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

VI. Insulin and Carbohydrate Metabolism
57
form β-hydroxy-β -methyl glutaryl-CoA (HMG-CoA). As
shown in Figure 3-10 , HMG-CoA is a common intermediate
for the synthesis of cholesterol and ketone bodies in the
liver cell. In liver, a deacylating enzyme is present, which
cleaves HMG-CoA to yield AcCoA and free AcAc. This
is the HMG-CoA cycle. The free AcAc then diffuses out
of the cell and enters the general circulation. For further
oxidations to occur, AcAc is “ reactivated ” with CoA in
extrahepatic tissues (muscle) by the transfer of CoA from
succinyl-CoA to form AcAcCoA. Increased ketogenesis
and ketonemia are the net result of alterations in metabolic
pathways or enzymes that favor the accumulation
of AcAcCoA. Prime examples are diabetes mellitus and
bovine ketosis.
The increased mobilization and utilization of fatty acids
are a well-known requisite for ketogenesis under conditions
of starvation and diabetes. Under these same conditions,
lipid synthesis from AcCoA is also depressed. The
net effect of either or both of these alterations favors the
accumulation of AcCoA and thus ketogenesis.
Increased ketogenesis is always associated with an
increased rate of gluconeogenesis in association with an
increased activity of the key gluconeogenic enzyme, PEPcarboxykinase
(PEP-CK). The increased rate of gluconeogenesis
in turn depletes OAA. There is an increase in the
NADH/NAD ratio, which would promote the conversion of
OAA to malate, thereby depleting OAA. With the depletion
of OAA and subsequent OAA deficiency, there is an insufficient
condensing partner for AcCoA for the Kreb’s cycle.
The AcCoA is then readily diverted to ketone bodies.
Hepatic ketogenesis is regulated by the rate limiting
transfer of FFA across the mitochondrial membrane.
Carnitine acyl transferase, the enzyme system responsible
for the mitochondrial uptake of FFA, is increased in diabetes
and contributes to the ketogenesis.
(e.g., diabetes), depression of lipogenesis is a characteristic
finding. When there is adequate glucose oxidation (e.g.,
successful insulin therapy in diabetes), lipid synthesis is
restored and the animal regains its weight.
In those conditions with decreased glucose use or availability
(e.g., diabetes, starvation, ruminant ketosis), there
is an increased release of glucose precursors (amino acids)
from muscle and FFA from adipose tissues mediated by
activated hormone-sensitive lipases (HSL) ( Khoo et al .,
1973 ). The amino acids and FFA are transported to the liver
where the amino acids follow gluconeogenic pathways.
Fatty acids follow pathways toward oxidation and ketogenesis
and, additionally, glucagon promotes hepatic ketogenesis.
There is also an underutilization of ketones in the
peripheral tissues of dogs ( Balasse and Havel, 1971 ; Foster
and McGarry, 1982 ). The net result is an overproduction of
glucose and ketones in liver and an underutilization of both
in the peripheral tissues.
VI . INSULIN AND CARBOHYDRATE
METABOLISM
The internal secretions of the anterior pituitary, adrenal
cortex and medulla, and the pancreas are closely associated
with carbohydrate metabolism. The pituitary and adrenal
factors were discussed in Section IV.C, together with glucagon.
More detailed information is available in the chapters
on pituitary and adrenal function. Since the successful
extraction of insulin by Banting and Best in 1921, a vast
amount of literature has accumulated on its role in carbohydrate
metabolism and continues to this day. The fine
details of insulin action are still being studied, and a basic
understanding of the major biochemical events that occur
in animals with and without insulin has evolved.
B . Influence of Glucose Oxidation on
Lipid Metabolism
In addition to the separation of the biochemical pathways
for lipid oxidation and lipid synthesis, an anatomical separation
of lipid metabolism is also present. The liver is the
major site of fatty acid oxidation and the adipose tissue is
the major site of lipid synthesis. Adipose tissue, in vitro,
converts glucose carbons to fatty acids faster than does
liver tissue.
It is well known that, with excessive carbohydrate feeding,
fat depots in the body increase. Fasting, on the other
hand, depresses the respiratory quotient (R.Q.) indicating
that the animal is now using body fat as the energy source.
During fasting, plasma FFA also increase, and when carbohydrate
is supplied, they decrease. The presence of glucose
both stimulates lipogenesis and spares fatty acid from
oxidation. In diseases with an inability to utilize glucose
A . Proinsulin and Insulin
The elucidation of the insulin structure by Sanger in 1959
was soon followed by the discovery of its precursor, proinsulin,
and its structure was quickly known. It has been
the subject of many reviews ( Raptis and Dimitriadis, 1985 ;
Steiner, 2004 ). Proinsulin is a single-chain looped polypeptide
linked by disulfide bridges ( Fig. 3-11 ). It varies in
length from 78 amino acid residues in the dog to 86 for
the human, horse, and rat. Its m.w. is near 9000 daltons.
Proinsulin is synthesized in the pancreatic β -cells on the
rough endoplasmic reticulum (RER) and transported and
stored in the secretory granules on the Golgi apparatus.
There, the central connecting polypeptide or C-peptide is
cleaved from the chain by proteolytic enzymes, and the
two linked end fragments are the monomeric insulin molecule.
C-peptide has an m.w. of 3600 daltons and is devoid
of biological activity.