Metabolic profiles in closely controlled diabetic pregnancies during the third trimester

Diabetologia, Apr 1979

J. Jervell, K. T. Stokke, N. Moe, H. N. Haugen, J. Vidnes

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Metabolic profiles in closely controlled diabetic pregnancies during the third trimester

Diabetologia J. Jervell 0 K. T. Stokke 0 N. Moe 0 H. N. Haugen 0 J. Vidnes 0 0 Departments of Medicine, Clinical Chemistry , Obstetrics and Gynaecology,and Paediatrics, Rikshospitalet, Oslo , Norway 0012-18 6X/7 9 / 0 0 1 6 / 0 2 2 9 / $ 0 1 . 0 0 Diabetic pregnancy; metabolic profile; diabetes mellitus; insulin therapy; metabolic control; glucagon; cortisol; growth h o r m o n e; k e t o n e bodies; blood glucose; b l o o d lactate; blood pyruvate; plasma non-esterified fatty acids - Summary. In 5 closely controlled pregnant diabetics (duration of pregnancy 2 3 7 - 2 6 6 days) and 5 pregnant non-diabetics (duration of pregnancy 2 1 0 - 2 7 8 days) 4-hourly blood samples were t a k e n throughout a 24 h period and analyzed for blood glucose, lactate, pyruvate, 3 - h y d r o x y b u t y r a t e and acetoacetate, plasma non-esterified fatty acids ( N E F A ) , glucagon and cortisol. 24 h urine specimen was analyzed for total catecholamines and 4 - h y d r o x y - 3 - m e t h o x y m a n delic acid. T h e r e were few significant differences in concentrations of metabolites and h o r m o n e s in the two groups at any time, although the variations about the m e a n was usually greater in the diabetics.Thus for blood glucose in diabetics, m e a n value was 4.4 mmol/1, coefficient of variation 4 3 % ; in non-diabetics 4.1 mmol/1 and 10% respectively. M e a n plasma 3 - h y d r o x y b u t y r a t e in diabetics was 0.47 mmol/1, coefficient of variation 5 5 % ; in non-diabetics 0.44 mmol/1 and 3 7 % respectively. Plasma non-esterified fatty acid levels were significantly higher in the diabetics (0.47 mmol/1) than in the non-diabetics (0.26 mmol/1). Coefficients of variation were 4 6 % and 3 3 % respectively. T w o conclusions can be drawn; first, w h e n n e a r normal m e a n values for blood glucose are achieved, o t h e r metabolite and h o r m o n e levels are also n e a r normal; second, even when the available means for diabetic control, strict diet and insulin-mixtures twice daily, are used at their maximum, metabolism in diabetics is m o r e unstable than in non-diabetics. Insulin treatment of the diabetic represents a form of replacement therapy. Subcutanously injected insulin, however, is not a physiological substitute for insulin p r o d u c e d by the/J-cells; its release into the circulation will be independent of the blood glucose concentration and the other metabolic, nervous and hormonal factors which regulate the normal release of insulin. F u r t h e r m o r e , insulin released from the subcutaneous tissues will reach the systemic circulation directly, bypassing the portal vein and liver. T h e balance b e t w e e n the effects of insulin on the liver and the peripheral tissues in insulin treated diabetics will t h e r e f o r e differ from that in normal individuals. In diabetic pregnancy normalization of metabolism is probably of m a j o r importance for the o u t c o m e [ 4, 12 ]. In most studies blood glucose normalization has b e e n the goal, and only recently have o t h e r metabolites been studied [ 5, 6 ]. T h e present study was u n d e r t a k e n to evaluate to what extent normalization of metabolism is possible in intensely controlled, hospitalized, insulin-dependent, pregnant diabetics. Materials and Methods Patients The diabetic subjects, all with long-standing juvenile diabetes, were taking part in a specialregimenfor pregnant diabetics[ 9 ].On this regimen they were admitted to the ward in the 33rd week of pregnancy; delivery usually took place 1-3 weeks before term. The studywas performed during this period. A standard diet of 3 main meals and two smaller meals was given. Blood glucoseconcentration was determined 4 times daily (0800, 1200, 1600, 2000 h) and insulin was given twice daily, before breakfast at 0800 h and at 1730h before the main eveningmeal, as a mixture of intermediate-acting (isophane) and soluble insulin, the dose being adjusted daily. During the hospital stay the patients were encouraged to exercise regularly. 27 27 27 29 22 27 20 22 34 29 0 0 2 2 0 Parity a Patient 1 - 4 had simple retinopathy only, patient 5 no signs of angiopathy b Insulin was given twice daily. The dose of isophane insulin is written first, the dose of soluble insulin second Duration of pregnancy at sampling (days) 248 249 260 237 266 Duration of pregnancy at delivery (days) 259 269 265 263 271 Birth weight of baby (g) 3210 4300 3250 3140 3520 Glucose was determined by a glucose oxidase method adapted for Auto-analyzer. Blood samples for lactate and pyruvate determinations were immediately mixed with equal volumes of ice-cold perchloric acid (1 tool/l), and samples were kept frozen ( - 2 0 ~ until analyzed. The concentrations of lactate and pyruvate were determined by the Biochemica Test Combination (Boehringer Mannheim GmbH). Ketone bodies (3-hydroxybutyrate and acetoacetate) were determined on the perchloric acid extracts by an enzymatic method [ 17 ]. The plasma concentration of nonesterified fatty acids (NEFA) was determined by a titrimetric method [ 13 ]. Plasma cortisol was determined by radioimmunoassay (Diagnostic Products Corporation, Los Angeles). The concentration of 4 hydroxy - 3 methoxy mandelic acid (HMMA) and catecholamines in urine were determined by routine methods, H M M A by spectrophotometry after oxidation with periodate, catecholamines by fluorimetry after conversion to lutin derivatives. Plasma glucagon was determined by radioimmunoassay [ 8, 14 ]. NOVO Research Institute kindly supplied the pancreas specific antiserum (K 964), glucagon for standards and (1251) glucagon. All samples were assayed in triplicate. Unspecific glucagon activity was determined after treatment with charcoal (Norit A) to remove true glucagon, and subtracted from total glucagon to give true glucagon. Coefficient of variation of the assay was 9.4% at glucagon concentration of 60 ng/1. The lower detection limit was approximately 20 ng/l. Student's t-test has been used to test for statistical significance, using p < 0.05 as the level of statistical significance. R e s u l t s T h e r e s u l t s a r e g i v e n i n T a b l e 3 a n d 4. B l o o d g l u c o s e v a l u e s d i d n o t d i f f e r s i g n i f i c a n t l y a t a n y t i m e , a l t h o u g h t h e v a r i a t i o n s w e r e g r e a t e r i n t h e d i a b e t i c s , 0800 5.3_+ 3.2 (2.5-10.4) 3.4_+ O.3 (3.1- 3.6) 0.9_+0.2 (0.7-1.3) 0.9_+0.4 (0.5-1.2) 0.07_+0.01 (0.06-0.09) 0.07-+0.01 (0.05-0.08) 12.5_+ 2.4 (10 -16.3) 12.2_+ 4.5 (8.3-17.1) 0.67 (0.25-1.05) 0.22 (0.19-0.28) 0.53 (0.31-0.96) 0.39 (0.16-0.49) 0.17 (0.09-0.29) 0.16 (0.08-0.28) Values are given as mean  SD, range in parenthesis the coefficient of v a r i a t i o n b e i n g 4 3 % versus 1 0 % in the non-diabetics. Figure 1 shows the individual curves for the two groups. M e a n b l o o d glucose t h r o u g h the whole p e r i o d was 4.4 mmol/1 for the diabetics, 4.1 in the n o n - d i a b e t i c s . P l a s m a N E F A w e r e o n the whole higher in the diabetic group, the difference did not, e x c e p t at 2000 h, r e a c h statistical significance. A g a i n the coefficient of v a r i a t i o n was higher for the diabetics, 4 6 % versus 3 3 % . Figure 2 shows the individual curves f o r the two groups. T h e m e a n N E F A for the 24 h was 0.47 mmol/1 for the diabetics, 0.26 mmol/1 f o r the n o n - d i a b e t i c s ; this difference is significant (p < 0.0005). T h r e e of the n o n - d i a b e t i c p a t i e n t s h a d relatively short d u r a t i o n of p r e g n a n c y ( 2 1 0 - 2 1 5 days) at the t i m e of testing, a n d two h a d a long d u r a t i o n (271 a n d 278 days). A s s h o w n in figure 1 a n d 2 this did not s e e m to influence their b l o o d glucose and N E F A levels. K e t o n e b o d y levels ( 3 - h y d r o x y b u t y r a t e a n d acet o a c e t a t e ) w e r e r e m a r k a b l y similar in the t w o groups, again the coefficient of v a r i a t i o n was g r e a t e r in the diabetics, 5 5 % versus 4 3 % in the non-diabetics. B l o o d lactate and p y r u v a t e levels a n d their v a r i a tion w e r e similar in the two groups. T h e l a c t a t e / p y r u v a t e ratios t e n d e d to b e higher in the diabetics t h a n in the non-diabetics, m e a n values for the whole p e r i o d 13.2 and 11.7 respectively; the difference is statistically significant (p < 0.005). P l a s m a glucagon levels a n d v a r i a t i o n did n o t differ significantly in the two groups. P l a s m a cortisol also t e n d e d to b e higher in the diabetics; the differences are not significant. U r i n a r y excretion of c a t e c h o l a m i n e s and H M M A did not differ in the two groups. T o t a l urine c a t e c h o l a m i n e s was 379 n m o l / 2 4 h and 306 n m o l / 2 4 h in diabetics a n d n o n - d i a b e t i c s respectively; u r i n a r y H M M A 14 g m o l / 2 4 h and 18 btmol/24h, respectively. ..............: .......................... . . ............................. ,,';,O,4Z 0,2"'""'"..e'"'"'"'"" ....'"..'.lb.,...... (4 5 08 12 16 iO 24 04 08 16 24 -~8 0 E ~6 I/I 0g4 m o 10,-'-80 E E6~~4r~ 2as t h e p r o g r a m has r e d u c e d t h e per m o r t a l i t y t h e p a r a m e t e r for a d j u s t i n g insulin d o s e , d i e t a n d general management also gives fairly normal blood levels for other metabolites and hormones. Nonesterified fatty acids are the exception; this may be of particular importance as it has been suggested that increased N E F A levels may explain adiposity in infants of diabetic mothers [ 11 ]. None of the 5 infants born to the diabetic mothers in the present study, however, were overweight. There is a greater variation in the blood levels of many metabolites in the diabetic group, illustrating that their metabolism is more unstable than in nondiabetics, and that completlely physiological conditions cannot be obtained with subcutanously injected insulin. Better stabilization in diabetic pregnancies can, however, probably be achieved by a glucose controlled insulin infusion system. At present this can only be used for short periods such as during labour [ 10 ]. It must be noted that the non-diabetic controls in this study are not normal controls; they were all hospitalized for various complications of pregnancy. Also they differed from the diabetics in duration of pregnancy. The influence of these factors is difficult to evaluate, but it is probable that if the non-diabetics had been completely normal and of the same duration of pregnancy, the variations in their blood metabolite levels might have been even smaller. Our blood samples were drawn at 4 - hourly intervals. Others [ 1, 2, 5, 6, 7, 15, 16 ] have demonstrated fluctuations which will not have been detected using our sampling schedule. Typical is the postprandial morning blood glucose, and postinsulin injection lactate rise found in insulin treated diabetics [ 1, 2 ]. Quite low blood sugars were reached in some of the diabetic subjects, the lowest values being 1.8 mmol/l. It is possible that some even lower values occurred during the sampling intervals. It is, however, our general experience that severe symptomatic hypoglycemia is relatively rare in pregnant diabetics on this program [9]. Alberti et al. [ 1, 2 ] have recently published studies showing poor metabolic control, sometimes with very abnormal metabolic rhythms, in insulin dependent diabetics under more ordinary circumstances where no special effort to optimalize the control was used. The regimen used for pregnant diabetics may be a model for improving metabolic control in diabetics in general. 1. Alberti , K. G. M. M. , Dornhorst , A. , Rowe , A. S.: Metabolic rhythms in normal and diabetic man . Isr. J. Med. Sci . 11 , 571 - 580 ( 1975 ) 2. Alberti , K. G. M. M. , Nattrass , M. : Metabolic abnormalities in juvenile diabetics . In: Diabetes og diabetes behandling , II. Aagen~es, O. (Ed.), p. 125 - 137 . Oslo: Nordisk Symposium 1976 3. Buckle , A. L.J. , Nattrass , M. , Cluett , B.E. , Stubbs , W.A. , Walton , R.J. , Alberti , K. G. M. M. , Clemens , A.H. : Blood metabolite concentrations in diabetics, effect of normalization of blood glucose using a glucose controlled insulin infusion system . Diabetologia 13 , 385 ( 1977 ) 4. Karlson , K. , Kjellmer , I. : The outcome of diabetic pregnancies in relation to mother's blood sugar level . Am. J. Obstet. Gynecol . 112 , 213 - 220 ( 1972 ) 5. Gillmer , M.D.G. , Beard , R.W. , Brooke , F.M. , Oakley , N. W. : Carbohydrate Metabolism in Pregnancy, Part I - D i u r - nal plasma glucose profile in normal and diabetic woman . Br. Med. J. 1973 II , 399 -- 402 6. Gillmer , M . D . G . , Beard , R.W. , Oakley , N.W. , Brooke , F. M. , Elphiek , M. C. , Hull , D. : Diurnal plasma free fatty acid profiles in normal and diabetic pregnancies . Br. Med. J. 1977 II , 670 - 673 7. Hansen , Aa. P. , Johansen , K. : Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics . Diabetologia 6 , 27 - 33 ( 1970 ) 8. Heding , L.G. : Radioimmunological determination of pancreatic and gut glucagon in plasma . Diabetologia 7 , 10 - 13 ( 1971 ) 9. Jervell , J. , Moe , N. , Skj~eraasen, J., Blystad , W. , Egge , K. : Diabetes mellitus and pregnancy . Management and results at Rikshospitalet , Oslo 1970-77. Diabetologia 16 , 151 - 155 ( 1979 ) 10. Nattrass , M. , Alberti , K. G. M. M. , Dennis , K. J. , Gillibrand , P. N. , Letchworth , A. T. , Buckle , A. L. J.: A glucose-controlled insulin infusion system for diabetic women during labour . Br. Med. J. 1978 II , 599 - 601 11. Szabo , A.J. , Szabo , O. : Placental free fatty acid transfer and fetal adiposetissue development: an explanation of fetal adiposity in infants of diabetic mothers . Lancet 1974 II, 498 - 499 12. Pedersen , J.: The pregnant diabetic and her newborn . Copenhagen: Munksgaard 1977 13. Trout , D.L. : Titration of free fatty acids: a study of current methods and a new modification . J. Lipid Res . 1 , 199 - 206 ( 1960 ) 14. Vidnes , J. , r S.: Glucagon deficiency causing severe neonatal hypoglycemia in a patient with normal insulin secretion . Pediatr. Res . 11 , 943 - 949 ( 1977 ) 15. Wildenhoff , K.E. : Diurnal variations in the concentrations of blood acetoacetate, 3-hydroxy butyrate and glucose in normal persons . Acta Med . Scand. 191 , 303 - 306 ( 1972 ) 16. Wildenhoff , K. E. : The influence of diabetic regulation on the diurnal variation in blood and the urinary excretion of ketone bodies. Studies in newly diagnosed diabetics . Acta Med . Scand. 198 , 127 - 133 ( 1973 ) 17. Williamson , D. H. , Mellanby , J. , Krebs , H. A. : Enzymic determination of D(- ) -/3-hydroxybutyric acid and acetoacetic acid in blood . Biochem. J . 82 , 90 - 96 ( 1962 ) Received: July 20 , 1978 , and in revised form: November 7 , 1978

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J. Jervell, K. T. Stokke, N. Moe, H. N. Haugen, J. Vidnes. Metabolic profiles in closely controlled diabetic pregnancies during the third trimester, Diabetologia, 1979, 229-233, DOI: 10.1007/BF01221948