Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IX. Disorders of Carbohydrate Metabolism
69
animal to utilize this inability is corrected by insulin
glucose and is clearly shown in its inability to convert
glucose- 14 C to 14CO
2 . This inability is corrected by insulin.
The inability to utilize glucose is reflected in the clinical
signs of diabetes, loss of weight, polyuria, polydipsia, and,
in the advanced stages, ketoacidosis.
Several reports have suggested that the development of
diabetes mellitus is the result of the interaction of several
hormones, principally insulin and glucagon ( Unger and
Orci, 1975, 1976 ). Although excess glucagon is observed
in diabetes and it can induce glucose intolerance or changes
in diabetic control, it can do so only as long as insulin
deficiency is present and pharmacological levels of glucagon
are induced ( Felig et al ., 1976 ). Thus, insulin deficiency
is sine qua non the cause of diabetes, and although
glucagon may modify the consequences, it is neither necessary
nor sufficient for the development of diabetes ( Felig
et al ., 1976 ). The modifying action of glucagon on diabetes,
however, has important implications because excess
glucagon will tend to exacerbate the posthypoglycemic
hyperglycemia (e.g., the Somogyi effect). A deficiency
of glucagon will tend to increase the effect of insulin and
contribute to a prolonged hypoglycemia after treatment.
Thus, glucagon plays a significant role in the variability of
diabetes.
The complex nature of the development of type II diabetes
is further illustrated by the ongoing controversy as to
the nature and value of the so-called metabolic syndrome
as a clinical disease entity ( Reaven, 2005 ) in an effort to
link insulin resistance to increased risk of cardiovascular
disease (CVD). Insulin resistance is a feature of type
II diabetes and the metabolic syndrome in effect describes
the interaction of the various hormones involved in carbohydrate
metabolism. It’s usefulness as a clinical disease
entity is open to question ( Reaven, 2006 ).
3 . Hyperglycemia
A persistent fasting hyperglycemia is the single most
important diagnostic criteria of diabetes mellitus. In the
normal animal, the homeostatic level of blood glucose is
maintained by the equilibrium between glucose supply
and removal, which in turn is based on the endocrine balance.
The effect of insulin tends to lower blood glucose,
whereas the opposing effects of growth hormone, glucagon,
and adrenal cortical hormones tend to raise it. In the
diabetic animal with an absolute or relative lack of insulin,
the equilibrium is shifted to a higher level of blood glucose.
Glucose utilization in the peripheral tissues decreases while
at the same time hepatic glucose production increases as a
result of increases in their gluconeogenic enzyme activities.
In the diabetic, the hyperglycemia itself tends to
compensate in part for the decrease in peripheral utilization.
This occurs as a mass action effect that promotes the
flow of glucose into the peripheral tissues. In this way, the
diabetic can continue to use some glucose when insulin is
decreased, but only at the expense of increased glucose
production and hyperglycemia. As the deficiency of insulin
progressively becomes more severe, the equilibrium level
of blood glucose is established at higher and higher levels,
and ultimately the equilibrium is never established without
therapeutic intervention. Blood glucose levels in canine
diabetics have reached 70 mmol/l (1260 mg/dl). When the
renal threshold of 11.1 mmol/l (200 mg/dl) for glucose is
exceeded, the diabetic is faced with excessive loss of glucose
in the urine. It is evident that the blood glucose level
is exquisitely sensitive to insulin and, conversely, the blood
glucose level is the mainstay for monitoring the success of
diabetes therapy. However, a marked posthypoglycemic
hyperglycemia or the Somogyi effect has long been known
to occur in humans after insulin therapy ( Bolli et al .,
1984 ), which indicates that glucose regulation by insulin
is not complete. This hyperglycemic effect is thought to
be due to an excess of glucagon, growth hormone, adrenal
cortical hormones, or epinephrine. This phenomenon
has been seen in diabetic cats given an inadvertent insulin
overdose ( McMillan and Feldman, 1986 ), which points to
the need for effective monitoring of diabetes.
4 . Glycated Proteins
The biochemical and physiological bases for using glycated
proteins as a monitor for long-term glucose control are
now commonplace in human diabetolgy (Section VIII.B).
Successful management of diabetes depends on the reliable
evaluation of blood glucose levels, and any blood glucose
sample only reflects the blood glucose level at the moment
of sampling. An effective method for estimating the average
blood glucose over an extended time period offers a
way of evaluating successful insulin therapy. This can be
done by use of the glycated proteins, HbA1c or FrAm.
Of these, FrAm offers the most cost effective method for
evaluating the average blood glucose over the preceding
2 weeks. However, although HbA1c is the test of choice
for indirect glucose monitoring by many academic programs,
Davison et al . (2005) have found that either test is
efficacious.
a . Hemoglobin A1c
The glycated hemoglobin, HbA1c, is known to reflect the
average blood glucose level over the preceding 60 days and is
now widely used to monitor human diabetics ( Nathan et al .,
1984 ). Several studies in diabetic dogs (Mahaffey and
Cornelius 1982; Wood and Smith, 1980 ) have also shown
that HbA1c is potentially useful for monitoring purposes.
Although the reference values for % HbA1c differed in the
two studies, 2.29% and 6.43%, the means for the diabetics
were increased in each to 4.97% and 9.63%, respectively.
Hooghuis et al . (1994), using thiobarbituric acid colorimetry