Blood glucose levels in diabetic and non-diabetic subjects

Diabetologia, Aug 1991

Georges Tchobroutsky

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Blood glucose levels in diabetic and non-diabetic subjects

I Paris Cedex B l o o d glucose levels in diabetic and non-diabetic subjects* 0 H6tel-Dieu~Universitd Pierre et Marie Curie , Paris , France Georges Tchobroutsky Most, if not all, diabetologists are convinced, on the basis of indirect evidence which has been accumulated over the decades that the microangiopathic and neurological complications of diabetes are primarily dependent on the duration and extent of chronic hyperglycaemia [1-5]. Hyperglycaemia is the necessary factor in the development of these complications even if other, secondary factors, sometimes responsive to treatment, such as blood pressure levels, smoking, protein intake, with or without genetic predisposition, may modulate its expression [6]. However, as emphasized by Krolewski et al. [7] and Mogensen [8] it is the degree (and duration) of hyperglycaemia which remains the most important aetiological factor in predisposed groups of patients. Before we are able to detect with accuracy on an individual basis the subjects at risk from diabetic complications, blood glucose control will be of paramount importance because, as emphasized by R o t h m a n [9]: "Identification of all the components of a givensufficientcauseis unnecessary for prevention, in that blocking the causal role of but one component of a sufficientcause renders the joint action of the other components insufficientand prevents the effect." 9 Springer-Verlag1991 A m o n g the advice given to an insulin-treated diabetic patient that which is related to glucose control is aiming to try to normalize blood glucose levels. Regarding blood glucose control we will discuss briefly the following points: What are "normal", fasting and post-prandial blood glucose levels? W h a t are fasting and post-prandial blood glucose levels of insulin-treated diabetic patients? W h a t are the limiting factors to the normalization of blood glucose levels in diabetic patients? How high is high? (harmfulness of hyperglycaemia), and H o w to advance presentday treatment? * 1989Claude Bernard Lecture of the European Association for the Studyof Diabetes delivered in Lisbon on September 1989 "Normal" fasting blood glucose levels It is wise, firstly, to question the meaning of the word normal. Table 1 lists, according to Murphy [ 10-12 ], the situations in which the word "normal" is used and the preferable term (the choice of which depends on the goal). Amidst the seven meanings proposed by this methodologist one is of particular importance for the epidemiologist: i. e. the reference value, namely that obtained from a population considered healthy and serving as reference. Another is probably much more useful in individual medical practice and is that which defines the norm as nonpathogenic and the abnormal as dangerous to one's health. A famous example well illustrates these points: when a group of European researchers, working on urinary bilharzia, asked the chief of a sub-tropical village to gather all his subjects presenting abnormal urines in the main square, only three appeared, their urine was perfectly limpid and the "normal" population was that which had red urine and was ill. Fasting plasma glucose levels are unimodally distributed within apparently non-diabetic adult populations except in a few highly inbred communities in Arizona and the South Pacific. In the French telecommunications adult employee population of 3220 adults studied by my colleague D.Simon and his collaborators [ 13 ] 95% of the values obtained regardless of sex, and age, are below 106 mg per 100 ml i. e. 5.8 mmol/1 (Table 2). According to Gaspart [ 14 ] the distribution of blood glucose values in a general population is asymmetric with a tail towards higher values and is true for both sexes. Fasting plasma glucose in apparently non-diabetic subjects tends to rise with age [ 13-15 ]. The younger the subjects the more their blood sugar levels are distributed below 5.5. mmol/1 (Table 2). Fasting glycaemia is lower in pre-menopausal w o m e n than in men [ 13, 16 ] (Table 2). We have also shown that natural oestrogen administration decreases fasting blood glucose levels in young healthy m e n [17]. The fact that pre-menopausal women have lower fasting blood glucose levels than men is an important fact to Paraphrase 1. Probability function (bell-shaped curve) 2. Most representative of its class 3. Commonly encountered in its class 4. Most suited to survival 5. Carrying no penalty 6. Commonly aspired to 7. Most perfect of its class [ 10-12 ] W h e r e used Statistics Descriptive sciences Descriptive sciences Genetics, operations research Clinical medicine Politics, sociology Metaphysics, esthetics, morals G.Tchobroutsky:Blood glucoselevels in diabetic and non-diabetic subjects ]['able3, Venous plasma glucose levels (mg/dl and mmol/1)in 244 pregnant non-diabetic women at 33-37 weeks of pregnancy and no diabetic risk factors Mean SD Range Fasting 80 8 55-108 98.4% < 100 mg/ml 4.4 0.4 3.0-6 < 5.5 mmol/1 Post meal 90 16 60-t50 97.5%< 126 mg/ml (not-standardized) 5 0.8 3.3-8.3 < 7 retool/1 Unpublished data from C.Tchobroutsky and M.Vray, Maternity University Hospital of Port-Royal (Paris) and INSERM U. 21 (Villejuif) consider when carrying out a fasting test period for the diagnosis of spontaneous hypoglycaemia. During a fasting state blood glucose levels decrease more in pre-menopausal women than in men or post-menopausal women [ 16 ]. Fasting plasma glucose values in non-diabetic pregnant women have also been studied. Unpublished data from the Maternity University Hospital of Port-Royal have shown that 98.4% of the fasting values are below 5.5 mmol/1 in healthy pregnant w o m e n with no diabetic risk factors at 33-37 weeks gestation (Table 3). Farmer and colleagues studied 917 pregnant non-diabetic women at 32 weeks gestation: 97.5% of the values observed were below 5.2 mmol/1 [ 18 ]. Thus, it appears that in non-diabetic pregnant women fasting blood glucose values are much lower than those often considered as "normal" at least on the highly specific criteria required by some authors for the determination of glycaemic abnormalities during pregnancy [ 19 ]. As is perfectly known, reference values include, when the distribution is unimodal, some subjects in the upper percentiles who are already ill or at high risk of becoming ill. The upper tail of these unimodal distributions sometimes shows surprisingly high values in supposed "healthy" populations used as reference [ 14, 15 ]. Although this might be due to bias in the selection of the subjects. Epidemiologists try to set up classifications which are simply tools for longitudinal studies or for comparison between groups and populations. In borderline cases definitions and classifications must not be interpreted as clues for individual diagnosis of diabetes or non-diabetes. Unfortunately despite constant warnings, particularly from the W H O expert committee [ 20 ], these arbitrary figures, neither sacrosanct nor eternal, are currently used for clinical practice or clinical studies leading to misleading titles and conclusions. The important issue is to know whether a slightly increased blood glucose level (e. g. above the 95th percentile in young subjects of above the 97.5th in elderly p a t i e n t s of the reference population) is the hallmark of diabetes or just one of the several markers (risk factors) of possible future diabetes mellitus as are other better known markers. "Normal" post-prandial blood glucose levels Few studies have been devoted to defining normal postprandial blood glucose values. W h e n they were done they usually concerned very small groups of subjects and were restricted to the midday meal with the exception of a 1976 study [ 21 ] and two non-standardized very large epidemiological studies [ 22, 23 ]. In 1970 we performed a study concerning 8 healthy subjects and 16 diabetic patients who consumed a standardized 880 kcal meal containing 90 g of carbohydrate [ 22 ]. All these normal, 20- to 40-year-old, adult subjects maintained their maximal post-prandial blood glucose levels on this standardized meal below 6 mmol/1 2 h after the beginning of the meal. We later studied the variations in glycaemia 45 to 120 min following a midday non-standardized meal in 110 non-diabetic subjects 45 of whom were apparently healthy and 65 who presented with non-metabolic diseases [ 23 ]. The increments in post-prandial plasma glycaemias were extremely small. Non-standardized post-prandial blood glucose levels rise with age according to the formula: second hour blood glucose = 0.516 x years + 88.2 (in mg/dl) [ 23 ]. F r o m the Port-Royal Maternity Hospital data it appears that post-prandial plasma glucose levels remain at a low level during pregnancy, even close to delivery since 97.5% of the values remain below 7 mmol/1 between i h 30 min and 2 h post cibum (Table 3). Blood glucose levels in insulin-treated patients Despite our efforts directed towards the ideal achievement of normalised blood glucose levels it is obvious that in Type 1 (insulin-dependent) diabetic patients, treatment remains far from optimal and blood glucose levels, in terms of means, never really attain the values observed in the reference populations. a) Pregnancy might be the best example to show, on the one hand, the progress we can achieve with routine treatment and, on the other, our limitations. This condition also serves to draw attention to an area in which there is general consensus as to the need for the best possible glycaemic control [ 24 ]. From unpublished data on 389 pregnancies in Type 1 diabetic patients conjointly followed with the Maternity Hospital of Port-Royal it appears that between 1971 and 1977 fasting and post-prandial blood sugar levels were never normalized in terms of means and that after 1978, despite technological advances in diabetology and obstetrics the values have, if anything, become worse: the blood glucose levels at entry and at 32 weeks were as follows: during the 1971-1977 period mean fasting plasma glucose (mmol/1, m e a n + SD) was 8.2 + 4.3 in the first trimester and 6.3 +2.8 at 32 weeks. Post-prandial levels (1 h 30 rain to 2 h after the beginning of the main meal) were 6.6 + 3.3 and 5.8 + 2.5, respectively. In the second period, the following values were found: fasting: 8.1 + 4.2 in the first trimester; 8.0 + 2.8 at 32 weeks; postprandial: 7.9+2.8 in the first trimester and 7.1 _+3.1 at 32 weeks. These differences were significant for fasting plasma values at 32weeks (p <0.001), post-prandial levels in the first trimester (p < 0.001) and at 32 weeks (p < 0.001). This may in fact be due to recent technological advances which have released both doctors and patients f r o m anxiety. Despite these changes in glycaemic control beneficial effects have b e e n obtained in p r e m a ture deliveries and in the n u m b e r of Caesarian deliveries without change in per mortality. This is due to the desirability of carrying the pregnancy as close as possible to full term. However, even w h e n corrected by the later term, it appears that although m e a n birthweights have risen significantly the n u m b e r s of malformations remain the same. E x a m p l e s f r o m the literature indicate than even in the most m o t i v a t e d of health-care systems, the percentage of well controlled patients is feeble apart f r o m a few experimental studies, where e n o r m o u s efforts have b e e n m a d e by practitioners such as Lo'fs Jovanovic and her colleagues [ 25 ] or Revers et al. [ 26 ]. In general what is obtained is a m e a n glycaemic control which is at best, 30 to 40% over reference values. D a t a f r o m Chicago [ 27 ] where definition of good control is empirical and reasonable, but where n o r m o g l y c a e m i a is not achieved, showed that at the beginning of the pregnancy only 27% of p r e g n a n t w o m e n had what was considered to be good glucose control. This n u m b e r rises to 62% f r o m w e e k 32 onwards. T h e author's aim was to show that the frequency of large for gestational age infants was conditioned by the m e t a b o l i c control achieved before w e e k 31 and not by that of the last trimester. D a t a presented by the late Ivo D r u r y in his Banting lecture [ 28 ], based on glycated h a e m o g l o b i n values (given along with their reference values) showed that 38% of the w o m e n followed in Dublin had HbAlc values within the n o r m a l reference range throughout the third trimester. The higher the glyco-haemoglobin values the heavier the children were (birthweight being corrected by gestational age). These data, including ours, cover the last 15 to 20 years. But results are no b e t t e r in a recent muir study done in the U S A [ 29 ]. With reference to some consequences of this lack of normal177 of blood glucose in terms of means during pregnancy F a r m e r et al. [ 18 ] r e m a r k upon the fact that in reference populations where the fasting blood glucose levels and other p a r a m e t e r s are in the lower n o r m a l range, birthweight and subcutaneous skin thickness in particular d e p e n d closely on " n o r m a l " m a t e r n a l blood glucose levels. As British authors have pointed out, birthweight values are distributed along Gauss distributions in reference as well as in diabetic populations [ 30 ]. One can p r o b a b l y extend this causal relationship b e t w e e n glycaemia and weight f r o m children of nondiabetic m o t h e r s to those of diabetic w o m e n who, due to our sub-optimal therapeutic conditions, are statistically and inexorably overweight for their term. W h e t h e r it is dangerous or not, whether it increases the n u m b e r of Caesarian deliveries or induces increased mortality in these children are questions I will not discuss but it is highly p r o b a b l e that all these risks are linearly related to m a t e r n a l blood glucose levels without clear pathogenic cut-off points. Table 4 shows the data we obtained in 1980 [ 31 ] concerning changes in the fetus as reflected in changes in amniotic fluid f r o m diabetic and non-diabetic mothers. T h e glucose concentration in amniotic fluid of the diabetic patients was m a r k e d l y higher than in the control subjects, before and after 36 weeks of gestation. This was responsible for an increased insulin-secretion in the child assessed on C-peptide levels in the amniotic fluid which reached twice those of control subjects. T h e r e was a close correlation between C-peptide and glucose concentrations in the amniotic fluid (p < 0.05) and the infant's birthweight (p < 0.01) (even after correction for gestational age) (p < 0.05). b) Blood glucose levels in the general non-pregnant Type 1 diabetic population. D a t a f r o m Dtisseldorf, Vienna and Bucharest [ 32 ] showed that HbAic values in Type i diabetic patients obtained with routine, yet highly-structured teaching and care systems were identical to those observed in so-called highly intensive research conditions. Thus, i m p r o v e m e n t s are possible when healthcare m a n a g e m e n t is structured and when methods using either multiple injections or continuous insulin infusion by p u m p s are implemented. The best that can be achieved in terms of means is as in pregnancy H b values 30 to 40% above m e a n reference values. Less than 10 years ago we carried out a cross-sectional study in inG.Tchobroutsky: Blood glucose levels in diabetic and non-diabetic subjects IO0.EE 804 Minutes after lunch Fig.1. Post prandial blood sugar (right) and plasma insulin (left) levels in 38 non-diabetic 9 and 30 Type i (insulin-dependent) diabetic subjects 9 Values are mean + SEM. Values for the 14 patients treated by 3 daily injections of insulin are given separately A. NS=non significant; *=p <0.05; **=p <0.01; ***=p <0.001; (based on data from Tchobroutsky et al. [ 36 ]) sulin-treated diabetic out-patients [ 33 ]. Only 19% of all the diabetic patients had HbAlo levels less than 3 SD above the m e a n reference value. But the percentage of subjects in w h o m HbAlc values could be considered as acceptable was 33% in those receiving three daily injections (usually fast-acting regular insulin before each meal associated with intermediate insulin either at bedtime or with the evening meal). As for post-prandial blood glucose values collected randomly 1 to 2 h after the beginning of a non-standard meal, it a p p e a r e d that they were very low ( " n o r m a l " ) in those who had received regular insulin before the meal. All that is n e e d e d is to prescribe the regular insulin! Table 5 shows data from four c e n t r e s which have participated in a multicentre E u r o p e a n trial [ 34 ]. G r e a t differences can be seen between the centres in m e a n fasting and post-prandial glycaemia as in Hb levels. Current limitation to blood glucose control in insulin-treated patients We are aware of the obstacles facing progress in blood glucose control in Type 1 diabetic patients with our current routine treatments: they are psychological, social and educational in nature but also reflect our inability to mimic native insulin physiology. Indeed, insulin is injected in the wrong place and as has often b e e n said at the wrong time, in the wrong way and in the wrong quantities. W h a t e v e r insulin-resistance there may be it appears that the major obstacle is our difficulty or inability to restore physiological portal insulin levels. After a meal control of glycaemic excursions in nondiabetic subjects depends, in my opinion, essentially on the insulin concentrations obtained in the portal vein and on the speed with which this p e a k of insulinaemia is reached. After the pioneering work of Blackard and Nelson [ 35 ], we studied in 1973 [ 36 ] non-diabetic subjects (and also Type 2 (non-insulin dependent)) diabetic patients as we benefitted at that time from the development of per-umbilical access to the portal vein. In non-diabetic subjects, peripheral blood insulin levels decline as early as 30 min following a meal, with an equal fall in portal vein blood levels where concentrations were at least 2 to 4 times higher that the peripheral levels from 60 min onwards. In Type i diabetic patients treated with insulin it is obvious that for physical reasons the systemic venous concentrations achieved by the peripheral administration of insulin are the same as those obtained in the portal vein since insulin is not injected into the portal system. In 1970 and 1973 we attempted to deal with this problem indirectly [ 22, 36 ] by studying the circulating peripheral exogenous plasma insulin levels in Type 1 diabetic patients. We t o o k well controlled patients treated for less than three or, m o r e often, one m o n t h who had previously been hospitalized with severe insulin deprivation presenting with diabetic coma or severe ketosis and in w h o m the absence of anti-insulin antibodies [37] allowed an estimate of exogenous circulating peripheral insulin levels. Blood glucose levels in treated diabetic patients were extremely high after meals, although less so in those who received three injections of regular insulin per day, but insulin l e v els were still higher in diabetic patients than in normal subjects, in spite of high concomittant blood sugar levels (Fig. 1). It seems unnecessary, but not to be excluded, to invoke insulin resistance to explain this p h e n o m e n o n (in fact insulin resistance in Type i diabetes is reversible after treatment [ 38 ]). In view of the fact that peripheral insulin levels are also the portal insulin levels of these treated diabetic patients these portal levels are quite obviously insufficient c o m p a r e d to those of non-diabetic subjects. In order to obtain normalisation of blood glucose levels, it is important to obtain in peripheral venous blood, both before and after meals, insulin levels at least two to three times as high as those observed in the peripheral blood-stream of control subjects as shown in 1974 [ 39 ], when we u n d e r t o o k a study to evaluate the secretion of growth h o r m o n e during exercise (Fig. 2) (which of course was normal when blood glucose levels were also normal). Johnsson 1960 Lawrence 1963 Lukens 1965 Aubertin 1965 Oakley et al. 1966 Chabanier (in Deuil) 1967 Turin et al. 1967 Danger of high blood glucose levels E p i d e m i o l o g i c a l studies have s h o w n that in Type 2 diabetic patients b l o o d glucose levels b e l o w 7.8 mmol/1 o n fasting and 11.1 mmol/1 after meals m a y n o t be h a r m f u l to the k i d n e y or the retina [ 40, 41 ]. M o g e n s e n [ 42 ] has e m p h a s i s e d that it could be possible that lesions m a y r e m a i n minimal w h e n HbAI~ levels are kept within 4 SD of the mean. I n a recent longitudinal study f r o m the U S A , Chase a n d colleagues [ 43 ] have s h o w n that the risk of developing m i c r o - a l b u m i n u r i a at any age, or the risk of developing any p r e o c c u p y i n g retinopathic lesions was p r o p o r t i o n a l l y m u c h lower w h e n m e a n H b A l c values were less t h a n 10% a b o v e the u p p e r n o r m a l range. T h e risk increases rapidly with higher but not necessarily catastrophic H b levels. A s m e n t i o n e d a b o v e in the field of obstetrics there is p r o b a b l y no threshold to the deleterious effect of glycaemia but rather a linear relationship b e t w e e n b l o o d glucose levels and m a c r o s o m i a even in healthy n o r m a l w o m e n . This m a y be true for miscarriage as s h o w n by Mills et al. [ 44 ] and p r o b a b l y also for congenital malformations. How to progress in routine conditions of treatment So I believe, as do m a n y o t h e r diabetologists, that it is very i m p o r t a n t to i m p r o v e b l o o d glucose control, as well as o t h e r p a r a m e t e r s such as b l o o d pressure, in diabetic patients. E v e n if ideal control c a n n o t be achieved the lower the b l o o d glucose level the better. P e r h a p s in the n e a r future it will be possible to identify all those diabetic patients at risk of d e v e l o p i n g complications and focus on t h e m our greatest efforts. T h e r e is n o w a growing trend, to use regular fast-acting insulin several times a day in c o n j u n c t i o n with intermediate insulin, for the night using an insulin pen-injection system. This r e g i m e n has b e e n a d v o c a t e d over the last 30 years (Table 6) [ 45 ]. A t least p o s t - p r a n d i a l glucose levels can be i m p r o v e d by using regular insulin injections b e f o r e each m e a l [ 23 ]. T h e use of regular insulin and the structuring of care and teaching h a v e induced, as we have shown [ 46 ] a m o n g others, b e t t e r equilibrium and b e t t e r results in terms of life-style for diabetic patients. H y p o g l y c a e m i c episodes are less f r e q u e n t and quality of life has b e e n i m p r o v e d by energetic m a n a g e m e n t . D u e to the limitations we are faced with, we k n o w that insulin t r e a t m e n t remains imperfect. Short-acting insulins and/or the use of intra-nasal administration o f the h o r m o n e , even if of s o m e help, will not allow per se physiological treatment. But the impossibility of attaining " n o r m a l " p l a s m a glucose levels is not a r e a s o n for pessimism. B e t t e r is b e t t e r than bad. Acknowledgements. I am greatly indebted to the European Association for the Study of Diabetes for the honour of having been selected as 1989 Claude Bernard Lecturer. I also wish to thank the Paul Neuman Foundation. I would like to thank all those who have participated in the studies mentioned in particular G.Rosselin, RFreychet, R.Assan, M.Hautecouverture, J.Dolais-Kibatchi, E.Eschwege, L.Papoz, N.Thibult, A.Fontbonne, J.Chwalow, D. Simon, E Elgrably, R Y.Traynard, H. Selmi, CI. Goldgewicht, M.Letanoux, G.Reach, D.Charitanski, M.Tutin, A.Basdevant, J.J. Altman, J.Boillot. I am also indebted to my mentors Maurice Derot and Marcel Legrain and to the team of skilled technicians, secretaries and nurses without whom my work would have been impossible: F. Bruzzo, A. Chevallier, N. Desplanques, M. Bros, A. Delage, H. Jacob, E Leblanc, M. Roman, M. Roulon, N. Klein, M. M. Thiebaut, J. Jacquesson, N. Grenier, A.M. Grapin and particularly Annick Forge. Last, but not least, I would like to thank my alter ego Gerard Slama who has put up with me (and vice versa) for decades. G. Tchobroutsky: Blood glucose levels in diabetic and non-diabeticsubjects 1. Tchobroutsky G ( 1978 ) Relation of diabetic control to development of microvascular complications . Diabetologia 15 : 143 - 152 2. Kilo C ( 1985 ) Value of glucose control in preventing complications of diabetes . Am J Med 79A [Suppl 2B] : 33 - 37 3. 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Georges Tchobroutsky. Blood glucose levels in diabetic and non-diabetic subjects, Diabetologia, 1991, 67-73, DOI: 10.1007/BF00500374