References Qwp
1. Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 1998 21 B161-7. 2. Ryan EA, O'Sullivan MJ, Skyler JS. Insulin action during pregnancy studies with the euglycemic clamp technique. Diabetes 1985 34 380-9. 3. Catalano PM, Tyzbir ED, Wolfe RR, et al. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol 1 993 264 E60-7. 4. Kuhl C. Insulin...
Pancreatic betacell function in normal pregnancy and gestational diabetes
Insulin is the main hormone controlling blood glucose concentration. Most commonly, assessment of beta-cell function is made by measuring the fasting insulin concentration or the response to glucose infusion. Fasting plasma insulin increases gradually during pregnancy - by the third trimester levels are 2-fold higher than before pregnancy. Patients with GDM have fasting insulin levels equal to or higher than those of women with non-diabetic pregnancies, with the highest levels occurring in...
References Vin
1. Cooperstein SJ, Watkins D. Action of toxic drugs on islet cells. In Cooperstein SJ, Watkins D, eds. The Islets of Langerhans. New York Academic Press 1981, pp. 387-425. 2. Shafrir E. Diabetes in animals. In Porte Jr. D, Sherwin R, Baron A, eds. Diabetes Mellitus, 6th edn. New York McGraw-Hill 2003. 3. Okamoto H. The molecular basis of experimental diabetes. In Okamoto H, ed. Molecular Biology of the Islets of Langerhans. Cambridge Cambridge University Press 1990, pp. 209-31. 4. Boquist L....
References Qel
1. Metzger BE. The legacy of Norbert Freinkel Maternal metabolism and its impact on the offspring, from embryo to adult. Diabetes in pregnancy. Norbert Freinkel memorial issue. Israel J Med Sci 1991 27 425-31. 2. Ingbar SH, Freinkel N, Hoeprich PD, Tthens FW. The concentration and significance of the butanol-extractable I131 of serum in patients with diverse states of thyroidal function. J Clin Invest 1954 33 388-99. 3. Ingbar SH, Freinkel N. Simultaneous estimation of rates of thyroxine...
Human placental lactogen
Human placental lactogen hPL levels rise at the beginning of the second trimester, causing a decrease in phosphorylation of insulin receptor substrate IRS -1 and profound insulin resistance.20 Beck and Daughday30 demonstrated that overnight infusion of hPL results in abnormal glucose tolerance, and increased insulin and glucose concentration in response to an oral glucose challenge. Accordingly, Brelje et al.31 found that in islet cell culture, hPL directly stimulates insulin secretion. This...
Cognitive development in children of diabetic mothers
Several studies evaluated the association between cognitive development and metabolic fuels in pre-existing and gt LGA infants of GDM mothers had a higher BMI, greater waist circumference and abdominal skinfold compared to AGA-GDM. gt No difference between non-GDM LGA and AGA. Modified from Vohr et al, Diabetes care, 1999 Figure 14.3 Long-term complications of the infant of the diabetic mother. Infant's age 4-7 years. Modified from Vohr B et al. Diabetes Care 1999 22 8 128-91. AGA-NON-GDM...
Neonatally STZadministered rats nSTZ
Among the syndromes resembling mild Type 2 diabetes as a consequence of reduced beta-cell mass are rats which received neonatal STZ injection nSTZ , either at the time of birth45,46 or 2 days after birth.46,47 It should be stressed, however, that these animals, although non-obese, do not represent a true Type 2 diabetes, but rather a model of limited insulin deficiency with little, if any, peripheral or hepatic insulin resistance. The i.p. or intravenous injection of 90-100 mg kg STZ into...
Metabolic change as teratogens
In the late 1970s and early 1980s, Freinkel and his group extended their focus beyond the factors that mediate insulin secretion in the fetus, insulin-dependent fetal growth and other manifestations of third trimester fetal hyperinsulinism to consider the consequences of an altered intrauterine metabolic environment throughout gestation. Describing pregnancy as 'a tissue culture experience'17 put this concept into sharp relief and Norbert Freinkel's 1980 Banting Lecture18 was a masterful blend...
Placental structure and morphology
The placenta is a complex organ made up of a variety of tissues that theoretically can contribute to transplacental transfer. All materials destined for transfer to the fetus must first be taken up by the microvillous membrane of the syncy-tiotrophoblast, the tissue which is in direct contact with maternal blood in the intervillous space. Once within the syncytium the molecules are either sequestered for modification lipids or metabolized for placental purposes glucose , or they leave the...
GotoKakizaki rats
Apart from animals with spontaneous alterations leading to inappropriate hyperglycemia, a diabetic line was isolated by repeated breeding of normal animals. The selection was of individuals with minimal deviation from the mean response to a glucose load. This emphasizes the polygenic basis of diabetes within a 'normal' genetic mosaic. A GK diabetic line was obtained by breeding Wistar rats for gt 35 generations in Japan, using a relative intolerance to a 2 g kg glucose load as a selection...
Hyperlipidemia
Hyperlipidemia normally develops during the last third of gestation and mainly corresponds to increases in triacylglycerols, with smaller rises in phospholipids and cholesterol.17,19 Besides an increase in VLDL levels as a result of their enhanced liver production and decreased removal from circulation as a consequence of reduced adipose tissue LPL activity, the increase in plasma triacylglycerols corresponds to their proportional enrichment in both LDL and HDL,19 lipopro-teins that are...
References Hlg
1. Knopp RH, Montes A, Childs M, Li JR, Mabuchi H. Metabolic adjustments in normal and diabetic pregnancy. Clin Obstet Gynecol 1981 24 21-49. 2. Knopp RH, Bonet B, Zhu XD. Lipid Metabolism in pregnancy. In Cowett RM, ed. Principles of Perinatal-Neonatal Metabolism. New York Springer 1998, pp. 221-58. 3. Catalana PM, Tyzbir ED, Wolfe RR, et al. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant woman. Am J Obstet Gynecol 1992 167...
Streptozotocininduced diabetes
Streptozotocin STZ -induced diabetes results from either intravenous or intraperitoneal i.p. injection of the toxin. Alloxan is also an effective diabetogenic agent but is now rarely used in pregnant animals. The mode of action of STZ and typical observations on the resulting diabetic derangements in various animal species have been extensively described in several reviews.1-5 A wide range of animals may be used to elicit diabetes in pregnancy by STZ, including rabbits, pigs, sheep, and...
Fetal glucose carbon contribution to glycogen formation
Many fetal tissues, including the placenta, as well as the brain, liver, lung, heart, and skeletal muscle, produce glycogen over the second half of gestation.63 Liver glycogen content increases with gestational age Figure 9.2 and is the most important store of glycogen for systemic glucose needs, because only the liver contains sufficient glucose-6-phosphatase for release of glucose into the circulation. Skeletal muscle glycogen content increases during late gestation, whereas lung glycogen...
The GDM controversy
Diabetes mellitus is one of the most common medical complications of pregnancy. Of all types of diabetes, gestational diabetes GDM accounts for approximately 90-95 of all cases of diabetes in pregnancy. GDM is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy. The definition is applicable regardless of whether insulin is used for treatment or the condition persists after pregnancy. It does not exclude the possibility that unrecognized...
References
1. Peel J. A historical review of diabetes and pregnancy. Obstet Gynaecol Br Commun 1972 79 385-95. 2. Reece EA. The history of diabetes mellitus. In Reece EA, Coustan DR, eds. Diabetes Mellitus in Pregnancy, 2nd edn. New York Churchill Livingstone 1995, pp. 1-10. 3. Banting FG, Best CH. The internal secretion of the pancreas. J Lab Clin Med 1 922 7 256-71. 4. Bliss M. The Discovery of Insulin. Edinburgh Paul Harris Publishing 1983, pp. 20-58. 5. Joslin EP. Pregnancy and diabetes mellitus....
Gross examination
The presence of chronic placental anomalies indicative of chronic insult small or large placenta size, infarcts or hemorrhages, anomalies of insertion and defects of the cord, variations of placental shape, loss of transparency or increases of thickening of membranes, etc. may already be diagnosed or suspected by gross macroscopic evaluation. Generally, human placentas are round or oval, but other shapes are not uncommon. Anomalies of the placenta shape or multilobated placenta may develop from...
Fetal hyperinsulinemia as a cause of macrosomia in pregnancy
Diabetes produces major changes in the hormonal and metabolic homeostasis in pregnancy that has divergent effects on maternal and feto-placental tissues. The hyperglycemia in cytotoxin-induced diabetes was considered to cause maternal tissue malfunction on the one hand and to induce the precocious commencement of fetal insulin secretion on the other. The profuse insulin secretion was assumed to promote fetal overgrowth by the excess of glucose, amino acids and other fuels.67 The fetuses of...
Summary Nvj
Gestational diabetes in all severity levels from one abnormal to maximum values is associated with decreased insulin sensitivity and secretion. Furthermore, the majority of GDM women are prone to develop metabolic syndrome and Type 2 diabetes later in life. All GDM severity levels will result in adverse neonatal outcome. Short-term neonatal complications include increased perinatal mortality, metabolic, respiratory, hematological complications, and neonatal trauma. Long-term neonatal...
Maternal and paternal factors associated with fetal growth
The problem of maternal diabetes and the increased population risk of obesity is becoming a greater problem not only in the developed areas of the world but also in developing countries with large populations and high birth rates. Because the increased risk of diabetes and obesity is now becoming manifest in adolescents and even children as young as 2-5 years,1 the concept of in utero fetal programming assumes even more importance. Fetal programming is the effect of the in utero environment on...
References Hll
1. Catalano PM, Tyzbir ED, Wolfe RR, et al. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. Am J Obstet Gynecol 1992 167 913-9. 2. Kalhan S, Rossi K, Gruca L, Burkett E, O'Brien A. Glucose turnover and gluconeogenesis in human pregnancy. J Clin Invest 1997 100 1775-81. 3. Herrera E, Knopp RH, Freinkel N. Carbohydrate metabolism in pregnancy. VI. Plasma fuels, insulin, liver composition, gluconeoge-nesis and nitrogen...
Diabetes and pregnancy 19401980
In 1946 it was decided, with Professor Brandstrup at the Rigshospital, University of Copenhagen, to centralize the management and study of diabetes and pregnancy to the Obstetrical Department of Professor Brandstrup, who previously had interest in the problems involved.1,2 The first study from the Copenhagen Centre was designed to find possible characteristics of the course of diabetes during pregnancy, to contribute to a quantitative elucidation of the incidence of alterations occurring and to...
Gestational diabetes
The concept of gestational diabetes, actually meaning hyper-glycemia due to the pregnancy itself but in practice defined as 'carbohydrate intolerance of varying severity with onset or first recognition during pregnancy,' is also recent.15 In the very first recorded case Bennewitz, in 1823, considered that the diabetes was actually a symptom of the pregnancy, and as the symptoms and the glycosuria disappeared after at least two successive pregnancies he had some evidence to support his views.16...
References Ync
1. Ballantyne JW. The Disease and Deformities of the Foetus, Vol. I. Edinburgh Oliver and Boyd 1892. 2. Benirschke K, Kaufman P, Baergen RN. The Pathology of the Human Placenta. Heidelberg Springer-Verlag 2006. 3. Roberts DJ, Oliva E. Clinical significance of placental examination in perinatal medicine. J Matern Fetal Neonat Med 2006 19 255-64. 4. Dominguez F, Avila S, Cervero A, et al. A combined approach for gene discovery identifies insulin-like growth factor-binding protein-related protein...
Fetal glucogenesis
Tracer studies in humans68 and sheep10 have shown that when glucose tracer is infused into the mother the specific activity or enrichment ratio of tracer labeled glucose to non-labeled glucose in the fetal plasma is the same as in the maternal plasma. This demonstrates that the only source of glucose in the fetus is from the maternal plasma, otherwise, new glucose production into the fetal plasma from either the fetus itself or from the placenta would dilute the tracer glucose coming from the...
Kinetics of glucose uptake and transport by the placenta
Although the effect of the maternal glucose concentration on net placental-to-fetal glucose transfer demonstrates saturation kinetics,10 this relationship does not necessarily define the quantitative characteristics of placental-to-fetal glucose transport capacity, because as maternal glucose concentration and placental glucose transport are increased, both fetal glucose concentration and fetal glucose utilization rates increase. Other studies in which glucose was infused directly into the...
JM Duncan On puerperal diabetes Trans Obstet Soc London 1882 24 2568529
Matthews Duncan graduated in Aberdeen and became one of the leading obstetricians of his day Figure 1.3 . This compilation of cases from the literature, from anecdotal reports and Figure 1.2 Die Charite in Berlin 1785-1800 from a lithograph by von C Koppen from Murken AH, Vom Armenhospital zum Grossklinikum die Geschichte des Krankenhauses, Vom 18. Jahrhundert biszur Gegenwart Koln, Durmont, 1988, 39 . Figure 1.2 Die Charite in Berlin 1785-1800 from a lithograph by von C Koppen from Murken AH,...
Microscopic evaluation
Placental pathology in pregnancies complicated by maternal diabetes relates to the different aspects of the maternal disease. Although some findings are thought to be related to the direct effect of insulin on the placenta, most are due to associated maternal pathologies, especially hypertension. This makes the study of placental effects of hyperinsulinemia in insulin resistance and hyperglycemia difficult as most diabetic pregnancies have other confounding variables, especially hypertension....
Norbert Frienkel
Professor Norbert Norbie Freinkel Figure 4.1 was a renowned scholar, investigator and teacher. Although it is now nearly two decades since his sudden, untimely death, Norbie's influence on the field of pregnancy and diabetes remains profound. What accounts for this enduring legacy Norbie was a brilliant, intense, dedicated and insightful investigator. He was a gifted and prolific writer and used language with great skill and flair. Norbert Freinkel was a member of prestigious academic societies...
Vitamin C
In addition to the prevention of scurvy, vitamin C has numerous other functions and is a co-factor for several enzyme systems. For humans, vitamin C is an essential vitamin, with an important antioxidant function. As antioxidant defense systems are important to protect tissues and cells from damage caused by oxidative stress, an imbalance between increased oxidative stress and decreased antioxidant defenses impairs fetal growth.45 Thus, pregnant women utilize a defense mechanism, composed of...
Northwestern Universitys Diabetes in Pregnancy Center Vehicle of the legacy
After making major, pioneering contributions to the understanding of thyroid hormone metabolism2-4 and to other areas of endocrinology early in his career, in the mid 1960s Norbert Freinkel turned his interests and talents to the study of intermediary metabolism in normal and diabetic pregnancy.4-7 By the early 1907s, he had established a Diabetes in Pregnancy Center DPC at Northwestern University and had attracted research collaborations globally. Over the next two decades, a virtual 'who's...
The later years
By the mid-point in her career, Priscilla White was undeniably the doyenne of diabetic pregnancy. She continued to publish reviews and papers which extended and refined her experience. J0rgen Pedersen, who became well established as a student of and expert in diabetic pregnancy in the 1950s and 1960s, used her classification in a modified form. It was included in The Pregnant Diabetic and Her Newborn, his classic treatise published in 1967. Although he did adopt and modify White's...
Summary on early growth delay
Some fetuses in early diabetic pregnancy are smaller than normal, i.e. exhibiting early growth delay. This is related to the quality of the diabetes regulation and gives a marked increase in the risk of fetal malformations, and predicts a poorer psychomotor development. A first trimester ultrasound study is essential and patient management should be guided by the ultrasound age. Since the foundation of the Diabetes Centre at the Obstetric Department of the Rigshospital, 13 theses for the DMSc...
JW Williams The clinical significance of glycosuria in pregnant women Am J Med
Whitfield Williams was Professor of Obstetrics at the Johns Hopkins University and wrote the first major American textbook on obstetrics, which still survives today in the eighteenth edition. He was concerned that the demonstration of sugar in the urine in pregnancy would be overinterpreted. 'I know of no complication of pregnancy the significance of which is more variously interpreted than the presence of sugar in the urine of pregnant women.' Williams blamed Matthews Duncan for concluding...
Box 21 Priscilla Whites first classification
Class A Abnormal glucose tolerance test, treated with diet alone Class B Onset before the age of 20, duration lt 10 years, no vascular disease Class C Onset between the ages of 10 and 19, duration 10-19 years or minimal vascular disease, including retinal arteriosclerosis or calcifications of lower extremity arteries Class D Onset before the age of 10, duration gt 20 years or retinitis, hypertension or albuminuria Class E Pelvic vascular calcification, iliac or uterine Class F All patients with...
Preface
The field of diabetes and pregnancy has come of age. From the conception of the terminology 'gestational diabetes' and 'diabetes in pregnancy' to the creation of an entire subspecialty, this textbook documents the 'gestation' of the field. Now we have even subdivided the field and have created subspecialists in gestational diabetes, and pregestational or diabetes in pregnancy, Type 1 and Type 2. In fact we have created our own internal debating groups as to the correct terminology for each type...
Accelerated starvation
In Freinkel's laboratory and others, it was demonstrated that the transition from a basal or overnight fasting metabolic status to the pattern that is characteristic of the 'prolonged fasted state or starvation' is exaggerated during pregnancy.7 Since the exaggerated changes differed in both temporal and absolute dimensions, Norbie characterized this pattern as 'accelerated starvation.'9 A number of clinical and epidemio-logical studies suggest that greater than normal levels of ketonemia...
Contents
1. History of diabetic pregnancy 1 David R. Hadden 2. The Priscilla White legacy 9 John W. Hare 3. The Pedersen legacy 15 Lars M0lsted-Pedersen 4. The Freinkel legacy 19 Boyd E. Metzger 5. Metabolism in normal pregnancy 25 Emilio Herrera and Henar Ortega 6. Intermediary metabolism in pregnancies complicated by gestational diabetes 35 Bartolom Bonet, Marta Viana and Isabel S nchez-Vera 7. Histopathology of placenta 41 Drucilla J. Roberts and Maria Rosaria Raspollini 8. The placenta in diabetic...
The Freinkel legacy and the future
This brief overview provides clear evidence that the legacy of Norbert Freinkel is being strongly sustained nearly two decades after his death. How this legacy will help shape the future directions of research and stimulate new clinical approaches is uncertain. However, the trail will not be difficult to follow. One area that will continue to reflect Norbie's concepts is future developments in GDM. Norbert Freinkel initiated and chaired the first two International Workshop Conferences on GDM....
Facilitated anabolism
The metabolic changes that can be observed during the disposition of food intake are numerous. Many aspects of a characteristic diurnal metabolic profile of pregnancy were described in reports from the Northwestern group. The mediation of the these changes and the implications for normal pregnancy as well as the states of altered nutrition or metabolism obesity, diabetes, malnutrition are not fully defined and continue to be of great interest to investigators. Norbie interpreted the...
References 1
1. Brandstrup E, Okkels H. Pregnancy complicated with diabetes. Acta Obstet Gyncol Scand 1938 18 136-41. 2. Okkels H, Brandstrup E. Studies on the thyroid gland X. Pancreas, hypophysis and thyroid in children of diabetic mothers. Acta Pathol Microbiol Scand 1 938 15 245-68. 3. Pedersen J. Course of diabetes during pregnancy. Acta Endocr 1 952 9 342-64. 4. Pedersen J, Brandstrup E. Foetal mortality in pregnant diabetics. Lancet 1956 1 607-1 1. 5. M0lsted-Pedersen L, Tygstrup I, Pedersen J....
The White classification
In 1949, White published the first version of the classification system which was to be the single most remembered thing about her work, and has been of immense clinical value to practictioners all over the world.7 Part of the success of this classification was no doubt rooted in its rationale and utility, but part must have also been that the world leader in the field of diabetic pregnancy espoused it. She was almost precisely at the mid-point in her career and had been on the staff of the...
HG Bennewitz Diabetes mellitus a symptom of pregnancy MD Thesis University of
This is the first reference to diabetes in pregnancy. Although the patient was young the clearly described onset of her symptoms during the pregnancy would now classify this as gesta-tional diabetes. Is it possible that she only survived because she was a milder case who responded to diet, while all the more severe Type 1 diabetic patients died Henry Gottleib Bennewitz publicly defended his thesis for the degree of Doctor of Medicine at the University of Berlin on 24 June 1824 Figure 1.1 . It...
Contributors
Salvatore Alberico, md Obstetrical amp Gynecologic Pathology, IRCCS Burlo Garofolo, Trieste, Italy Emily Albertson, md Sansum Diabetes Research Institute, Santa Barbara, CA, USA Zarko Alfirevic, md phd frcog Professor of Fetal-Maternal Medicine, Liverpool Women's Hospital, Liverpool, UK Yossef Bahagon Clalit Health Services, Hebrew University-Hadassah Medical School, Jerusalem, Israel Madhuri S. Balaji, mb, frsh Consultant Diabetologist, Dr V. Seshiah Diabetes Care amp Research Institute,...