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Hemoglobin A1C in childhood diabetes
Hemoglobin
Al, in
Childhood Diabetes
By Elsa P. Paulsen
with asymptomatic hyperglycemia and high in children with overt insuiindependent disease.
hemoglobin is a glycoprotein Ale hemoglobin formed in greater than normal amounts in overt diabetes mellitus. Levels were normal in nine children
NE OF THE MOST PRESSING NEEDS in research on diabetes mellitus is a reliable genetic marker. I wish to report on our studies with hemoglobin alterations in diabetes mellitus. Although the evidence at this point does not document these alterations as specific genetic markers, it does open up a new field of investigation into the genetic aspects of diabetes mellitus. The original findings were made by Dr. Rahbar in his laboratory in Tehran, 1ran.l These studies were later expanded by him in the laboratory of Dr. Helen Ranney of the Albert Einstein College of Medicine where Dr. Rahbar was a visiting fellow in 1968-69. Ale hemoglobin is unique in that it is a glycoprotein with a hexose bound by a Schiff base linkage to each beta chain (Fig. 1). We have measured Ale hemoglobin in 48 normal children and in a number of children with diabetes mellitus (Fig. 2). The mean concentration of A~A-c hemoglobin in normal children is 6.9% C 1.7% of total hemoglobin (1 SD). This is identical to the mean results reported in normal adults by Dr. Ranney.2 The levels of Ale hemoglobin in children with insulin-requiring diabetes mellitus range from 10%-22% of total hemoglobin. We have found only one child with diabetes mellitus with an Ale hemoglobin in the normal range. At the present time we detect no correlation between the age of onset or duration of diabetes and the level of Ale hemoglobin. The mean concentration in our children with insulin-requiring diabetes is 13.4 mg/loo ml. A unique
hemoglobin
to the terminal SCHIFF
nitrogen
- it has a HEXOSE
attached
of both Beta chains by a
BASE LINKAGE. 0
HEXOSE=N+-N-t-
I Valine Fig. 1. Structure Ale hemoglobin.
Thus, Ale
of
linked
Histidine
is a GLYCOPROTEIN
to the globin
by a very labile
etc,
etc.
with a hexose bond.
From the Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Vu. Presented uf the Conference on Chemical Diabetes Meltitus in Childhood, Ponfe Vedru Beach, Florida, December 5-6, 1970. Received for publication April, 1972. Elsa P. Paulsen, M.D.: Associate Professor, Department of Pediafrics, University of Virginia School of Medicine, Charlottesville, Vu. Metabolism,
Vol. 22, No. 2 (February),
1973
269
270
ELSA P. PAULSEN
24
t HEMOGLOBIN
AIc
.
20
16
PER CENT OF TOTAL
12
HCB
-6.9%
.
‘: .
.. .
:
*
1
L
Juvenile
Normal Children 1-15
yrs
(48)
Fig. 2. Hemoglobin
7-18
+DM Cystic
Diabetics
I
I
I
No
DM
Flbrotics
Asymptomatic Hyperglycemics
yrs (32)
(9)
AIc as per cent of normal
hemoglobin.
Six children with cystic fibrosis who have insulin-requiring diabetes mellitus have concentrations in the diabetic range. Nine children with asymptomatic hyperglycemia have been studied and all have Ale hemoglobin in the normal concentration. Further work in this area is directed toward confirming the structural alterations of A&z hemoglobin in diabetic patients in order to determine whether the abnormalities are primary or secondary to some metabolic changes associated with diabetes mellitus. It is possible that structural abnormalities in Ale hemoglobin may be found even though the present concentration is within normal limits. REFERENCES I. Rahbar, S.: Abnormal hemoglobin in red cells of diabetics. Clin. Chim. Acta 22 ~296, 1968. 2. Trivelli, L. A., Ranney, H. M., and
Lai, A.: HemogIobin components tients with diabetes mellitus. N. Med. 264 :353,1970.
in paEngl. J.
HEMOGLOBIN
Al,
IN CHILDHOOD
DIABETES
271
Discussion Dr. O’Brien: Dr. Paulsen, have you done any studies on the Al, hemoglobin content in parents or relatives of children with insulin-requiring diabetes mellitus? Dr. Paulsen: These studies have just been initiated. Results we have so far would indicate that such subjects have normal Al, percentages. Dr. O’Brien: Do you mean that you cannot detect the heterozygous state by this method? Dr. Paulsen: No, not with the simple determination of percentage concentration of Ale hemoglobin; however, we have hope that with analysis of the structure of the hemoglobin, that we may be able to detect the heterozygous state. Dr. Fajans: Dr. Paulsen, does not the observation that you do not detect an abnormal concentration of Alo hemoglobin in the asymptomatic or chemical diabetic, while it is almost invariably present in the child with insulin requiring diabetes, suggest that the hemoglobin alteration may be a secondary rather than a primary abnormality? Dr. Paulserz: I would agree if we find that the hemoglobin structure as we11 as the percentage concentration is normal in relatives or asymptomatic chemical diabetes that the change is a secondary one; however, it may be possible that the hemoglobin structure is different prior to determination of a percentage change.
Al, in
Childhood Diabetes
By Elsa P. Paulsen
with asymptomatic hyperglycemia and high in children with overt insuiindependent disease.
hemoglobin is a glycoprotein Ale hemoglobin formed in greater than normal amounts in overt diabetes mellitus. Levels were normal in nine children
NE OF THE MOST PRESSING NEEDS in research on diabetes mellitus is a reliable genetic marker. I wish to report on our studies with hemoglobin alterations in diabetes mellitus. Although the evidence at this point does not document these alterations as specific genetic markers, it does open up a new field of investigation into the genetic aspects of diabetes mellitus. The original findings were made by Dr. Rahbar in his laboratory in Tehran, 1ran.l These studies were later expanded by him in the laboratory of Dr. Helen Ranney of the Albert Einstein College of Medicine where Dr. Rahbar was a visiting fellow in 1968-69. Ale hemoglobin is unique in that it is a glycoprotein with a hexose bound by a Schiff base linkage to each beta chain (Fig. 1). We have measured Ale hemoglobin in 48 normal children and in a number of children with diabetes mellitus (Fig. 2). The mean concentration of A~A-c hemoglobin in normal children is 6.9% C 1.7% of total hemoglobin (1 SD). This is identical to the mean results reported in normal adults by Dr. Ranney.2 The levels of Ale hemoglobin in children with insulin-requiring diabetes mellitus range from 10%-22% of total hemoglobin. We have found only one child with diabetes mellitus with an Ale hemoglobin in the normal range. At the present time we detect no correlation between the age of onset or duration of diabetes and the level of Ale hemoglobin. The mean concentration in our children with insulin-requiring diabetes is 13.4 mg/loo ml. A unique
hemoglobin
to the terminal SCHIFF
nitrogen
- it has a HEXOSE
attached
of both Beta chains by a
BASE LINKAGE. 0
HEXOSE=N+-N-t-
I Valine Fig. 1. Structure Ale hemoglobin.
Thus, Ale
of
linked
Histidine
is a GLYCOPROTEIN
to the globin
by a very labile
etc,
etc.
with a hexose bond.
From the Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Vu. Presented uf the Conference on Chemical Diabetes Meltitus in Childhood, Ponfe Vedru Beach, Florida, December 5-6, 1970. Received for publication April, 1972. Elsa P. Paulsen, M.D.: Associate Professor, Department of Pediafrics, University of Virginia School of Medicine, Charlottesville, Vu. Metabolism,
Vol. 22, No. 2 (February),
1973
269
270
ELSA P. PAULSEN
24
t HEMOGLOBIN
AIc
.
20
16
PER CENT OF TOTAL
12
HCB
-6.9%
.
‘: .
.. .
:
*
1
L
Juvenile
Normal Children 1-15
yrs
(48)
Fig. 2. Hemoglobin
7-18
+DM Cystic
Diabetics
I
I
I
No
DM
Flbrotics
Asymptomatic Hyperglycemics
yrs (32)
(9)
AIc as per cent of normal
hemoglobin.
Six children with cystic fibrosis who have insulin-requiring diabetes mellitus have concentrations in the diabetic range. Nine children with asymptomatic hyperglycemia have been studied and all have Ale hemoglobin in the normal concentration. Further work in this area is directed toward confirming the structural alterations of A&z hemoglobin in diabetic patients in order to determine whether the abnormalities are primary or secondary to some metabolic changes associated with diabetes mellitus. It is possible that structural abnormalities in Ale hemoglobin may be found even though the present concentration is within normal limits. REFERENCES I. Rahbar, S.: Abnormal hemoglobin in red cells of diabetics. Clin. Chim. Acta 22 ~296, 1968. 2. Trivelli, L. A., Ranney, H. M., and
Lai, A.: HemogIobin components tients with diabetes mellitus. N. Med. 264 :353,1970.
in paEngl. J.
HEMOGLOBIN
Al,
IN CHILDHOOD
DIABETES
271
Discussion Dr. O’Brien: Dr. Paulsen, have you done any studies on the Al, hemoglobin content in parents or relatives of children with insulin-requiring diabetes mellitus? Dr. Paulsen: These studies have just been initiated. Results we have so far would indicate that such subjects have normal Al, percentages. Dr. O’Brien: Do you mean that you cannot detect the heterozygous state by this method? Dr. Paulsen: No, not with the simple determination of percentage concentration of Ale hemoglobin; however, we have hope that with analysis of the structure of the hemoglobin, that we may be able to detect the heterozygous state. Dr. Fajans: Dr. Paulsen, does not the observation that you do not detect an abnormal concentration of Alo hemoglobin in the asymptomatic or chemical diabetic, while it is almost invariably present in the child with insulin requiring diabetes, suggest that the hemoglobin alteration may be a secondary rather than a primary abnormality? Dr. Paulserz: I would agree if we find that the hemoglobin structure as we11 as the percentage concentration is normal in relatives or asymptomatic chemical diabetes that the change is a secondary one; however, it may be possible that the hemoglobin structure is different prior to determination of a percentage change.