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

IX. Disorders of Carbohydrate Metabolism
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cell transplantation has corrected these diabetics for a short
time. Type II obese and the type III dogs with even a small
insulin reserve would be the most likely subjects for successful
oral hypoglycemic therapy. The early detection of
diabetes and being able to treat these patients using oral
drugs would have obvious advantages. Nelson et al . (1993)
have successfully treated cats with diabetes using oral
hypoglycemic drugs. Prognostically, the severity of the diabetes
can be assessed by the degree of glucose intolerance
and the nature of the insulin response.
Atkins et al . (1979) identified diabetes in dogs less than
1 year of age, and Atkins and Chin (1983) examined their
insulin responses to glucose loading. All dogs were glucose
intolerant but could mount a minimal insulin response
somewhat akin to the type II diabetic dogs. It could also be
that these young diabetic dogs were identified during the
early stages of their natural history of progression of their
diabetes to type I or II.
7 . Glucagon Stimulation and the Insulin Response
The GST has been used in humans and cats to differentiate
type I from type II diabetes. Type I diabetic cats have
a minimal or no insulin response to glucagon. Type II diabetic
cats have a significant insulin response in the GST.
Nondiabetic obese cats also have an insulin response that
is similar to that observed in the type II diabetic cats. Thus,
obesity is predisposing to the development of diabetes in
animals as well as in humans. Type II diabetes is known
to be characterized by various forms of insulin resistance
(Section VIII.C.2).
8 . Ketonemia and Lipemia
As the utilization of glucose progressively decreases in the
diabetic, the utilization of fatty acids for energy purposes
progressively increases to compensate. The supply of fatty
acids for hepatic utilization is obtained by mobilization
from the body fat depots. Mobilization of fatty acids progressively
increases as insulin deficiency becomes more
severe, and this is due to increases in hormone sensitive
lipase. This enzyme is separate and distinct from the hepatic
lipoprotein lipase.
In severe diabetes, lipid mobilization is so intense that
the subsequent hyperlipemias are often so marked that the
blood appears as tomato soup. A cream layer may separate
out on storage overnight in the cold because of hyperchylomicronemia.
The plasma is turbid due to the presence
of lipoproteins (very low density lipoproteins [VLDLs]).
On chemical analysis, total triglycerides and cholesterol
are elevated ( Rogers et al ., 1975 ). Diabetic hyperlipemia
appears to be caused by impaired lipolysis of chylomicra
secondary to a deficiency of hepatic lipoprotein lipase
rather than to an overproduction of VLDL.
Concurrently with increased fatty acid oxidation in
liver, a progressive decrease in fatty acid synthesis occurs.
The net effect of the alterations in hepatic fatty acid metabolism
is that AcCoA is generated in excess by the liver
because of the increased rate of fatty acid β -oxidation
catalyzed by the increased activity of the enzyme carnitine
acyltransferase. Fatty acyl-CoA from fat mobilization is
also a strong inhibitor of citrate synthase, which removes
another route for disposal of AcCoA. The accumulated
AcCoA units are then diverted into alternate pathways as
described in Section V.B, and with the activation of ketogenic
mechanisms, excessive synthesis of ketone bodies
( Kreisberg, 1978 ) and cholesterol results. In the peripheral
tissues, there is an underutilization of ketone bodies in the
diabetic dog ( Balasse and Havel, 1971 ). Ketosis is thus the
result of an overproduction of ketone bodies by the liver
and an underutilization by the peripheral (muscle) tissues.
The type I diabetic has a greater tendency to develop ketoacidosis
than does the type II diabetic. The pathophysiology
of the ketoacidosis in the type II diabetic remains
unclear, but the most likely mechanism is the depth of the
insulinopenia ( Linfoot et al ., 2005 ).
It has been suggested that the development of ketosis
requires both a deficiency of insulin and an excess of glucagon
( Foster and McGarry, 1982 ). Dobbs et al . (1975) and
Unger and Orci (1975) proposed that diabetes develops as
a result of a bihormonal interaction of insulin and glucagon
because glucagon levels are high in insulin deficiency. The
excess glucagon is thought to be caused by an abnormality
in the alpha cell. There is also an excessive secretion
of glucagon after protein ingestion or amino acid infusions
( Unger, 1981 ). The excess glucagon may then exacerbate
the insulin deficiency and lead to the ketoacidosis.
In the ketoacidotic state, marked cholesterolemias as
high as 18mmol/l (700mg/dl) have been observed in clinical
diabetes of the dog. Net gluconeogenesis from fatty
acid does not occur, and the precursors for gluconeogenesis
are the proteins. Excesses of glucagon, cortisol, and growth
hormone in the diabetic also contribute to protein catabolism
and gluconeogenesis. The cofactors that provide the
reductive environment required for gluconeogenesis can
be provided by the increased production of reduced cofactors
during the increased fatty acid oxidation. This increase
in the reductive environment of the cell is the mechanism
that stimulates gluconeogenesis, which is corollary to the
development of ketoacidosis.
8 . Electrolyte Balance and Ketoacidosis
A mild glucosuria with only a few grams of glucose loss
per day does not in itself precipitate the acidotic state
because some compensation occurs. The liver increases
its production and output of glucose even though there
is a hyperglycemia, so glucose metabolism continues.
However, with continued and severe loss of glucose, all