Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1141
GPA feeding of rats caused an increase in the mass of
brown adipose tissue (BAT) as well as in BAT DNA,
glycogen, and total protein content, suggesting a tendency
to hyperplasia of the BAT (727, 1072, 1133). On the other
hand, the contents of mitochondrial protein and uncoupling
protein showed a tendency to be decreased, which
correlated with decreases in thermogenic activity and
both colonic and skin temperature. It was suggested that
the impairment of BAT thermogenic activity reflects a
sparing of ATP in compensation for a reduction in highenergy
phosphate levels, with resultant hypothermia.
The results published on the effects of GPA on mitochondrial
composition and function require further comment.
As mentioned above, the contents and activities of
several mitochondrial proteins were considerably increased
in skeletal muscle by GPA feeding. In isolated
mitochondria, however, the specific activities of pyruvate
dehydrogenase, 2-oxoglutarate dehydrogenase, NAD � -
isocitrate dehydrogenase, hydroxyacyl-CoA dehydrogenase,
and citrate synthase were virtually unchanged (887),
suggesting a general increase in mitochondrial mass. On
top of that, there seems to be an additional specific increase
in the protein contents of Mi-CK and adenine nucleotide
translocase (718–720) that is thought to be a
metabolic adaptation to compensate for the decreased
tissue levels of Cr and PCr. The increased amounts of
Mi-CK tend to aggregate and form large paracrystalline
intramitochondrial inclusions (see Refs. 718–720, 1125).
Mi-CK-rich intramitochondrial inclusions were seen in
skeletal muscle, to a lesser extent in heart, and not at all
in brain, liver, and kidney of GPA-treated rats (718, 719).
Because similar intramitochondrial inclusions were also
seen in adult rat cardiomyocytes cultured in medium
devoid of Cr (228), their formation is unlikely to be due to
a toxic side effect of GPA, but rather to Cr deficiency. In
line with the expectation that the aggregated Mi-CK may
be nonfunctional, Cr-stimulated mitochondrial respiration
was severely impaired in skinned cardiac and soleus muscle
fibers as well as in isolated heart mitochondria of
GPA-treated rats (130, 718–720).
Although not strictly related to the findings discussed
so far, one additional effect of GPA administration is
worth mentioning. In KKA y mice, an animal model of
non-insulin-dependent diabetes, GPA and GAA decreased
the plasma glucose level, whereas 4-GBA, Arg, �-alanine,
Cr, or guanidino-undecanoic acid were ineffective (629).
GPA was more potent than even metformin, a clinically
effective antidiabetes agent. Glucose incorporation into
glycogen was increased by GPA in hindlimb muscle, but
not in cardiac muscle. GPA’s antihyperglycemic effect
was corroborated in two other models of non-insulindependent
diabetes, namely, in ob/ob mice and in insulinresistant
rhesus monkeys, but was absent in normoglycemic
animals, insulinopenic Chinese hamsters, and
streptozotocin-diabetic rats. Together, these studies sug-
gest that the antihyperglycemic action of GPA requires
the presence of at least some circulating insulin as well as
hyperglycemia, and that improved insulin sensitivity is the
mode of action for GPA. Not fully in line with these
results, GPA-fed normal mice and rats displayed a decreased
plasma concentration of insulin, a tendency to
decreased blood glucose levels, and significantly increased
glycogen contents in both tibialis anterior muscle
and liver (724). In addition, glucose tolerance was considerably
enhanced, i.e., after intraperitoneal infusion of
glucose, its blood concentration increased less in GPA-fed
animals than in controls. In a phase I study in terminal
cancer patients as well as upon intravenous infusion in
rabbits (O’Keefe et al. and Schimmel et al., unpublished
data), cCr decreased blood glucose levels significantly.
This effect was reversible upon addition of a dextrose
solution. It therefore seems attractive to speculate that Cr
analogs may become a new class of antidiabetes compounds.
Interestingly, in diabetic db/db mice, administration
of Cr reduced the concentrations of both N-carboxymethyllysine
and hydroxyproline and, thereby, most
probably inhibited the accumulation of collagen type IV in
the kidney (578). Thus Cr supplementation may reduce
diabetic long-term complications in this mouse model of
type II diabetes. Hypoglycemic effects of guanidino compounds,
including Cr (see Refs. 208, 820), as well as
hypotheses on how high-energy phosphate and glucose
metabolism may influence each other in both pancreatic
�-cells and peripheral tissues (281), have also been reported
in other studies.
To conclude, all these results demonstrate that the
effects of Cr analogs, and of GPA in particular, are not
strictly muscle specific and that clear-cut discrimination
between (beneficial or toxic) side effects and effects related
entirely to energy depletion may often be difficult, if
not impossible. Nevertheless, the functional and biochemical
alterations elicited by this Cr analog are strikingly
similar to those observed in transgenic CK knock-out
mice, thus suggesting that the changes are due to a considerable
extent to the functional deficit in the CK/PCr/Cr
system.
X. CREATINE METABOLISM
AND (HUMAN) PATHOLOGY
A. Cr Metabolism and Muscle Disease
In mammals, the highest concentrations of Cr and
PCr and the highest specific CK activities are found in
skeletal muscle. Consequently, it is thought that the CK/
PCr/Cr system plays an important role in the energy metabolism
of this tissue. In accordance with this concept, a
multitude of experimental findings suggest a close relationship
between disturbances of Cr metabolism and various
muscle diseases.