Ronald J. Koenig

Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus.

We studied the increased levels of hemoglobins AIa+Ib and AIc in five hospitalized diabetic patients to determine whether changes in diabetic control would cause parallel changes in the levels of these hemoglobins. Before control of diabetes the mean fasting blood sugar for all patients was 343 mg per deciliter (range, 280 to 450), and hemoglobin AIc concentration 9.8 per cent (range, 6.8 to 12.1). During optimal diabetic control the blood sugar concentration was 84 mg per deciliter (range, 70 to 100), and hemoglobin AIc concentration 5.8 per cent (range, 4.2 to 7.6). Hemoglobin AIc concentration appears to reflect the mean blood sugar concentration best over previous weeks to months. The periodic monitoring of hemoglobin AIc levels provides a useful way of documenting the degree of control of glucose metabolism in diabetic patients and provides a means whereby the relation of carbohydrate control to the development of sequelae can be assessed.

Hemoglobin AIc as an indicator of the degree of glucose intolerance in diabetes

Hemoglobin AIc concentration, fasting blood sugar, response to an oral glucose tolerance test, and skeletal muscle capillary basement membrane thickness were measured in diabetic patients. Hemoglobin AIc concentration correlates with both response to a glucose tolerance test (r = 0.82, p < 0.001) and fasting blood sugar (r = 0.62, p < 0.001). The correlation of hemoglobin AIc concentration with glucose tolerance is independent of fasting blood sugar concentration (partial r = 0.61, p < 0.005), whereas that of hemoglobin AIc with fasting blood sugar probably reflects the relationship between fasting blood sugar levels and glucose tolerance (partial r = 0.22, p < 0.05). Hemoglobin AIc levels do not correlate with basement membrane thickness (r = 0.15, p < 0.05).

Reversible Hematologic Sequelae of Diabetes Mellitus

Seven patients with diabetes mellitus were hospitalized and their blood sugar concentrations regulated as a result of fasting blood sugar, sugar around meals, urinary sugar, and hemoglobin AIC assays. Erythrocyte half-life as measured by 51 Cr increased in all patients from a mean of 27 days to 31 days, while hemoglobin AIC levels decreased from a mean of 10.1% to 5.6%. Leukocyte adherence increased in all patients from a mean of 28% to 51%. Most striking were the changes observed in platelet function in response to epinephrine. The length of the secondary lag phase of platelet aggregation, after a stimulus with final concentration of 70 muM of epinephrine, increased from a mean of 19 seconds to 65 seconds. Studies in additional patients confirmed an inverse correlation between hemoglobin AIC concentration and the secondary lag phase (r = 0.87, P less than 0.001). These studies found that certain secondary sequelas of diabetes can be corrected by strict carbohydrate control and confirmed that hemoglobin AIC assays provide a useful means of showing the degree of control of glucose metabolism in diabetic patients.

Correlation of serum triglyceride levels and hemoglobin AIc concentrations in diabetes mellitus.

Studies in 10 nonketotic diabetic subjects (five juvenile- and five adult-onset) before and after control of carbohydrate metabolism showed a high degree of correlation between hemoglobin AIc (Hb AIc) concentrations and serum triglyceride levels. Serum triglyceride levels were found to correlate more dosely with Hb AIc (r = 0.91, p < 0.001) than did serum cholesterol (r = 0.47, p > 0.05), thus indicating a more direct relationship to carbohydrate metabolism.

Increased Hemoglobin AIc in Diabetic Mice

The minor hemoglobins AIa, AIb, and AIc were studied in mice with either genetic or chemically induced diabetes. Hemoglobin AIc was elevated approximately twofold in all the phenotypically diabetic mice studied (C57BL/KsJ-db/db, C57BL/KsJ-ob/ob, C57BL7/6J-db/db, and alloxan- and streptozotocin-treated mice). Elevation of the hemoglobin Ale in C57BL/6J-db/db mice was of short duration, reflecting the transitory diabetes characteristic of these mice. The degree of increase of hemoglobin AIclevels was unrelated to severity of hyperglycemia, duration of diabetes, age of mouse, or body weight. It is not-known what factor(s) dictates the steady-state concentration of hemoglobin AIc.

Hemoglobin AIc as a model for the development of the sequelae of diabetes mellitus

Hemoglobin A Ic is a glycosylated form of hemoglobin A, the level of which is an integrated index of a persons blood-sugar concentration over the previous several weeks. Measurement of the level of hemoglobin A Ic offers a new means of assessing the degree of carbohydrate control in diabetic patients.

Haemoglobin Alc and diabetes mellitus.

The adult human erythrocyte has several minor haemoglobins (haemoglobin A,, haemoglobin F, haemoglobin A,,, haemoglobin A,, and haemoglobin AJ in addition to the major haemoglobin (haemoglobin A). The three minor glycohaemoglobins Hb A la-c are particularly interesting because thcir concentrations are elevated in patients (Trivelli ef ai, 1971) and animals (Koenig & Cerami, 197s; Koenig et al, 1976a) with diabetes mellitus. The increase in glycohacmoglobin concentration is found in humans with both maturity and juvenile onset diabetcs as well as in mice with genetic and drug induced diabetes. These observations have stimulated a number of studies on the structure and biosynthesis of these minor haemoglobins and thcir relationship to the development of the sequelae of diabetes. Two important results from these studies are: ( I ) the proposal of the glycosylation of hacmoglobin as a biochemical modcl for the events leading to the sequelae of diabetes; and ( 2 ) the development of a new clinical method to assess carbohydrate control in diabetic patients by monitoring the amount of haemoglobin A The following is a brief review of the structure, biosynthesis and clinical rclcvance of the glycohaemoglobins to diabetes.

Chapter 25 Non-enzymatic Glycosylation

Publisher Summary This chapter summarizes the glycosylation of proteins by nonenzymatic processes in humans and related species. The prototype molecule for this process must be considered to be hemoglobin A Ic (Hb A Ic ), as this was the first protein recognized to be nonenzymatically glycosylated. Glucose reacts to form a schiff base with NH 2 -terminus of the β chain of Hb A, and subsequently undergoes an amadori rearrangement to yield 1-amino- 1-deoxyfructose. This modified hemoglobin, named Hb A Ic, is a normal red cell constituant present in increased concentration in patients with diabetes mellitus. Hb A Ic is synthesized throughout the life of the erythrocyte in a slow, nearly irreversible raction. The rate of synthesis is a function of blood glucose concentration. These properties of Hb A Ic combine to make it an indicator molecule whose concentration at one point in time reflects the patients mean blood glucose level for the preceding month. This gives Hb A Ic a unique and invaluable role in clinical medicine, for it is the only known parameter that accurately assesses long term carbohydrate control. While Hb A Ic itself is not likely to have deleterious effects, the nonenzymatic glycosylation of other proteins may result in altered enzymatic activity, solubility, antigenicity etc., and thereby result in many of the clinical sequelae of long-standing diabetes. In this regard, lens proteins undergo increased glycosylation in high carbohydrate environments, and such glycosylation increases the ease with which the proteins oxidize to form high molecular weight aggregates and opacities. In fact, nonenzymatic glycosylation may play a major role in the normal aging process as the complications of diabetes are frequently considered to resemble accelerated aging.