Review

Pathogenesis of feline diabetes mellitus

T.D. OBrien *
Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, Veterinary Diagnostic Laboratory, University of Minnesota, 1333
Gortner Avenue, St. Paul, MN 55108, USA
Abstract
The common form of spontaneous diabetes mellitus that occurs in domestic cats bears close resemblance clinically and
pathologically to human type 2 diabetes mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged, and has
low but detectable circulating insulin levels. However, the most striking similarity is the occurrence of islet amyloidosis (IA) in nearly
all diabetic cats and in over 90% of humans with T2DM. IA in both humans and cats is derived from islet amyloid polypeptide
(IAPP, or amylin) which is a hormone produced and secreted along with insulin by the pancreatic b cells. Since all cats and humans
normally produce IAPP, additional factors must be invoked in order to explain the development of IA. Several lines of evidence
support the concept that IA is caused by chronically increased stimulus for b cells to secrete IAPP (and insulin). For example,
peripheral insulin resistance such as in chronic obesity results in increased IAPP and insulin secretion. A recent study, in which
diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was induced by treatment with a sulfonylurea drug
and resulted in 4/4 cats in this group developing IA. In contrast, cats treated with insulin had low IAPP secretion and minimal IA
developed in 1/4 cats. Several human-IAPP transgenic mouse models, in which there is IAPP overexpression, also support the notion
that prolonged high expression of IAPP leads to IA. In vitro models of IAPP overexpression also support this mechanism for IA
formation and by demonstrating an association between IA formation and b cell toxicity, suggest a linkage between IA formation
and loss of b cells in T2DM. A recent study has indicated that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell
membranes and therefore, may be involved in the destruction of b cells. Striking parallels between the pathogenesis of IA and b-
amyloid plaque formation in Alzheimers disease suggest possible parallel pathogenetic mechanisms of cell death and provide
potential avenues for future studies into the pathogenesis of IA.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus; Amyloidosis; Islet amyloid polypeptide
1. Summary
Diabetes mellitus in the domestic cat closely resembles
human type 2 diabetes mellitus (T2DM) clinically and
pathologically. Islet amyloidosis (IA) is an almost
invariant feature of feline diabetes (FDM) and T2DM,
and is associated with significant loss of b cells in the
pancreatic islets. Islet amyloid in cats has been shown to
be derived from islet amyloid polypeptide (IAPP), as has
islet amyloid in humans. Evidence from in vitro studies
has demonstrated that fibrillar forms of IAPP are
cytotoxic and can trigger apoptosis, thus providing a
potential pathogenetic link between IA and b cell loss in
FDM. Evidence from transgenic mouse models also
strongly supports a role for IAPP-derived amyloid in the
pathogenesis of FDM and T2DM. Further studies are
needed to delineate the mechanisms by which IAPP-
derived amyloid triggers cell death and to unequivocally
demonstrate these mechanisms in spontaneous FDM.
The most common form of diabetes mellitus in the
domestic cat bears close clinical and pathological
resemblance to human type 2 diabetes mellitus
(T2DM) (Johnson et al., 1986). This review will focus
on this form of feline diabetes mellitus (FDM) and will
not consider other less common forms of diabetes in the
cat such as type 1-like diabetes or secondary forms of
diabetes such as may occur with pancreatitis.
Clinical similarities between FDM and T2DM include
clinical onset in middle age; FDM occurs in cats greater
than 6 years of age with the peak incidence occurring
between 9 and 13 years of age, which corresponds to
middle age in the domestic cat (Johnson et al., 1986,
* Tel.: /1-612-625-8175; fax: /1-612-624-8707
E-mail address: obrie004@tc.umn.edu (T.D. OBrien).
Molecular and Cellular Endocrinology 197 (2002) 213/219
www.elsevier.com/locate/mce
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PII: S 0 3 0 3 - 7 2 0 7 ( 0 2 ) 0 0 2 6 5 - 4
1989b; OBrien et al., 1993; Panciera et al., 1990). Other
clinical similarities include obesity, resistance to ketoa-
cidosis, low but measurable fasting serum insulin con-
centration, absent or attenuated first phase insulin
secretion, and exaggerated or absent second phase
insulin secretion (OBrien et al., 1985). All of these
features of FDM closely parallel those of T2DM and
therefore suggest a common pathogenesis. However, the
most striking and provocative similarities between
T2DM and FDM are the lesions occurring in the
pancreatic islets, namely islet amyloidosis (IA) (Fig. 1)
and partial loss of b-cells (Johnson et al., 1986, 1989b;
OBrien et al., 1993).
Islet amyloidosis occurs in over 90% of cats with
diabetes and occurs in a similar proportion of humans
with T2DM (Johnson et al., 1986, 1989b; OBrien et al.,
1993). Furthermore, IA in FDM is associated with a
mean loss of b-cells of approximately 50% (OBrien et
al., 1986). Several similar studies of T2DM have shown
a similar loss of up to 50% of b-cell mass (Rahier et al.,
1983; Saito et al., 1979; Westermark, 1972). Non-
diabetic cats with IA also show a partial, but less severe,
loss of b-cells, further supporting a link between IA and
loss of b-cells (OBrien et al., 1986). Additional evidence
linking IA and diabetes has also been demonstrated in
type 2-like diabetes occurring in macaque species
(OBrien et al., 1996; de Koning et al., 1993; Hansen
and Bodkin, 1986; Howard, 1986). In macaques IA
development has been shown to precede the onset of
diabetes, and IA is significantly more extensive in
diabetic macaques than in age-matched non-diabetic
controls. Yet another parallel situation is seen in human
patients with cystic fibrosis. IA is found in approxi-
mately 67% of diabetics but in only 27% of age-matched
non-diabetic CF patients (Couce et al., 1996b). Further-
more, the IA in CF is associated with a 50% loss of b-
cells. Thus, there is a strong link between IA and loss of
b-cells in several similar forms of diabetes mellitus.
The understanding of the pathogenesis of feline and
human islet amyloidosis was greatly advanced by the
discovery that the precursor protein of this form of
amyloid was a previously unknown hormone which we
named islet amyloid polypeptide (IAPP, also known as
amylin) (Westermark et al., 1987a,b; Cooper et al.,
1987). The pancreatic islets are the predominant site of
IAPP production and, within the pancreatic islets of all
species thus far studied, IAPP immunoreactivity is
predominantly located in the pancreatic b-cells, and at
least in some species, the d-cells (Johnson et al., 1988;
Lukinius et al., 1989). Ultrastructurally, IAPP immu-
noreactivity resides predominantly in the b-cell secretory
vesicle (Johnson et al., 1988; Lukinius et al., 1989). In
situ hybridization studies of the rat pancreatic islets also
indicate that IAPP mRNA is predominantly located in
the b-cells (Leffert et al., 1989). The localization of IAPP
immunoreactivity in the b-cell secretory vesicles pro-
vided the first evidence that IAPP was co-secreted with
insulin. As the morphologic studies predicted, IAPP and
insulin secretion are qualitatively and temporally simi-
lar, consistent with the concept that they are co-secreted
(Butler et al., 1990; Fehmann et al., 1990; Inoue et al.,
1991; OBrien et al., 1991).
IA occurs in only a limited number of species (e.g.
human beings, macaques, and cats), usually in conjunc-
tion with diabetic syndromes associated with aging, and
does not occur in rats or mice (Johnson et al., 1989b;
OBrien et al., 1993). This observation prompted the
comparison of IAPP structures in these species to
determine whether primary or secondary structural
differences within or between species might be asso-
ciated with these observations. Such comparisons of
mammalian species revealed highly conserved regions in
the amino-terminal region (residues 1/19) and in the
carboxy-terminal region (residues 30/37) (Betsholtz et
al., 1989a). The intervening region (residues 20/29)
showed notable sequence variations. Secondary struc-
tural predictions of this latter region indicated a
propensity for beta pleated sheet configuration for
human IAPP whereas this was not present in mouse or
rat (Betsholtz et al., 1989b). Since b-sheet secondary
structure is often linked to amyloid fibril formation, this
region was further investigated for the formation of
amyloid fibrils. Indeed, peptides corresponding to hu-
man IAPP20/29 readily formed amyloid fibrils whereas
mouse and rat sequence did not (Westermark et al.,
1990). Evidence gathered so far indicates that no
mutation in the IAPP coding region is required for the
development of IA in NIDDM and in animal models
(Westermark et al., 1987a,b; Sanke et al., 1988; Bet-
sholtz et al., 1989b, 1990; Nakazato et al., 1990).
However, it has recently been shown that a mutant
form of human IAPP, the S20G mutant, is associated
Fig. 1. (A) Pancreatic islet from a cat showing lesions characteristic of feline diabetes mellitus including extensive islet amyloid deposits (arrows) and
markedly reduced islet cell mass (arrowheads). H & E stain. (B) Pancreatic islet from a diabetic cat immunohistochemically stained for insulin. Note
extensive amyloid deposits which show no insulin immunoreactivity (arrows) and few remaining b-cells showing insulin immunoreactivity (arrow
heads). Avidin/biotin immunohistochemistry, AEC chromogen, Meyers hematoxylin counterstain. (C) Adjacent section of pancreatic islet in B,
immunohistochemically stained for IAPP. Note IAPP immunoreactivity of amyloid deposits (arrows) and of remaining b-cells (arrow heads).
Avidin/biotin Immunohistochemistry, AEC chromogen, Meyers Hematoxylin counterstain. (D) Pancreatic islet from a normal cat demonstrating
normal cellular content and structure. H & E stain. (E) Insulin immunoreactivity (arrow) in a normal cat pancreatic islet demonstrating the
predominance of b-cells. Avidin/biotin immunohistochemistry, AEC chromogen, Meyers hematoxylin counterstain. (F) IAPP immunoreactivity
(arrow) in a normal cat pancreatic islet, demonstrating the localization of IAPP in the b-cells. Avidin/biotin immunohistochemistry, AEC
chromogen, Meyers hematoxylin counterstain.
T.D. OBrien / Molecular and Cellular Endocrinology 197 (2002) 213/219 214
Fig. 1
T.D. OBrien / Molecular and Cellular Endocrinology 197 (2002) 213/219 215
with early onset T2DM (Sakagashira et al., 1996; Lee et
al., 2001).
Simply having an IAPP sequence capable of forming
amyloid fibrils is obviously not sufficient for IA to
develop, because if this were the case, the prevalence of
IA in human beings, cats, and macaques would
approach 100% in the general population. It therefore
appears likely that abnormalities in IAPP synthesis,
processing, trafficking, secretion, or degradation by b-
cells must play a role in the pathogenesis of IA. The
notion that increased IAPP secretion predisposes to IA
formation is supported by studies in which increased
IAPP secretion has been associated with obesity, an
important predisposing factor for the development of
T2DM. In further support of this concept, it has been
shown that the b-cells of cats with impaired glucose
tolerance have increased IAPP immunoreactivity com-
pared to normal controls (Johnson et al., 1989a; Ma et
al., 1998). This suggests that there is an imbalance
between IAPP production and secretion/degradation in
these cats. The importance of the increase in IAPP
content in cats with impaired glucose tolerance in the
pathogenesis of IA is also supported by the observation
that these cats also have an increased incidence of IAPP-
derived IA as compared to normal control cats (Johnson
et al., 1989a).
Since increased and/or altered IAPP synthesis or
secretion may be important in the pathogenesis of
IAPP-derived IA, studies investigating the synthesis
and secretion of IAPP under varying circumstances
may provide additional clues as to the sequence of
events leading to IA. Evidence in support of this
hypothesis was recently demonstrated in an experimen-
tal cat model (Hoenig et al., 2000). Partially (/50%)
pancreatectomized cats (all IA negative) had stable
diabetes induced by treatment with dexamethasone
and growth hormone. This was followed by treatment
with either glipizide or insulin for 18 months. Glipizide-
treated cats had significantly increased basal and
glucose-stimulated serum IAPP concentrations versus
insulin-treated cats. Furthermore, 4/4 glipizide-treated
cats developed IA while only 1/4 insulin-treated cats had
detectable IA. Several in vitro studies have shown that
islets in culture under varying conditions can show an
increase in the relative amounts of IAPP secreted
relative to insulin. For example, perfused pancreas
from rats treated with dexamethasone or intraperitone-
ally administered glucose (hyperglycemic) show signifi-
cantly increased IAPP:insulin ratio in the perfusate
when stimulated by 16.7 mM glucose, while pancreases
from fasted rats showed a significantly reduced IAP-
P:insulin ratio (OBrien et al., 1991). A recent study has
also shown that when human islets in culture are
exposed to 24.4 mM glucose there is an increase in the
cellular IAPP:insulin ratio and a similar increase in the
mRNA ratios of these hormones. Under these condi-
tions the human islets also showed an increase in the
amount of IAPP secreted through the constituative
pathway (Gasa et al., 2001). In a mouse model of
insulin resistance, a high fat diet was associated with
maintenance of IAPP mRNA levels but decreased
expression of insulin mRNA compared to mice on the
low fat control diet (Mulder et al., 2000). These findings
taken together show that conditions present in the
diabetic state (hyperglycemia, corticosteroid excess)
and prediabetic state (insulin resistance, hypertriglycer-
idemia) may increase the absolute amount of IAPP
synthesized and secreted. Furthermore, these conditions
may increase the IAPP:insulin ratio. Experiments show-
ing that insulin inhibits IAPP-amyloidogenesis suggest a
possible role for increased IAPP:insulin expression in
the development of IA (Charge et al., 1995; Westermark
et al., 1996; Kudva et al., 1998).
The associations discussed between IA formation and
the development of type 2 DM, and IA formation and
the loss of b-cells have, in the past, been considered
intriguing but did not reveal whether the association was
merely coincidental (i.e. an epiphenomenon), or if there
was a direct cause and effect relationship. Now however,
several additional lines of evidence strongly support the
role of IA in the development of FDM and T2DM.
These include evidence from: (1) several lines of human
IAPP (hIAPP) transgenic mice; (2) in vitro experiments
showing cytotoxic effects of fibrillar forms of hIAPP;
and (3) evidence concerning the serine to glycine
mutation at position 20 of hIAPP (S20G) which is
associated with early onset T2DM.
Transgenic mouse models provide strong evidence of
the importance of hIAPP fibrillogenesis in the destruc-
tion of b-cells and the development of diabetes mellitus
(de Koning et al., 1994; Couce et al., 1996a; Jansen et
al., 1996; Verchere et al., 1996; Soeller et al., 1998;
Hoppener et al., 2000). For example, male, heterozy-
gous, human-IAPP-transgenic mice which were made
insulin resistant by treatment with dexamethasone and
growth hormone developed diabetes mellitus and islet
amyloidosis within 6 weeks while non-transgenic mice
were unaffected (Couce et al., 1996a). b-cells in these
human-IAPP-transgenic mice frequently contained ab-
normal IAPP-immunoreactive deposits within the cyto-
plasm and in many instances had classical amyloid
deposits within their cytoplasm (Couce et al., 1996a). It
was also noted that affected b-cells often showed
ultrastructural degenerative changes and alterations
consistent with apoptosis. Furthermore, male homozy-
gous hIAPP-transgenic mice developed spontaneous
diabetes mellitus with selective and extensive b-cell loss
by 8 weeks of age without any induction of insulin
resistance (Jansen et al., 1996). Female hIAPP-trans-
genic mice of this strain also developed diabetes, islet
amyloidosis, and b-cells loss at a more advanced age. In
another unrelated strain of mice, transgenic for hIAPP,
T.D. OBrien / Molecular and Cellular Endocrinology 197 (2002) 213/219 216
a close association between the development of hyper-
glycemia and islet amyloidosis was found (Verchere et
al., 1996). Recently, it was shown that insulin-resistant
male agouti mice, which were heterozygously transgenic
for hIAPP, spontaneously developed diabetes and islet
amyloidosis (Soeller et al., 1998). In each of these
transgenic models, the production of high levels of
hIAPP by the b-cells was associated with the formation
of abnormal IAPP aggregates, selective b-cell loss, and
the development of diabetes mellitus. Thus, mice
transgenic for hIAPP develop lesions that closely
resemble the islet lesions in humans with T2DM, while
mice transgenic for non-amyloidogenic rodent IAPP do
not develop either IA or loss of b-cells.
Data supporting the concept that IAPP-derived
amyloid fibrils are cytotoxic and associated with apop-
totic cell death and/or necrosis are becoming increas-
ingly abundant. Studies using hIAPP transfected COS-1
cells which expressed hIAPP at high levels demonstrated
the formation of intracellular IAPP-derived amyloid
fibrils which was associated with cellular degeneration
and death by 96 h (OBrien et al., 1995). In contrast,
COS-1 cells transfected with non-amyloidogenic rat
IAPP also showed high expression of IAPP but showed
no adverse effects. Subsequent experiments with this
system have demonstrated that there is a significant
increase in apoptosis of COS-1 cells expressing hIAPP
but no increase in apoptosis in cells expressing rodent
IAPP (Hiddinga and Eberhardt, 1999). Human IAPP-
derived fibrils have also been shown to be toxic to
isolated islets in culture (Lorenzo et al., 1994). The
mechanism of cell death in this study involved synthesis
of RNA and protein, plasma membrane blebbing,
chromatin condensation and DNA fragmentation, con-
sistent with apoptotic cell death. Lastly, there have been
several studies demonstrating toxic effects of hIAPP-
derived fibrils on neurons and PC12 cells (rat pheochro-
mocytoma cell line) (May et al., 1993; Mattson and
Goodman, 1995; Dore et al., 1997). In these systems
hIAPP demonstrates cytotoxic effects that are identical
to those of Ab (the fibrillogenic protein that forms
amyloid deposits in Alzheimers disease) whereas, ro-
dent IAPP is non-toxic (May et al., 1993). For both
IAPP and Ab, it is the fibrillar forms that are cytotoxic
while monomers and related non-amyloidogenic poly-
peptides are not cytotoxic (Howlett et al., 1995; Lorenzo
and Yankner, 1994, 1996; Schubert et al., 1995). Recent
data indicates that it is fibrillar assemblies in the range
of 50 000/200 000 Da that are cytotoxic and disrupt
cellular membranes (Janson et al., 1999). Interestingly,
the toxicity of both hIAPP and Ab fibrils can be
counteracted in cultured neurons by IGF-1 (Dore et
al., 1997) and Congo red (Burgevin et al., 1994), while
rifampicin and its analogues inhibit the toxicity of
fibrillar IAPP and Ab on PC12 cells (Mattson and
Goodman, 1995). These similarities in cytotoxicity by
IAPP and Ab fibrils support the concept that similar
mechanisms are involved in neuronal cell death in
Alzheimers disease and b-cell death in T2DM.
Given the similarities of IAPP and Ab fibril cytotoxi-
city, the mechanisms of Ab toxicity in neurons are of
particular interest, in that they may illuminate cytotoxic
mechanisms involved in b-cell damage by IAPP fibrils.
Mechanisms involved in Ab cytotoxicity include oxida-
tive damage by reactive oxygen species, lipid peroxida-
tion, reduced mitochondrial transmembrane potential,
and destabilization of intracellular calcium homeostasis
(Hensley et al., 1994; Mark et al., 1997a,b). Membrane
lipid peroxidation initiated by Ab induces apoptosis in
PC12 cells and cultured hippocampal neurons. This
process is mediated by 4-hydroxynonenal and is pre-
vented by Bcl-2 and antioxidants (Kruman et al., 1997).
The neuroprotective actions of cycloheximide against
Ab induction of apoptosis is mediated by increased
expression of the bcl-2 gene product (Furukawa et al.,
1997). Ab toxicity on hippocampal neurons is also
prevented by EUK-8 a synthetic catalytic free radical
scavenger (Bruce et al., 1996). Of special interest is the
finding that membrane lipid peroxidation initiated by
Ab is also associated with impaired glucose transport
into cultured rat hippocampal neurons (Mark et al.,
1997b). If similar alterations are induced in b-cells by
IAPP fibrillogenesis, this may be of critical importance
in impairing normal b-cell function.
The recent discovery of the S20G hIAPP has provided
yet another line of evidence supporting a role of IA in
the development and progression of T2DM (Sakaga-
shira et al., 1996). Patients identified with this mutation
had relatively early onset of diabetes ( 5/35 years of age),
relatively severe diabetes, and a strong family history of
T2DM. A role for IAPP amyloidogenesis in T2DM
would therefore be supported if the S20G mutant is
more amyloidogenic than the more common allele of
hIAPP. Indeed, COS-1 cells transfected with the S20G
hIAPP showed significantly more apoptosis 96 h after
transfection versus the common hIAPP allele (Sakaga-
shira et al., 2000). It was shown in an in vitro
fibrillogenesis assay that the S20G mutant formed
approximately twofold more amyloid and at a rate
approximately 3-fold higher than the common hIAPP
allele. Thus, these experiments provide evidence for a
linkage between increased amyloidogenicity of hIAPP
and early onset of T2DM.
In summary, the evidence for an important role for
IAPP-derived IA in the pathogenesis of FDM and
T2DM is increasing. However, a great deal of work still
needs to done to elucidate the mechanisms underlying
the initiation and toxicity of IAPP fibrillogenesis, and
the apoptotic pathways involved in b-cell death.
Furthermore, these mechanisms need to be unequivo-
cally demonstrated to be operational in the feline and
T.D. OBrien / Molecular and Cellular Endocrinology 197 (2002) 213/219 217
human b-cell during the development and progression of
FDM and T2DM.
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