Peripheral blood flow and metabolic control in juvenile diabetes

Diabetologia, Jun 1974

H. J. G. Gundersen

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Peripheral blood flow and metabolic control in juvenile diabetes

Peripheral Blood Flow and Metabolic Control in Juvenile Diabetes I-I.J. G. Gundersen 0 0 Second University Clinic of Internal Medicine, University of Aarhus , Denmark Summary. Peripheral blood flow was measured during periods of good and poor metabolic control in juvenile diabetics with less than five years duration of the disease. Previously insulin treated patients, in whom the insulin was withdrawn for a few days, showed elevated blood flow in muscular, adipose and cutaneous tissue, whereas a group of newly diagnosed diabetics before treatment showed elevated blood flow in adipose and cutaneous tissue only. In good metabolic control the diabetics had normal values of both muscular, adipose and cutaneous tissue blood flow. In poorly controlled diabetics blood pressure, pulse rate and body temperature were elevated. These parameters are also normalized when the metabolism is brought under control. It is suggested, that the increased peripheral blood flow seen in diabetics in poor control is the effect of a generally increased turn-over of energy in combination with local factors, different from tissue to tissue. Adipose tissue blood flow; metabolic control; muscle blood flow; normalization of metabolism; skin blood flow - During the past few years some authors have found higher tissue blood flow in diabetics, most often in the forearm [ 6, 3, 9 ], but also in adipose tissue [ 13 ]. However, the degree of metabolic control was not welt defined in these studies. The present investigation was undertaken in order to study the relationship between the elevated peripheral blood flow and the metabolic disturbance in diabetics. I t is clearly demonstrated, t h a t diabetics have normal blood flow in muscle, skin and fat tissue during good control. Furthermore, it is shown, that changes in some of the important parameters of the circulation are related to metabolic factors characteristic of the diabetic condition during poor control. Material and Methods Eighteen patients (three of them females) with classic juvenile diabetes were studied, their age ranging from 17 to 35 years, mean age 23 years. Seven of them (two females) were admitted with newly diagnosed diabetes. They were investigated before treatment was started and again on one or several occasions during treatment with insulin and diet. The other 11 patients (one female) were diabetics with 9 months to 5 years duration of disease, who had been treated with insulin and diet all t h a t time. These patients were hospitalized for the specific experimental purpose. After having been investigated in clinically well controlled conditions their insulin was withdrawn for a few days under carefully clinical and biochemical supervision. The measurements were carried out during the deterioration of their metabohsm. Most of them were also investigated one or two times after the reestablishment of the insulin treatment. None of the patients were allowed to develop clinical coma or precoma. The mean number of investigations per patient was four (ranging from two to seven), but only results from occasions where the individual patient was in his best and poorest c o n t r o l state will be considered in the present communication. Nine healthy volunteers (four females) with age from 23 to 36 years, mean age of 25 years, served as controls. All patients and control persons had given their informed consent to participate in the study. The measurements were performed in the morning after an overnight fast. During treatment the diabetics were given their last dose of insulin the day before at 6 p.m. During each experiment blood samples were obtained two or more times through an indwelling venous catheter. Blood glucose was determined with a glucose-oxidase method [ 8 ] and free f a t t y acids in serum (FFA) with a titremetric micromethod [ 15 ]. The concentration of standard bicarbonate (st-HCOs-i, potassium, and sodium in serum, the urinary glucose content and the haematocrit value were determined with routine laboratory methods. The subjects were at rest, lying on a bed, for at least one hour before the measurements were initiated. They were dressed in nnderwear and shirt and covered with one or two blankets, depending on their subjective feeling of thermal comfort. Total forearm blood flow was measured with a mercury-in-rubber strain gauge employing the venous occlusion principle. The blood flow was measured every 10 sec for two minutes on five to ten occasions distributed over a two to four hour period. The forearm blood flow is the mean of these 50--100 individual measurements and is expressed in ml of blood per 100 ml of tissue per minute (ml/100 ml/min). Abdominal fat tissue blood flow was measured by the clearance of 133-Xe [ 14 ] employing a distribution I-I.J. G. Gundersen: Peripheral Blood Flow and Metabolic Control coefficient of Xenon between blood and fat tissue of 10.0 in the calculations. Blood flow in cutaneous and subcutaneous tissue was measured on the proximal third of the dorsal side of the forearm after atraumatic gaseous 133-Xe labelling [ 18 ], using distribution coefficients of Xenon of 0.7 and 10.0, respectively. The blood flow in both tissues is expressed in ml/100 ml/min. The blood pressure was measured with a sphygmomanometer, and is expressed as the mean blood pressure, i.e. diastolic pressure q-one third of the pulse amplitide. The blood pressure was usually measured in every interval between the two-minutes periods of forearm blood flow measurements. The pulse rate was calculated from the plethysmographic recordings of forearm blood flow. The body temperature was measured on the tympanic membrane. This organ is perfused from the internal carotic artery and its temperature therefore reflects t h a t of the heat regulating centre in hypothalamus [ 5 ]. This temperature as well as the cutaneous temperature on the forearm and the abdomen was measured with thermistors to the nearest decigrade of Celcius. The room temperature was 21 to 24~C. or even in a state of cloudy consciousness. The values of the four biochemical parameters, on which the evaluation of the degree of control was based and of serum-K are shown in Table 2. The figures show the extreme situation in the individual patient, i.e. they are from occasions in which t h a t particular patient was in respectively the best and the poorest degree of regulation. I t appears t h a t there is no difference between blood glucose, FFA, st-tiC03- or the urinary glucose excretion observed in the two groups of diabetics, the newly diagnosed cases and the patients who had previously been on insulin treatment. However, when the serum-K values of these two groups are compared a clearcut difference appears. The average values in the poorest control state is 0.7 meq/1 higher in the group of previously insulin treated patients than in the newly diagnosed ones, 2P = 0.011. The same tendency is apparent when looking at the difference between the serum-K values observed in the poorest and in the best state of control. I n the previously insulin treated cases there was a difference of 0.4 d=0.5 meq/1 (all patients) which was also statistically significant, 2P = 0.044. On the other hand, in the newly diagnosed cases where the serum-K was low during poor control, there was no statistically signifi The skin fold on the forearm and the abdomen was estimated with Harperden's caliper at the places where the 133-Xe clearances were measured. The degree of metabolic disturbance was evaluated on the basis of fasting blood glucose, F F A and sttICOs- in serum and the 24 h urinary excretion of glucose. These four parameters were divided into five classes, shown in Table 1. The metabolic disturbance at the time of investigation was then calculated as the arithmetic mean of the class numbers of the four parameters. This figure is called the patient's degree of regulation (DR). D R ~ 1 is a very good control state, which is unusual in a juvenile diabetic, whereas a patient with DI~ = 4 probably will be in precoma or coma the next day. Results Biochemical Parameters The range of metabolic control in the patients studied varied between almost complete normalization and moderate ketoacidosis with s t - H C Q - of 10 meq/1. None of the patients in poor control were unconscious cant difference between the values in poor and best control: --0.3 d=0.6 meq/1 (all patients) 21) = 0.16. The haematocrit value was determined as a rough measure of dehydration. The difference between values obtained in the best and in the poorest state of control was quite small and nearly identical in the two groups of patients. I t was 2 ~o higher during poor control in the newly diagnosed patients, 3% higher in the previously insulin treated cases. Blood Flow Measurements The results of the blood flow measurements in the forearm and the other tissues will be considered from three different points of view, endeavouring to answer the following three questions: a) is the blood ftow in various organs abnormal when the diabetic state is very good controlled ? b) is there a demonstrable difference between blood ftow in good and poor control as defined b y the composite four parameter index used in the present study? c) can a relationship be shown between blood flow and a n y individual biochemical parameter measured? Forearm Blood Flow. The forearm flow was measured in all patients and control subjects. a) Fig. 1, A shows the t o t a l f o r e a r m blood flow values in the control subjects and in those p a t i e n t s in the two groups of diabetics in w h o m it was m e a s u r e d at times w h e n the D R ~ 1. There is neither any difference b e t w e e n t h e normals a n d t h e diabetics in v e r y this difference is statistically h i g h l y significant, whereas the newly diagnosed showed no difference b e t w e e n the u n t r e a t e d and t h e best r e g u l a t e d condition. The m e a n changes in the two groups of diabetics were statistically significantly different, 2P = 0.024. B-gl: Blood glucose, rag/100 ml F F A : Free f a t t y acids in serum, nM/1 HCOa: Standard bicarbonate, meq/1 U-gl : 24 h urinary glucose excretion Se-K: Potassium in serum, meq/1 a D R > 1 in best control b Median c I n "Best control" only patients with very good control (i.e. Dig =<1) are included. Blood Flow and Metabolic Control Cutaneous Blood Flow. The cutaneous blood flow was measured in 10 diabetics, seven of whom had a D R ~ 1 in best control. a) These v e r y good controlled diabetics showed the same m e a n cutaneous blood flow as the nine normals, see Fig. 2, A and Table 3. b) Fig. 2, ]3 and Table 3 show t h a t the difference the abdomen and the forearm was 14.7, 7.2--22.9 m m (median and range) and 7.1, 4.9--8.1 mm, respectively, whereas the figures in the diabetics with D R ~ 1 were 6.7, 4.6--16.2 m m and 4.6, 3.0--6.8 ram. The values in the diabetics are statistically significantly lower t h a n in the normals, 2P < 0.05 and 21) < 0.01 (Wilcoxon r a n k sum), respectively. Only diabetics with skinfold , Fig. 1. A) Forearm blood flow in normals and diabetics with degree of regulation < 1. The blood flow is expressed in ml/100 ml/min. The filled circles represent the previously insulin treated diabetics, and the open circles represent newly diagnosed diabetics. B) The difference in forearm blood flow between poorest and best regulation in diabetics. The filled triangles are the previously insulin treated patients and the open triangles are newly diagnosed diabetics in cutaneous blood flow measured in poor and good metabolic conditions in all 10 diabetics is statistically highly significant. The difference between poor and good regulation is equal in the two groups of diabetics. c) As with forearm blood flow, correlation analysis did not reveal relationship between cutaneous blood flow and any individual biochemical parameter. However, there was a trend towards a correlation between the changes in b o d y t e m p e r a t u r e and cutaneous blood flow in the individual patient, r = 0.65, although not statistically significant. Fat Tissue Blood Flow. The blood flow in the subcutaneous fat layer was measured b o t h on the abdomen and on the forearm. I t is known t h a t the local fat tissue blood flow is inversely related to the thickness of the skinfold at the point of measurements [ 14 ]. I n order to m a k e comparisons of blood flow, it i s therefore necessary to select groups with a p p r o x i m a t e l y equal skkLfold thickness. I n the group of normals the thickness of the skinfold on A '+ + , "nil100mi/min -10 98 -6 * ~ B -4 "0 --2 "nil100mi/min 9 + normals oo diabetics in good contro[ 99 change durmg poor control Fig. 2. A) The cutaneous blood flow in normals and in diabetics with degree of regulation < 1. B) The difference between cutaneous blood flow in the poorest and the best degree of regulation in diabetics. Symbols and units as previously thickness greater t h a n the leanest normal has been included in the comparisons of blood flow between diabetics and normals. a) The m e a n blood flow in the abdominal subcutaneous fat tissue of four diabetics in very good control and with skinfold thickness > 7.2 m m was the same as t h a t of the normals, see Fig. 3, A and Table 3. Only two of the diabetics with D R ~ 1 had normal skinfold thickness of the forearm and showed blood flow values of the subcutaneous fat, which are comparable to t h a t of the normal group. b) Figs. 3, ]3 and 4, ]3 show the differences between the subcutaneous fat tissue blood flow on the abdomen and forearm, respectively, in poor and good control. Although the variances are great, both of the mean differences are statistically significant. The difference between the fat tissue blood flow in poor and good control was equal in lean and " f a t " diabetics. c) Neither the subcutaneous fat tissue blood flow during metabolic derangement nor its changes were correlated to any of the individual biochemical parameters. Blood Pressure, Pulse and Body Temperature a) I t appears from Table 4 t h a t diabetics in v e r y good control showed normal values of m e a n blood pressure, pulse rate and body temperature. b) The values of these three parameters in poorest control are also shown in Table 4. The average difference in all diabetics between poorest and best control with respect to mean blood pressure was statistically significant, 2P----0.016. The difference in mean blood pressure was due to elevations in both diastolic (4 ~= 6 m m H g ) and systolic (17  13 m m H g ) blood pressure. Similar moderate but consistent differences were observed in pulse rate (2P = 0.0021 and in body temperature (2P = 0.0014). Discussion The results obtained in the present study show t h a t the blood flow of the forearm, the cutaneous tissue and the subcutaneous fat is elevated in poorly controlled diabetic patients after withdrawal of insulin. The same is true for the blood flow of cutaneous and subcutane B .1/, 12 -10 -8 -6 -4 -2 -0 --2 mt/100m[/min A l m,lAkm A ~ m[/100 mt/min -12 H . J . G . Gundersen: Peripheral Blood Flow and 1Y[etabolic Control shown to be elevated i n diabetics who were n o t wellcontrolled, a n d the flow was h a l v e d 30 rain after insulin i.v. [ 13 ]. I t t h u s appears t h a t elevated blood flow i n the forearm a n d the adipose tissue is a characteristic finding i n diabetics w h e n their state of metabolic control is poor, a n d t h a t i n s u l i n t r e a t m e n t for hours or days will lower the elevated blood flow. t e m p e r a t u r e i n c o m b i n a t i o n with a high skin blood flow d u r i n g metabolic d e r a n g e m e n t f o u n d i n the present s t u d y is a n i n d i r e c t expression of the increased heat production. Similarly, the h y p e r m e t a b o l i s m i n thyrotoxicosis is accompanied b y a n elevated muscle blood flow t h a t falls i n parallel w i t h the basal metabolic r a t e after t r e a t m e n t [ 2 ]. F u r t h e r m o r e , i n a group of diabetics a n d n o r m a l s a correlation b e t w e e n the local 1VIean b 81 63 36.5 81 64 36.6 88 76 36.9 SD 7 8 0.3 8 8 0.1 9 15 0.3 a DR > 1 in best control b I n "Best control" only patients with very good control (i.e. DR =<1) are included c The body temperature was measured on another occasion t h a n the corresponding values of blood pressure and pulse rate. The n o r m a l blood flow i n well controlled diabetics f o u n d i n the p r e s e n t s t u d y shows t h a t this progresses to complete n o r m a l i z a t i o n w h e n t r e a t m e n t is optimal. This finding suggests t h a t the elevated blood flow is caused b y one or more metabolic factors or b y a factor closely r e l a t e d to the m e t a b o l i s m i n diabetics. I t has been k n o w n for m a n y years t h a t the basal metabolic r a t e is elevated i n diabetic p a t i e n t s , particularly u n d e r b a d control [ 4, 11 ]. The elevated b o d y oxygen u p t a k e a n d blood flow i n b o t h adipose a n d m u s c u l a r tissue has b e e n shown [12]. I t t h u s seems reasonable to suggest t h a t one of the reasons for the elevated peripheral blood flow i n diabetics d u r i n g poor control is a n increased t u r n - o v e r of energy i n all tissues. I n addition, factors h a v i n g specific effects on the blood flow i n the i n d i v i d u a l tissues m u s t also be considered. One such factor is p r o b a b l y the s y m p a t h e t i c n e r v o u s system. I t has recently b e e n shown [ 10 ] t h a t t h e c o n c e n t r a t i o n of p l a s m a n o r a d r e n a l i n e is cons i s t e n t l y raised i n diabetics w i t h ketosis, a n d t h a t some p a t i e n t s i n severe ketosis show v e r y high levels of p l a s m a adrenaline. The local effect of n o r a d r e n a l i n e on fat tissue is a n increase i n b o t h lipo]ysis a n d blood flow [ 16, 17 ], whereas the action of a d r e n a l i n e is less well defined. I n the skin, b o t h eatecholamines produce a r e d u c t i o n i n blood flow, a n d the small b u t consistent elevation seen i n diabetics i n poor control m u s t therefore be the result of a more p o t e n t opposing mechanism, m o s t likely the t h e r m o - r e g u l a t o r y response to the increase i n b o d y t e m p e r a t u r e . The effect of a d r e n a l i n e on muscle is am i n c r e a s e d b l o o d flow, whereas n o r a d r e 1. Abramson , D. I. : Circulation in the extremities , p. 408 . New York: Academic Press 1967 2. Abramson , D.I. , Fierst , S.M.: l~esting peripheral blood flow in the h y p e r t h y r o i d state . Arch. intern. Med . 69 , 409 -- 416 ( 1942 ) 3. Alexander , K. , Teusen , R. , Mitzkat , N . 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J . : A reversible vascular a b n o r m a l i t y associated with diabetic ketosis . Clin. Sei . 39 , 539 -- 548 ( 1970 ) 10. Christensen , N . J . : Diabetic angiopathy and neurop a t h y . Acta reed. scand. Suppl . 541 ( 1972 ) 11. Holten , C. : The r e s p i r a t o r y metabolism in diabetics and the influence of insulin upon it . (Thesis ) Copenhagen: Levin and Munksgaard Publishers 1925 12. H/iggendal, E., Kerstell , J. , Steen , B. , Svanborg , A. : Blood flow and u p t a k e of oxygen and substrates in forearm muscle and subcutaneous fat tissue in man . Acta reed. seand. 183 , 79 -- 82 ( 1968 ) 13. Hiiggendal , E. , Steen , B. , Svanborg , A. : Blood flow in subcutaneous fat tissue in patients with diabetes mellitus . Acta reed. seand. 187 , 49 -- 53 ( 1970 ) 14. Larsen , O.A. , Lassen , N.A. , Quaade , F . : Blood flow through h u m a n adipose tissue determined with radioactive xenon . Aeta physiol, stand. 6 6 , 3 3 7 - 345 ( 1966 ) 15. Laurell , S. , Tibbling , G.: Colorimetric mierodeterruination of free f a t t y acids in plasma . Clin. ehim. Aeta 16 , 57 -- 62 ( 1967 ) 16. Levin Nielsen , S. , Bitseh , V. , Larsen , O.A. , Lassen , N.A. , Quaade , F. : Blood flow through h u m a n adipose tissue during lipolysis . Seand. J. din. Lab. Invest . 22 , 124 -- 130 ( 1968 ) 17. Quaade , F. , Larsen , O.A. , Lassen , N.A. , Levin Nielsen , S. : Observations on the influence of glucose upon subcutaneous adipose tissue blood flow . Acta reed. seand. Suppl . 476 , 85 -- 90 ( 1967 ) 18. Sejrsen , P. : Blood flow in cutaneous tissue in man studied b y washout of radioactive xenon . Circular. Res . 25 , 215 -- 229 ( 1969 )

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H. J. G. Gundersen. Peripheral blood flow and metabolic control in juvenile diabetes, Diabetologia, 1974, 225-231, DOI: 10.1007/BF00423039