Student Theses and Dissertations

Date of Award

1977

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by abnormally high blood glucose concentrations and a relative or absolute deficiency of insulin. Approximately 5 per cent of the American population are afflicted with this disease, which is a leading cause of morbidity and mortality in the United States today. Diabetes may result in the dysfunction of many different organ systems, yet the biochemical mechanism(s) underlying these dysfunctions is unknown. Even the importance of hyperglycemia in the development of the sequelae of diabetes is unsettled. One of the metabolic abnormalities known to characterize this disease is an increase in the peripheral blood concentration of hemoglobin Alc. This minor red cell component comprises 3-5 per cent of the total hemoglobin in non-diabetic humans but up to 15 per cent in diabetics. There is evidence to suggest that it is a glycosylated derivative of hemoglobin A. The aim·of these investigations has been to increase our understanding of the significance of increased hemoglobin Alc concentrations in diabetics. The studies described here in the diabetic mouse demonstrate increased hemoglobin Alc to be a marker for the diabetic phenotype regardless of the cause of diabetes. The increase in hemoglobin Alc concentration occurs 3-4 weeks after the onset of diabetes. Hemoglobin Alc is made as a post-synthetic modification of hemoglobin A at a constant slow rate throughout the life of the red cell. In diabetic humans, hemoglobin Alc concentration correlates with the severity of disease. Changes in the quality of diabetic control are followed, after a 3-4 week delay, by proportionate changes in hemoglobin Alc concentration. Hemoglobin Alc concentration reflects the mean blood glucose concentration for the 3-4 weeks prior to the measurement. Thus, infrequent hemoglobin Alc measurements would be sufficient to assess the quality of long-term diabetic control, a feature unique to this measurement. The periodic monitoring of hemoglobin Alc concentration should permit patients to achieve better diabetic control than is currently possible and should make it possible to determine whether hyperglycemia is important in the development of the sequelae of diabetes. The structure of hemoglobin Alc is identical to that of hemoglobin A, with the addition of l-deoxy fructose attached at the amino terminus of the B chains. The increased formation of hemoglobin Alc in diabetes is an example of the increased glycosylation of a protein (hemoglobin A) occurring in this disease process. The biosynthesis of hemoglobin Alc provides a conceptual framework that may explain the molecular basis for many of the sequelae of diabetes. Thus, the abnormal or excess glycosylation of other proteins may cause structural or functional changes in those proteins and thereby result in the diverse sequelae known to occur secondary to this disease.

Comments

A thesis submitted to the Faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

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