, b. The lwer the hepatic and peripheral insulin sensitivity, the greater the dawn phenmenn. Crrelatin between insulin sensitivity (hepatic and peripheral) and the magnitude f the dawn phenmenn (see legend t Fig.2 fr definitin) in 10 subjects with Type 1 diabetes. Insulin sensitivity was assessed by means f the euglycaemic clamp technique at lw insulin infusin rate (0.25 mu kg 1-min 1) and high insulin infusin rate (1 mu.kg -1. rain-l), a) The greater the hepatic glucse prductin (calculated frm the clamp studies at lw insulin infusin rate), the greater the magnitude f the dawn phenmenn (y= x, r= 0.78, p < 0.005). b) The lwer the increase in peripheral glucse utilizatin (calculated frm the clamp studies at high insulin infusin rates), the greater the magnitude f the dawn phenmenn (y = x, r = ,p < )

6 26 tude f the dawn phenmenn (r = 0.78, p < 0.005), and between the rate f peripheral glucse utilizatin (calculated ver the last 2 h f the clamp studies at the plasma free insulin cncentratin f pml/1) and the magnitude f the dawn phenmenn (r=-0.70, p < 0.025) (Fig. 9). Thus, the greater the insulin sensitivity, bth at the hepatic and extrahepatic level, the smaller the magnitude f the dawn phenmenn and vice-versa. Discussin The present studies indicate that the dawn phenmenn is a very frequent event in subjects with Type I diabetes mellitus; its magnitude is lwer than initially indicated by previus Bistatr studies; it is highly reprducible frm day t day, and it is influenced by factrs such as duratin f diabetes, quality f antecedent glycaemic cntrl, state f ctmterregulatin system t hypglycaemia and insulin sensitivity. In the past few years, a number f studies have examined the dawn phenmenn in peple with Type 1 diabetes [19]. In thse studies it was difficult t establish the frequency, the intra-subject variability and ther clinically imprtant aspects f the dawn phenmenn, either because the number f subjects examined was small [3, 42], r the artificial endcrine pancreas Bistatr was used [2, 4, 11, 14, 16, 43, 44]. In fact, because f the prgressive lss f the bilgical activity f the insulin infused ver time by the peristaltic pump f the Bistatr [17, 45], it is likely that in the previus Bistatr studies - at least in thse in which albumin was apparently nt added t the insulin infusate [2, 4, 11, 43, 44] - the magnitude f the dawn phenmenn has been verestimated. In the present studies, a large ppulatin f subjects with Type 1 diabetes (n = 114) was examined. The ncturnal insulin requirements were studied during insulin delivery by means f a Harvard syringe pump, an apprach which des nt result in a lss f the bilgical activity f the insulin infused ver time [17, 45]. Under these cnditins, the fllwing bservatins were made. First, the insulin requirements after midnight initially decreased t a nadir value f mu- kg- 1. rain -1 at 02.40hurs and subsequently increased t mu. kg -~. rain -~ at hurs. Thus, in the present studies, the peak increase at dawn as cmpared t the early night hurs was 30%, whereas the magnitude f the dawn phenmenn (percent increase in the insulin requirements ccurring between and hurs as cmpared t thse ccurring between and h) was 20%. It is likely that the magnitude f the dawn phenmenn in these experiments has been underestimated, because the plasma glucse cncentratin increased after hurs despite the increase in insulin infusin rate, implying that the insulin requirements at that time f day were in fact greater than thse indicated by ur experiments. Nevertheless, the figures f the magnitude f the dawn phenmenn bserved in the present study are three times smaller than thse suggested by early Bistatr studies [2, 4] in which the insulin requirements after hurs were fund t increase by as much as 100% G. Perriell et al: Dawn phenmenn in Type 1 diabetes cmpared t thse f the early night hurs - an verestimatin mst likely due t the previusly discussed Bistatr artifact [17, 45]. Interestingly, the nadir t peak increase in ncturnal insulin requirements bserved in the present studies in Type i diabetes is similar t that bserved in previus studies in Type 2 diabetes [6] as well as in nrmal nn-diabetic subjects [10]. This finding suggests that the dawn phenmenn is nt a specific feature f diabetes, but rather it is a physilgical event which is part f a circadian variatin in insulin sensitivity [10, 46]. Secnd, the dawn phenmenn ccurred in virtually all f the subjects examined (89%). Thus, the dawn phenmenn is a persistent event in subjects with Type 1 diabetes. Third, the ncturnal insulin requirements in general and the dawn phenmenn in particular were remarkably reprducible frm day t day in the same diabetic subjects. It is likely that the results f a previus study in which the ppsite cnclusin was reached [4], were due t the Bistatr artifact, i. e. t the unpredictable lsses f bilgically active insulin infused by the Bistatr n different nights. In fact, when human albumin was added t the insulin infusate delivered by the Bistatr, a prcedure which prevents lss f bilgical activity f the infused insulin [17, 45], the dawn phenmenn was fund t be reprducible even using the Bistatr [47]. Thus, since the ncturnal insulin requirements and the dawn phenmenn are remarkably reprducible frm day t day, it is likely that the clinical bservatin f the large intraindividual day-t-day variability f fasting plasma glucse cncentratin in subjects with Type 1 diabetes treated with s.c. insulin injectins [48], is explained by the large variability f absrptin f s. c. injected insulin n the previus evening [21], rather than by the variability f the dawn phenmenn. Furth, in the present studies it was fund that the quality f antecedent bld glucse cntrl is an imprtant factr fr the magnitude f the dawn phenmenn, i.e., pr glycaemic cntrl is assciated with exaggerated, whereas gd glycaemic cntrl with attenuated dawn phenmenn. Since the dawn phenmenn is basically a difference in insulin sensitivity between the early night and early mrning hurs [13], and since glycaemic cntrl prfundly influences insulin actin in Type 1 diabetes [49], it is likely that the effects f either pr r gd glycaemic cntrl n the dawn phenmenn bserved in the present studies are the result f augmented r attenuated insulin resistance, respectively, accrding t the cncept f dwn- r up-regulatin f glucse transprters by prevailing bld glucse cncentratin [50]. In this regard, the results f the present study might accunt fr the bservatin that subjects with Type i diabetes underging intensive insulin therapy barely exhibit a dawn phenmenn [51]. Fifth, in the present studies the ability t cunterregulate t hypglycaemia in a standardized insulin infusin test was fund t be f imprtance fr the magnitude f the dawn phenmenn. Subjects with inadequate cunterregulatin had a less prnunced dawn phenmenn as cmpared t thse with adequate cunter-

7 G. Perriell et al.: Dawn phenmenn in Type i diabetes regulatin. It is likely that the chrnically impaired secretin f cunterregulatry hrmnes glucagn, epinephrine, grwth hrmne and crtisl bserved in this grup explains their attenuated dawn phenmenn [28]. Since impaired cunterregulatin is a functin f diabetes duratin [25], as indeed it was in the 18 subjects examined in these experiments [29], it is likely that the finding f the inverse relatinship between the diabetes duratin and magnitude f the dawn phenmenn f Figure 3 in the present studies might be explained by the lss f secretin f cunterregulatry hrmnes and greater insulin sensitivity in lng-term diabetes. Thus, the present studies indicate that the lnger the duratin f Type 1 diabetes, the greater the impairment in the secretin f cunterregulatry hrmnes, and the smaller the dawn phenmenn. Sixth, insulin sensitivity bth at hepatic and extrahepatic level was fund t be inversely crrelated with the magnitude f the dawn phenmenn, i. e., the less insulinsensitive the subjects were, the mre marked the dawn phenmenn was and vice-versa. It is likely that factrs such as glycaemic cntrl and state f cunterregulatin which in these studies have been fund t have imprtant effects n the dawn phenmenn, might d s primarily by influencing insulin actin. In subjects with Type 1 diabetes the plasma free insulin cncentratins in the early mrning hurs usually range between 100 and 200 pml/1 [52, 53]. On the ther hand, when the plasma insulin cncentratin was increased in this range during the clamp experiments f the present studies, nly glucse prductin, but nt glucse utilizatin was affected. Thus, it is likely that decreased insulin sensitivity at the liver, rather than at the peripheral level, plays the primary rle in the pathgenesis f the dawn phenmenn in Type 1 diabetes, as recently suggested [13], at least in the fasting (pre-breakfast) perid. In cnclusin, the present studies demnstrate that the dawn phenmenn is a very frequent and reprducible event in Type i diabetes mellitus, as lng as factrs which usually influence insulin actin remain cnstant. Hwever, shuld fr any reasn insulin actin either imprve r deterirate, an attenuatin r exaggeratin f the dawn phenmenn, respectively, will ccur. Overall, the magnitude f the dawn phenmenn is smaller than that indicated by previus Bistatr studies. Further studies are needed t establish the extent t which the dawn phenmenn cntributes t pre-breakfast hyperglycaemia in Type i diabetes. Acknwledgements. This wrk was supprted by the Cnsigli Nazinale delle Ricerche (C. N. R. grants and ). The Authrs are grateful t Drs. 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Lancet II: Francis AJ, Hme PD, Hanning I, Alberti KGMM, Turnbridge WMG (1983) Intermediate acting insulin given at bedtime: effect n bld glucse cncentratins befre and after breakfast. Br Med J 286: Received: 11 January 1990 and in revised frm: 26 June 1990 Prf. G.B.Blli Istitut di Patlgia Medica dell'universita' Via E. Dal Pzz Perugia Italy