Charles M. Peterson

Abnormal glucose tolerance in β-thalassemia major

The question of whether iron overload causes glucose intolerance was studied in a group of 26 multiply transfused homozygous beta thalassemics. Of the 26, 13 (50%) had some abnormality in their oral glucose tolerance test, 5 fitting criteria for definite diabetes. Glucose intolerance correlated significantly with number of transfusions received and with age of the subjects, while a positive family history for diabetes was more common in the subjects with glucose intolerance. These data and a chart review of four deceased thalassemics with overt diabetes are consistent with the following conclusions: (1) glucose intolerance is common in multiply transfused thalassemics; (2) the incidence of abnormal glucose tolerance correlates with the number of transfusions received and the age of the subject; (3) a family history of diabetes may predisose multiply transfused thalassemics to glucose intolerance.

Relation of hemoglobin A1 and blood glucose to cardiac function in diabetes mellitus

To examine the relation of short- and long-term changes in glucose metabolism to cardiac function, radionuclide cineangiography and echocardiography were performed in 10 young insulin-dependent diabetic patients without clinical evidence of heart disease. Cardiac assessments were performed before and after both acute variations in blood glucose, and induction of chronic tight glucose control involving normalization of hemoglobin A1 concentrations. In diabetic patients, left ventricular (LV) ejection fraction (EF) at normal blood glucose concentration was indistinguishable from values in 11 normal subjects. However, during hyperglycemia (about 300 mg/dl), the average EF at rest was 61%, significantly higher than that during normoglycemia (56%, p less than 0.001). No significant change in LV diastolic dimension was noted in association with shifts between high and normal blood glucose concentrations. Normalization of hemoglobin A1 was achieved within 6 to 25 weeks. This alteration had no significant effect on LVEF, mitral valve E-F slope, or the response of systolic function to blood glucose levels. In addition, no correlation was found between LVEF and hemoglobin A1 concentrations in 4 of 5 evaluation periods. Thus, in young insulin-dependent diabetic patients without overt heart disease, variation in blood glucose concentration is associated with small but significant variation in EF at rest; normalization of hemoglobin A1 has no significant effect on LVEF or the response of systolic function to blood glucose levels.

Fetal Islet Transplantation

Proceedings of the October 1994 symposium at Sansum Medical Research Foundation in Santa Barbara, CA, focus on the use of fetal islet tissue in controlling diabetes and repairing islets that have been damaged by autoimmune disease. Papers detail research on fetal islet growth, differentiation, immun

Glucose Metabolism in Pregnancy

Pregnancy is a state of ever-increasing fetal demand for fuel. This demand is met through increased caloric intake, hyperinsulinemia, insulin resistance, and maternal pancreatic islet hypertrophy. In addition, fasting in the pregnant state results in maternal hypoglycemia, elevated plasma lipid concentrations, and hypoaminoacidemia. These maternal adaptive changes serve the unique purpose of self-preservation, with an attempt to use lipid as an alternative fuel in the face of the uninterrupted siphoning of glucose and amino acids to the fetus. The regulation of maternal glucose homeostasis, nutrient flow, and hormonal regulation of maternal and fetal pancreatic function is the subject of this chapter. This discussion of glucose metabolism in pregnancy is divided into three time periods: the first, second, and third trimesters, and a discussion of the postpartum changes is included. For each time period there is a discussion of the normal physiological changes in the pregnant woman and the potential pathological changes in the woman and the fetus.

Insulin, Oral Agents, and Monitoring Techniques

In the normal individual, glucose is perhaps the metabolic substrate least subject to deviation from the “norm.” This metabolite is highly regulated and has minimal alternatives for metabolic conversion. Glucose may be entered into enzymatic degradation through glycolysis, glycogen formation, or the pentose shunt. In general, the initial enzyme steps in these reactions are rate-limiting and, therefore, they have little influence on substrate concentration. Gluconate and sorbitol pathways are also possible, although these latter pathways have high km values and therefore probably play a small role in biology during periods of extremely high glucose concentrations. Another alternative to substrate utilization of glucose is through the nonenzymatic glycosylation of proteins. These reactions, known as the Maillard Reaction, occur in two forms: (1) nonenzymatic glycosylation and (2) nonenzymatic browning resulting from rearranged products of the glycosylation reaction itself.

Fetal Islet Transplantation and Pregnancy

Several animal models are now available for the study of pregnancy complicated by diabetes mellitus and thus studies of islet transplantation in these pregnant animals can also be performed. Animals may be made hyperglycemic by the use of alloxan or streptozotocin. Infusion protocols of glucose and/or insulin have been described in several species including rats and monkeys. Recently described genetic models include the BB Wistar rat, the NOD mouse, the C57/KsJdb+/+m mouse, and the Chinese hamster with spontaneous diabetes (CHAD). The NOD mouse is particularly attractive for studies of transplantation since it has several features in common to the human autoimmune counterpart. Studies of subcutaneous fetal islet transplantation in this model as well as in humans during gestation suggest improved graft survival and insulin secretory capacity. The nature of the factors during pregnancy that lead to enhanced tissue vascularization, improved tissue growth and secretory capacity, and decreased immunological response in pregnant recipients are noteworthy and warrant further study.

The Use of Human Fetal Islet Tissue for Adjunctive Treatment in Insulin-Dependent Diabetic Patients: The Case for “Partial Success”

In 1922, Mrs. Thompson pleaded with doctors in Toronto to save her dying child. Banting and Best (1) had recently shown that a pancreatic extract could lower blood glucose in diabetic dogs, but never before had the hypoglycemic hormone, insulin, been given to a human being. Leonard Thompson thus became the first person to receive insulin. He not only recovered but grew into his third decade, eventually dying from pneumonia.

The Use of Human Fetal Pancreatic Tissue for Transplantation

The idea of using fetal pancreata as a source of insulin-secreting tissue is not new. A number of investigators, including Banting and Best, have favored the use of fetal tissue at one time or another, citing the relative lack of development of exocrine tissue and hence the relative abundance of endocrine cells with lessened possibility of enzymatic digestion of insulin or insulin-containing cells (1). In 1928 the human fetal pancreas was first used for tranplantation purposes (2). In that year Fichera placed pancreatic tissue from three fetuses into various sites in an 18-year-old man with diabetes mellitus. The experiment failed in that the recipient died in a diabetic coma three days later.

Perspectives on Use of Human Fetal Pancreatic Tissue in the Field of Research on Diabetes Mellitus: An Introduction

The idea of using fetal pancreata as a source of insulin-secreting tissue is not new. A number of investigators, including Banting and Best, have favored the use of fetal tissue at one time or another because of the relative lack of development of exocrine tissue in the fetal environment and, hence, a relative enrichment of endocrine cells as well as a lessened possibility of enzymatic digestion of insulin or insulin-containing cells (1). The human fetal pancreas was first used for transplantation purposes in 1928, when Fichera placed pancreatic tissue from three fetuses into various sites in an 18-year-old male with diabetes mellitus (2). The experiment failed in that the recipient died in diabetic coma three days later.

Thyroid Disorders in Pregnant Women With Type I Diabetes

The association of diabetes with thyroid disorders is well documented (1–9). The incidence of clinical and subclinical thyroid disorders in patients with type I diabetes (insulin-dependent diabetes or IDD) has been reported to be as high as 30% (10). The incidence of hypothyroidism in a diabetic population varies from 0.2% to 12%, with a female prevalence over males as high as 7:1 (2). Hyperthyrodism may also be increased in patients with insulin-dependent diabetes mellitus, with a ratio of females to males between 2 and 5:1 (9). If the prevalence of thyroid dysfunction is so high in women with diabetes mellitus, then the clinician who cares for pregnant women (up to 20% with thyroid problems), type I diabetic (up to 30% with thyroid problems) women (sevenfold increase in prevalence over males) should be especially aware of the strategies for diagnosis and management of thyroid disorders. This chapter briefly reviews the literature concerning thyroid disease and type I diabetes, thyroid disease and pregnancy, and the occurrence of all three together. It also suggests surveillance and treatment protocols for managing the thyroid problems that complicate pregnancies in the woman with IDD.