REVIEW ARTICLE doi: 10.1111/j.1463-1326.2004.00392.

Development and application of rodent models for type 2

diabetes

Desu Chen and Ming-Wei Wang

The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China

The increasing worldwide incidence of diabetes in adults constitutes a global public health burden. It is predicted that
by 2025, India, China and the United States will have the largest number of people with diabetes [1]. According to
the 2003 estimates of the International Diabetes Federation, the diabetes mellitus prevalence in the USA is 8.0%
and approximately 9095% of diabetic Americans have type 2 diabetes about 16 million people. Type 2 diabetes
is a complex, heterogeneous, polygenic disease characterized mainly by insulin resistance and pancreatic b-cell
dysfunction. Appropriate experimental models are essential tools for understanding the molecular basis, pathogenesis
of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase
the risks of type 2 diabetes. Among the animal models available, those developed in rodents have been studied most
thoroughly for reasons such as short generation time, inherited hyperglycaemia and/or obesity in certain strains and
economic considerations. In this article, we review the current status of most commonly used rodent diabetic models
developed spontaneously, through means of genetic engineering or artificial manipulation. In addition to these
models, the Psammomys obesus, rhesus monkeys and many other species are studied intensively and reviewed by
Shafrir [2], Bailey and Flatt [3,4] and Hansen [5].
Keywords: pharmacology, rodents, type 2 diabetes
Received 23 December 2003; returned for revision 5 April 2004; revised version accepted 20 April 2004

Spontaneously Diabetic Rodents
The information described in this review was obtained
through a search of MEDLINE/PubMed for literatures
published between 1993 and 2003. Search terms used
include type 2 diabetes, OLETF rats, GK rats, db/db
mice, ZDF rats and ob/ob mice. The analysis of our
search results is summarized in table 1, and the details
of each model are given in the order of its citation
frequency and synopsized in table 2.
Otsuka Long-Evans Tokushima Fatty Rats
A spontaneously diabetic rat with polyuria, polydipsia and
mild obesity was discovered in 1984 in an outbred colony
of Long-Evans rats, which was purchased from Charles
River, Canada in 1982. A strain of rats developed from
this rat by selective breeding has since been maintained
at the Otsuka Pharmaceutical and named OLETF [6].
The characteristics of Otsuka Long-Evans Tokushima
Fatty (OLETF) rats include: (a) late onset of hypergly-
caemia (after 18 weeks of age); (b) a chronic course of
disease; (c) mild obesity; (d) clinical onset of diabetes
mostly in males; (e) multiple recessive genes are
involved in the induction of diabetes, and the transmit-
tal of one of the diabetogenic genes, designated as odb-1,
is linked to the X-chromosome of OLETF rats; (f)
the changes of pancreatic islets can be classified into
three stages an early stage (less than 9 weeks of age)
with mild lymphocyte infiltration, a hyperplastic stage

Correspondence:
Dr Ming-Wei Wang, The National Center for Drug Screening, 189, Guo Shou Jing Road, Shanghai 201203, PR China.
E-mail:
mwwang@siniwest.com

# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 307317 307
RA Rodent models for type 2 diabetes
Table 1 Citation frequency of spontaneously diabetic rodents
Rodent Model Articles Frequency (%)
Otsuka Long-Evans Tokushima Fatty rats 290 33.8
Goto-Kakizaki rats 170 19.8
db/db (C57BL/KsJ-db/db) mice 148 17.3
Zucker Diabetic Fatty rats 135 15.8
ob/ob (C57BL/6J-ob/ob) mice 114 13.3
(1040 weeks of age) with hyperplastic alterations
and fibrosis in or around islets and a final stage
(more than 40 weeks of age) showing atrophy of islets;
and (g) diabetic nephropathy manifested by diffused
glomerulosclerosis and nodular lesions (e.g. thickening
of basement membranes, mesangial proliferation
and fibrin cap). These clinical and pathological fea-
tures in OLETF rats resemble those of human type 2
diabetes [7].
Expression of cholecystokinin A (CCK-A) receptor
mRNA in the pancreas, small intestine and brain was
not detected in OLETF rats by the reverse transcriptase
polymerase chain reaction (RT-PCR). The lack of CCK-A
receptors results in a reduced ability to process nutrient-
elicited gastrointestinal satiety signals, which leads to
Table 2 Synopsis of pharmacological applications of spontaneously diabetic rodents
Species Pharmacologically related characteristics
OLETF rats Lack of CCK-A receptors; deficit
in dorsomedial hypothalamus neuropeptide Y
signalling; elevated triglyceride storage in islets;
significantly decreased total content of GLUT4 in muscles
GK rats Twofold higher activities of both basal and
insulin-stimulated PTP1B; GK-VMH rats as a
useful model for non-obese type 2 diabetes
with microangiopathy and macroangiopathy
db/db mice Correlations between the glucagon/insulin ratio
and the hepatic glucose-6-phosphatase/fructose-
1,6-diphosphatase activities; elevated renal
cortical activities of PI3 kinase, protein kinase B,
extracellular signal-regulated protein kinase 1/2-type
mitogen-activated protein kinase
ZDF rats 2555% reduction of GLUT4 in the adipose tissue,
heart and skeletal muscle; loss of pancreatic
duodenal homeobox gene expression;
FFA and nitric oxide induced suppression
of insulin output
ob/ob mice Overproduced neuropeptide Y in the hypothalamus;
45% higher hepatic microsomal TG transfer protein
mRNA level; b-adrenergic receptor mRNA levels
in white and brown adipose tissues reduced by
300-fold
CCK-A, cholecystokinin A; FFA, free fatty acid; GLUT4, glucose transporter protein 4; GLP-1, glucagons-like peptide 1; GK, Goto-Kakizaki;
OLETF, Otsuka Long-Evans Tokushima Fatty; PTP1B, protein tyrosine phosphatase 1B; TG, triglyceride.
308 Diabetes, Obesity and Metabolism, 7, 2005, 307317
D. Chen and M.-W. Wang
increases in meal size, overall hyperphagia and obesity
[810]. Analyses of patterns of hypothalamic gene
expression in OLETF rats indicate the presence of a
primary deficit in dorsomedial hypothalamus neuropep-
tide Y signalling. Thus, the obesity in OLETF rats may be
the outcome of two regulatory disruptions, one depending
upon a peripheral pathway such as meal satiety and the
other relating to a central pathway critical to overall
energy balance [11].
In OLETF rats, hypertriglyceridaemia led to elevated
triglyceride (TG) storage in islets, which subsequently
inhibited glucose-induced insulin secretion, via reduced
glucokinase activity in the islet. Fat droplets in islets
may play an important role in accelerating the develop-
ment of diabetes [12].
The total content of glucose transporter 4 (GLUT4)
protein significantly decreased while the plasma mem-
brane content of the GLUT4 protein in muscles of the
diabetic OLETF rats was increased in the basal state.
Hyperinsulinaemic clamps increased GLUT4 levels in
the plasma membrane in muscles of normal rats but
failed to do so in diabetic OLETF rats. The distribution
of GLUT4 in OLETF rats is reminiscent of the character-
istics of human type 2 diabetes [13].
Studies of anti-diabetic agents
Beneficial effects of Ca2 antagonist (Cilnidipine),
metformin and truncated GLP-1 on insulin-resistance;
PPARg (pioglitazone) agonist improves daily profiles
of energy expenditure
Long-term and favourable influences of GLP-1 or
exendin-4 on b-cell mass and glycemic control
Long-lasting glycemic control by GLP-1 receptor
agonist in a dose-dependent manner; combination
therapy of PPARg and PPARa agonists improved
body weight and glucose-stimulated insulin secretion;
PTP1B inhibitors modulates insulin signalling in
the liver and fat tissues
Nicotinamide or aminoguanidine halted inducible nitric
oxide synthase expression in islets; metformin
significantly reduced FFA levels; rosiglitazone
maintained cell proliferation and blocked b-cell death;
b-3-adrenergic receptor agonist improved glucose
tolerance and insulin responsiveness
GLP-1 increased frequency of large, rapid spikes
of [Ca2]i; exendin-4 treatment led to weight loss
and improved insulin sensitivity; PTP1B antisense
oligonucleotides decreased PTP1B protein and
elevating other elements in insulin signalling pathway
# 2004 Blackwell Publishing Ltd
D. Chen and M.-W. Wang
Exercise training is effective at preventing the
development of diabetes mellitus in OLETF rats. The
cumulative incidences of diabetes mellitus in sedentary
(in conventional cages) and trained-control rats (in
cages with a fixed rotary wheel) were 78 and 50%,
respectively, while neither trained OLETF rats (in
exercise wheel cages) nor non-diabetic Long-Evans
rats became diabetic. The preventive effect of exercise
training against the development of type 2 diabetes
lasted for at least 3 months after the cessation of exercise
[14,15].
Injection of insulin to OLETF rats was effective at
preventing b-cell dysfunction and morphological
changes in the pancreas [16]. Cilnidipine, a long-acting
dihydropyridine Ca2 antagonist, had beneficial effects
on both insulin resistance and hypertension in OLETF
rats [17]. Metformin-induced improvement of insulin
resistance in OLETF rats could lower blood pressure,
decrease sympathetic activity and reduce body weight
[18]. Acarbose prevented and reversed the metabolic
derangement and histopathological changes of pancreas
in OLETF rats. Moreover, treatment with acarbose, even
for a short period, produced a marked delay in the devel-
opment of insulin insensitivity and obvious diabetes
[19]. Administration of pioglitazone, a peroxisome pro-
liferator-activated receptor g (PPARg) agonist, improved
daily profiles of energy expenditure through affecting
glucose and fat metabolism [20].
A long-term infusion of truncated glucagon-like
peptide 1 (GLP-1) increased the glucose infusion rate
significantly during a euglycaemichyperinsulinaemic
clamp experiment. This suggests that truncated GLP-1
is capable of augmenting insulin action in peripheral
tissues of diabetics, which can contribute, in part, to
improve glucose intolerance in OLETF rats [21].
Goto-Kakizaki Rats
The Goto-Kakizaki (GK) rat is a non-obese rodent model
of mild type 2 diabetes with early hyperglycaemia,
hyperinsulinaemia and insulin resistance. This model
was obtained by selective breeding of individuals with
mild glucose intolerance from a non-diabetic Wistar rat
colony.
In GK rats, the neonatal b-cell-mass deficit is con-
sidered to be the primary defect leading to basal hyper-
glycaemia, which is detectable around 3.5 weeks of age.
After 8 weeks, hyperglycaemia deteriorates and glu-
cose-stimulated insulin release by the islets is more
severely impaired [22]. Heritability of defective b-cell
mass and its function in the GK model is thought
to reflect the complex interactions of the following
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Rodent models for type 2 diabetes RA
pathogenic factors: (a) three independent loci containing
genes responsible for impaired insulin secretion;
(b) heritable gestational metabolic (hyperglycaemic)
impairment inducing deficiency in endocrine pancreas;
and (c) secondary (acquired) loss of b-cell differentiation
due to long-term exposure to hyperglycaemia (glucotoxi-
city) [23].
Through metabolism, glucose generates adenosine
triphosphate (ATP) needed for the closure of the
ATP-sensitive K channels and membrane depolar-
ization. In the GK rat pancreatic islet, K induces a
delayed [Ca2]i response that probably results from a
defective metabolism of glucose in this tissue [24,25].
Immunoprecipitation of protein tyrosine phosphatase
1B (PTP1B) from skeletal muscle lysates, and analysis
of the enzyme activity indicate that both basal and
insulin-stimulated PTP1B activities were twofold higher
in skeletal muscle of diabetic GK rats than those of
normal rats. This alteration was associated with an
increased expression of the enzyme protein. Elevated
PTP1B activity would enhance tyrosine dephosphoryl-
ation of insulin receptor and its substrates and thereby
lead to impaired glucose tolerance and insulin resist-
ance in GK rats [26].
The effects of GLP-1 and its long-acting analogue,
exendin-4 (Ex-4), were investigated during the predia-
betic period of GK rats. Treatment with GLP-1 or Ex-4
demonstrated long-term and favourable influences on
b-cell mass, resulting from enhancement of differentia-
tion (neogenesis), proliferation and glycaemic control in
adulthood. Compared to untreated animals, basal
plasma glucose levels in 2-month-old treated rats were
significantly decreased [27].
In GK rats, a marked prolongation in mean circulation
time and a significant reduction in segmental blood flow
appeared at an early stage of diabetes. This tendency
continued for a period of 5 months, and the endothe-
lial/pericyte ratio was found to be higher in 8-month-old
animals as well as in animals greater than 2430 months
of age. These findings suggest that the GK rat appears to
be a suitable model for experimental studies on initial or
latent-phase diabetic retinopathy [2830].
Prolonged exposure to hyperglycaemia is one of Key
factors in the induction of progressive diabetic nephrop-
athy in humans. The same phenomenon was observed
in GK rats. Noticeable morphological changes in kid-
neys, such as segmental glomerulosclerosis and tubu-
lointerstitial fibrosis, were found only in 2-year-old
animals. The renal alterations seen in GK rats at a later
stage were similar to those of progressive human diabetic
nephropathy [31]. Experimental ventromedial hypo-
thalamic (VMH) lesions induced marked hyperglycaemia
Diabetes, Obesity and Metabolism, 7, 2005, 307317 309
RA Rodent models for type 2 diabetes
and a distinct reduction in pancreatic insulin content in
male GK rats. Histological examinations of the kidneys
from these rats revealed that the glomerular basement
membrane was thicker than that of controls. The
descending aorta in GK-VMH rats also showed
morphologic changes in the intima, characteristic of an
early stage of atherosclerosis. Thus, male GK-VMH rats may
be a useful animal model for non-obese type 2 diabetes
with typical complications such as microangiopathy and
macroangiopathy [32,33].
Db/db (C57BL/KsJ-db/db) Mice
The diabetes db gene mutation occurred spontaneously
in the leptin-receptor-deficient C57BL/KsJ strain of mice
from Bar Harbor, ME, USA [34]. It is an autosomal reces-
sive mutation on chromosome 4 with complete pene-
trance.
In diabetic mutant db/db mice, progressive impair-
ment of insulin response to glucose is observable with
increasing age. Blood glucose levels do not differ signifi-
cantly between 5-week-old db/db and / mice but
increase with age in the former until they are 16 weeks
old. Consistent with the idea of a protective effect of
oestrogen on the pancreatic b-cell, female diabetic db/
db mice survive longer than males.
While plasma levels of insulin and glucagon in db/db
mice, which peaked at 7 weeks of age, do not reflect the
state of hyperglycaemia, the G/I (glucagon/insulin) ratio
is roughly in parallel with the development of hypergly-
caemia. Analysis of individual values revealed statistic-
ally significant correlations between plasma glucose
levels and hepatic glucose-6-phosphatase or fructose-
1,6-diphosphatase activities. There were also marked
correlations between the G/I ratio and activities of
these two hepatic gluconeogenic enzymes [35].
NN2211, a long-acting, metabolically stable GLP-1
derivative, with enhanced stability due to attachment
of the fatty acid moiety, dose dependently reduced gly-
caemia levels in db/db mice, with an antihyperglycaemic
activity still evident 24 h after treatment. b-Cell
proliferation rate and mass size were also significantly
increased [36]. Another novel GLP-1 receptor agonist,
ZP10A, decreased db/db mouse glycosylated haemo-
globin A1c (HbA1c) from 8.4% to 6.2% in a dose-
dependent manner. Fasting blood glucose and glucose
tolerance after an oral glucose tolerance test were
notably improved. These effects lasted for 40 days after
cessation of treatment [37].
Studies have shown that combination therapy of
PPARg and PPARa agonists may have beneficial effects
on body weight and glucose-stimulated insulin secretion
310 Diabetes, Obesity and Metabolism, 7, 2005, 307317
D. Chen and M.-W. Wang
(GSIS) in db/db mice. Body-weight gain in db/db mice
was less with dual PPAR agonists treatment than with a
single agonist such as pioglitazone or pioglitazone plus
bezafibrate. Plasma glucose, insulin, TG and free fatty
acid (FFA) levels were significantly ameliorated and
GSIS was increased [38]. Adipocyte complement-related
protein (30 kDa) (Acrp30, adiponectin or AdipoQ) is a
fat-derived secreted protein that circulates in blood.
Adipose tissue expression of Acrp30 is lower in insulin-
resistant state, and it is implicated in the regulation
of in vivo insulin sensitivity. In obese diabetic db/db
mice, mean plasma Acrp30 protein levels increased
after long-term treatment using PPARg agonists. Induc-
tion of adipose tissue Acrp30 expression and conse-
quent rises in circulating Acrp30 levels represent a
novel potential mechanism for PPARg-mediated
enhancement of whole-body insulin sensitivity. Acrp30
is likely to be a biomarker of in vivo PPARg activation
[39].
In db/db mice, PTP1B antisense oligonucleotide treat-
ment normalized plasma glucose levels, postprandial
glucose excursion and HbA1c. Hyperinsulinemia was
also reduced, with improved insulin sensitivity. PTP1B
protein and mRNA were reduced in liver and fat tissues
with no effect on skeletal muscle. Insulin signalling
proteins, insulin receptor substrate 2 and phosphatidy-
linositol 3 (PI3) kinase regulatory subunit p50a were
increased, and PI3-kinase p85a expression was
decreased in the liver and fat tissues. These changes
in protein expression correlated with
increased insulin-stimulated protein kinase B phosphor-
ylation. The expression of liver gluconeogenic enzymes,
phosphoenolpyruvate carboxykinase and fructose-1, 6-
bisphosphatase, was also downregulated. The findings
suggest that PTP1B modulates insulin signalling in the
liver and fat tissues and that therapeutic modalities tar-
geting PTP1B inhibition may have clinical benefits in
type 2 diabetes [40]. Indeed, a series of azolidinediones,
prepared as PTP1B inhibitors, with IC50 values in the
range of 0.120.30 mM, normalized plasma glucose and
insulin levels in db/db mice [41].
Experimental data demonstrate that a variety of
receptor signalling pathways are activated in the
renal cortex of db/db mice, pointing to a role of
augmented insulin receptor activity in nephropathy
of type 2 diabetes. In db/db mice, renal cortical
activities of PI3 kinase, protein kinase B (PKB) and
extracellular signal-regulated protein kinase (ERK)1/2-
type mitogen-activated protein (MAP) kinase were all
elevated considerably. The increased renal cortical
PI3 kinase activity was partially due to insulin recep-
tor activation, as PI3 kinase activity associated with
# 2004 Blackwell Publishing Ltd
D. Chen and M.-W. Wang
insulin receptor b-chain was increased nearly
fourfold. Additionally, the kinase activity of immuno-
precipitated b-chain in the diabetic renal cortex and
tyrosine phosphorylation of insulin receptor were
both augmented [42].
Zucker Diabetic Fatty Rats
The diabetic trait in this model originated from a colony
of outbred Zucker rats in the laboratory of Dr Walter
Shaw at Eli Lilly Research Laboratories in Indianapolis,
IN, USA, during 19741975. Several groups of animals
with diabetic lineage were identified and redefined at
the beginning of 1981. The inbred line of Zucker diabetic
fatty (ZDF) rats was established in 1985 and developed
to a genetic model in 1991.
Male Zucker rats homozygous for non-functional lep-
tin receptors (fa/fa) develop obesity, hyperlipidemia and
hyperglycaemia, but rats with homozygous dominant
(/) and heterozygous (fa/) genotypes remain lean
and normoglycaemic. Insulin resistance occurs in
young fa/fa rats followed by evolution of an insulin-
secretory defect that triggers hyperglycaemia [43].
Thus, the ZDF male rat has become an experimental
model for type 2 diabetes, with a predictable progression
from prediabetic to diabetic state. Hyperglycaemia is
initially manifested at about 7 weeks of age, and all
obese male rats are fully diabetic by 12 weeks. Between
7 and 10 weeks, serum insulin levels are high but subse-
quently drop as pancreatic b-cells cease to respond to
glucose stimulus [44]. In this diabetic model, GLUT4 in
the adipose tissue, heart and skeletal muscle is reduced
by 2555% [45].
The ZDF rat has both insulin resistance (as a result of a
mutant leptin receptor that causes obesity) and inad-
equate b-cell compensation. Studies demonstrate that
the ZDF rat carries a genetic defect in b-cell transcription
that is inherited independently of the leptin receptor
mutation and insulin resistance. The genetic reduction
in b-cell gene transcription in homozygous animals
probably contributes to the development of diabetes in
the background of insulin resistance [46]. In prediabetic
ZDF rats, there is no change in insulin mRNA levels.
However, significant reductions (3070%) of many other
islet mRNA levels, such as glucokinase, mitochondrial
glycerol-3-phosphate dehydrogenase, voltage-dependent
Ca2 and K channels, CA2-ATPase and transcription
factor islet-1, could be detected. In contrast, glucose-6-
phosphatase and 12-lipoxygenase mRNA levels are
increased by 4050%. Gene-expression patterns in the
islets of diabetic ZDF rats show marked alterations,
including a decrease in insulin mRNA levels associated
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Rodent models for type 2 diabetes RA
with reduced islet insulin secretion [47]. Chronic and
progressive hyperglycaemia in diabetic ZDF rats is
related to the loss of insulin and pancreatic duodenal
homeobox (PDX-1) mRNAs and lack of glucose-
stimulated insulin secretion. Prevention of hyperglycae-
mia could block the associated defects in insulin and
PDX-1 gene expression and improve insulin secretion
[48].
The lipoapoptosis of b-cells observed in fat-laden
islets of ZDF rats results from the overproduction of
ceramide, an initiator of the apoptotic cascade which is
induced by long-chain fatty acids (FA). The onset of type
2 diabetes is preceded by a striking increase in the
plasma levels of FFA and by a sixfold rise in TG content
in the pancreatic islets. FFA could be the signal from
adipocytes that elicits b-cell compensation sufficient to
prevent diabetes [49,50]. Studies show that FFA-
induced suppression of insulin output in prediabetic
ZDF rats is mediated by nitric oxide (NO). In cultured
prediabetic ZDF islets, FFA induced a fourfold rise in
NO, upregulated mRNA of inducible nitric oxide
synthase (iNOS) and reduced insulin output. Both nico-
tinamide and aminoguanidine, which lower NO, pre-
vented the FFA-mediated increase in iNOS mRNA,
reduced NO and minimized the loss of insulin secretion.
In vivo nicotinamide or aminoguanidine treatment of
prediabetic ZDF rats stopped iNOS expression in islets
and mitigated b-cell dysfunction through blocking b-cell
destruction and hyperglycaemia [51].
In ZDF rats, hyperphagia leads to hyperinsulinemia,
which upregulates transcription factors that stimulate
lipogenesis. This causes ectopic deposition of triacylgly-
cerol in non-adipocytes, thereby providing FA substrate
for pathological non-oxidative metabolism, such as cer-
amide synthesis. In b-cells and myocardium, the resulting
functional impairment and apoptosis lead to diabetes
and cardiomyopathy. Interventions that lower ectopic
lipid accumulation or block FA non-oxidative metabo-
lism and ceramide formation could completely prevent
these complications [52].
Metformin prevented hyperglycaemia in diabetic ZDF
rats aged between 6 and 12 weeks and significantly
reduced TG and FFA levels. It delays the onset of dia-
betes in the ZDF rat, which is correlated with improve-
ment in b-cell function, consistent with the lipotoxicity
hypothesis for adipogenic diabetes [53]. Treatment with
rosiglitazone protected obese ZDF rats against loss of
b-cell mass through maintaining cell proliferation and
blocking increased b-cell death [54].
Insulin release was defective in ZDF obese rats and
could be partially restored by GLP-1 therapy. In ZDF islets,
the action of GLP-1 is mediated via Ca2-independent
Diabetes, Obesity and Metabolism, 7, 2005, 307317 311
RA Rodent models for type 2 diabetes
signalling pathway. Infusion of GLP-1 (737) in
hyperinsulinemic and hyperglycaemic ZDF rats
produced a transitory increase in plasma insulin
concentration and normalized blood glucose level
[5557]. Studies on dipeptidyl peptidase-IV (DPP-IV)
inhibitors in ZDF rats indicated their therapeutic
value of delaying progression from impaired glucose
tolerance to type 2 diabetes [58].
Long-term b-3-adrenergic receptor agonist treatment
in obese ZDF rats improved glucose tolerance and insu-
lin responsiveness through a mechanism similar to that
induced by chronic cold exposure, i.e. by stimulating
facultative thermogenesis, mitochondriogenesis and glu-
cose utilization in brown and white adipose tissues. The
reduction in plasma FFA levels may enhance glucose
uptake in skeletal muscles (a tissue that does not express
typical b-3-adrenergic receptors) via the glucosefatty
acid cycle [59].
Ob/ob (C57BL/6J-ob/ob) Mice
The C57BL/6J-ob/ob mouse originated from the Jackson
Laboratory in Bar Harbor, ME, USA [60]. The ob gene
was transferred from the stock of origin onto the B/6
genomic background and is located on chromosome 6.
The obesity syndrome, which is prominent in ob/ob
mice, results from the lack of leptin, a hormone released
by fat cells and which acts on brain to suppress feeding
and stimulate metabolism. The ob/ob mice are less
hyperglycaemic than the db/db mice.
Neuropeptide Y (NPY) is a neuromodulator impli-
cated in the control of energy balance and is overpro-
duced in the hypothalamus of ob/ob mice. The same
strain of mice deficient in NPY is less obese because of
reduced food intake and increased energy expenditure.
As a result, these animals are less affected by diabetes,
sterility and somatotropic defects. This suggests that
NPY is a central effector of leptin deficiency [61].
Chronically elevated NPY levels in the hypothalamus,
as seen in genetically obese ob/ob mice, are associated
with obesity, a typical symptom of type 2 diabetes,
and infertility. Crossing the Y2-receptor knockout
mouse [Y2(/)] onto the ob/ob background attenuates
increased adiposity, hyperinsulinaemia, hyperglycaemia
and increased hypothalamicpituitaryadrenal axis
activity of ob/ob mice [62].
Recent studies demonstrate that microsomal TG trans-
fer protein (MTP) is a rate-limiting factor for the assem-
bly and secretion of apoB-containing lipoproteins.
Obese diabetic ob/ob mice have 45% higher hepatic
MTP mRNA level, 54% higher microsomal TG transfer
activity and 70% higher TG concentration compared to
312 Diabetes, Obesity and Metabolism, 7, 2005, 307317
D. Chen and M.-W. Wang
ob/ mice. These observations indicate that obesity-
induced type 2 diabetes in mice causes increases in
hepatic MTP expression and increases the secretion of
TG-rich lipoproteins [63].
All b-adrenergic receptor (b-AR) mRNA levels in
white and brown adipose tissues were dramatically
reduced (by approximately 300-fold) in 12-week-old
obese mice. The reduction in the expression of b-1AR
and b-3AR impaired b-AR agonist-stimulated, adenylyl-
cyclase response, over a broad concentration range, by
greatly lowering the maximum stimulation and shifting
the adrenergic sensitivity at low concentrations from a
mixed b-1AR/b-2AR response to predominantly b-2AR
[64].
The effects of GLP-1 (736 amide, GLP-1a) on [Ca2]i
were determined using Fura-2 fluorescence ratio
imaging on cultured ob/ob mouse pancreatic b-
cells. GLP-1a increases the frequency of sustained, stable
plateau responses to elevated glucose and the frequency
of large, rapid spikes of increased [Ca2]i associated with
either plateaus or oscillations [65]. A series of novel
GLP-1 analogues displays resistance to plasma DPP-IV
degradation and enhances insulin-releasing and antihy-
perglycaemic activities in 20- to 25-week-old obese dia-
betic ob/ob mice [66]. Administration of Ex-4 leads to an
anti-diabetic effect associated with weight loss and
improved insulin sensitivity (up to 32% and 49% respect-
ively) in ob/ob mice [67]. Studies on the effects of the
GIP receptor antagonist and exendin (939) amide on
GIP- and GLP-1-induced cyclic AMP generation, insulin
secretion and postprandial insulin release in ob/ob mice
provide evidence that GIP is the major physiological
incretin of the enteroinsular axis. Administration of
(Pro3)GIP, exendin (939) amide or a combination of
both peptides to fasted ob/ob mice decreased the plasma
insulin responses by 42%, 54% or 49% respectively.
The hyperinsulinaemia of non-fasted ob/ob mice was
decreased by 19%, 27% or 18%, respectively, following
injection of (Pro3)GIP, exendin (939) amide or com-
bined peptides [68].
Semiquantitative RT-PCR experiments show that
PPARg2 mRNA was significantly upregulated in ob/ob
mouse liver in comparison with that of wild-type mice.
In addition, insulin resistance index was positively asso-
ciated with liver PPARg2 mRNA expression. The find-
ings suggest a possible compensatory response through
which type 2 diabetic and obese animals strive to main-
tain insulin sensitivity in liver [69]. Experimental obes-
ity in rodents is related to severely defective resistin
expression. In response to several different classes of
PPARg agonists, resistin expression in ob/ob mouse adi-
pose tissue was increased [70].
# 2004 Blackwell Publishing Ltd
D. Chen and M.-W. Wang Rodent models for type 2 diabetes RA

Recent studies indicate that a reduction in PTP1B Artificially Induced Diabetic Rodents
activity is sufficient to increase insulin-dependent
metabolic signalling and to improve insulin sensitivity Neonatal Streptozotocin-induced Diabetes
in ob/ob mice. In PTP1B-antisense-oligonucleotide-
Intraperitoneal administration of streptozotocin (STZ) to
treated mice, in which PTP1B protein was decreased
neonatal rats (2 days postpartum) produces a type 2
by 60% in the liver, there was elevated tyrosine
diabetes mellitus model in adulthood. At the fourth
phosphorylation of insulin receptor and its substrates
week, fed serum glucose concentration is normal or
(IRS-1 and IRS-2). A threefold increase in IRS-2-
mildly elevated due to b-cell regeneration. However,
associated PI3 kinase activity was accompanied by
hyperglycaemia develops progressively with age, and
augmentations of PKB serine phosphorylation in the
by the twelfth week, marked impairment of glucose-
liver upon insulin stimulation, phosphorylation of PKB
stimulated insulin release could be observed [7375].
substrates and glycogen synthase kinases (3a and 3b)
[71].
STZ-Spontaneously Hypertensive Rat (SHR)

Two-day-old SHRs intraperitoneally injected with STZ

Genetically Engineered Diabetic Mice
In recent years, genetically engineered mouse models,
including transgenic and knockout mice, have been
developed for the study of the pathophysiological con-
sequences of defined alterations in a single gene or in a
set of candidate diabetogenes, especially the expression
of key actors in insulin signalling, action or secretion
(table 3 reproduced with permission of EMBO Reports)
[72]. In this review, besides the phenotypic alterations of
the knockout models, the specific roles of individual
genes in the control of glucose homeostasis are also
comprehensively addressed.
Genetically engineered mice open the door for inves-
tigating the role of genegene or geneenvironment
interactions in the development of type 2 diabetes.
develop a hyperglycaemic syndrome, associated with
other biochemical, morphological and haemodynamic
properties that, to some extent, confer insulin resistance
combined with hypertension. Plasma glucose levels in
STZ-SHRs increase in a dose-dependent manner at the
twelfth week. During long-term observations, hyper-
glycaemia persisted until the twenty-eighth week but later
gradually ameliorated, accompanied by continued hyper-
tension as measured at the fifty-second week [76,77].
Fat-fed/STZ-induced Diabetic Rodents
Fat-fed/STZ diabetic rodents, developed by combination
of diet-induced insulin resistance and relatively-low-dose
STZ, provide a novel animal model for type 2 diabetes. It

Table 3 Monogenic and polygenic diabetic mice

General or tissue-specific knockout mice Phenotypic alterations

GK/ or b-cell GK/ Impaired insulin secretion, mild diabetes

GLUT2/ Moderate insulin resistance, glucose intolerance, decreased adipose mass
GLUT4/ Insulin resistance, diabetic hypertension
GLUT4/ Diabetic ketoacidosis, early postnatal death
IR/ Growth retardation, mild insulin resistance, b-cell hyperplasia, hyperinsulinaemia
IRS-1/ Severe insulin resistance, b-cell hyperplasia, diabetes in 50% of adult mice
IRS-2/ Severe insulin resistance in liver, limited b-cell hyperplasia, diabetes in adult mice
IR/IRS-1/ Sever insulin resistance, early onset of diabetes, marked b-cell hyperplasia
IR/IRS-1/IRS-2/ Insulin resistance, b-cell hyperplasia, diabetes in adult mice
IRS-1/GK/ Lack of glucose-induced first phase insulin release, glucose intolerance with ageing
bIRKO Sever insulin resistance, fasting hyperglycaemia, b-cell hyperplasia
LIRKO Mild hyperglycaemia
Liver GK/ Normal glucose homeostasis, dyslipidaemia, increased adiposity
MIRKO Insulin resistance, glucose intolerance
MG4KO Diabetic ketoacidosis, early postnatal death
PG4KO Insulin resistance in muscle and liver, glucose intolerance, hyperinsulinaemia

GK, Goto-Kakizaki; GLUT, glucose transporter protein; IR, insulin receptor; IRS, insulin receptor substrate.

# 2004 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 7, 2005, 307317 313
RA Rodent models for type 2 diabetes
simulates the human syndrome and is suitable for
expedient in vivo evaluation of anti-diabetic agents.
In C57BL/6J mice, insulin resistance could be induced
by diets enriched in either fructose or fat, and hypergly-
caemia is introduced by injecting a dose of STZ that does
not cause diabetes in chow-fed mice. Insulin concentra-
tions initially increase in response to the fructose- or fat-
rich diets and then decrease to levels still higher than
those in chow-fed mice following STZ injection. Accom-
panied by this decrease in insulin levels after STZ injec-
tion, fat- or fructose-fed C57BL/6J mice become
significantly hyperglycaemic [78].
Another rodent model employs 7-week-old, non-
obese, outbred male SpragueDawley rats. They are fed
with a high-fat diet (40% of calories as fat) for 2 weeks
and then injected with STZ (50 mg/kg intravenously).
Before STZ injection, fat-fed rats have glucose con-
centrations similar to chow-fed counterparts. Plasma
insulin levels in response to oral glucose are increased
twofold by fat feeding, and adipocyte glucose clearance
under maximal insulin stimulation is significantly
reduced, suggesting that fat feeding induces insulin
resistance. STZ injection elevates glucose, insulin, FFA
and TG concentrations. Fat-fed/STZ rats are not insulin
deficient compared to normal chow-fed rats but display
hyperglycaemia associated with reduced insulin-
stimulated adipocyte glucose clearance [79].
Summary
With worldwide rises of metabolic disease incidences,
development of novel investigational methods and tech-
nologies becomes one of the top priorities in combating
this health crisis. Newly emerged and available rodent
models for the study of obesity, diabetes, hyperlipid-
aemia and other metabolic complications would
accelerate the ongoing process of finding a cure.
Spontaneously diabetic rodent models such as OLETF
rats, GK rats, db/db mice, ZDF rats and ob/ob mice are
most commonly used in drug discovery. OLETF rats
closely simulate the metabolic abnormalities of the
human syndrome, especially the diabetic nephropathy.
While the GK rat appears to be a suitable model for non-
obese diabetes, ZDF rats are generally applied to studies
of diabetes with obesity and cardiovascular complica-
tions due to the dyslipidaemia background. Obesity is
necessary but not sufficient alone for the development of
type 2 diabetes. Inheritance is the more important factor.
Genetically engineered diabetic mice represent new
tools that provide us with invaluable insights into the
pathogenesis, and further studies may identify potential
targets for the development of novel therapeutic stra-
314 Diabetes, Obesity and Metabolism, 7, 2005, 307317
D. Chen and M.-W. Wang
tegies aimed at improving insulin action or b-cell func-
tion. The newly developed fat-fed/STZ-induced diabetic
model offers significant advantages in replicating the
natural history and metabolic characteristics of human
conditions and is also cost-effective compared to the
genetic models currently available. Because it is a com-
plex, heterogeneous, multifactorial syndrome resulting
from both genetic susceptibility and environmental risk
factors, more promising animal models that closely
simulate human type 2 diabetes regarding inheritance
traits, environmental risks, pathogeneses and complica-
tions have yet to be developed in the future.
Acknowledgement
We are indebted to Dr D. E. Mais for his valuable comments
and suggestions.
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