Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological
Relevance to the Human Condition
William T. Cefalu
Abstract
The prevalence of diabetes throughout the world has increased dramatically over the recent past, and the trend will
continue for the foreseeable future. One of the major concerns associated with diabetes relates to the development of
micro- and macrovascular complications, which contribute
greatly to the morbidity and mortality associated with the
disease. Progression of the disease from prediabetic state to
overt diabetes and the development of complications occur
over many years. Assessment of interventions designed to
delay or prevent disease progression or complications in
humans also takes years and requires tremendous resources.
To better study both the pathogenesis and potential therapeutic agents, appropriate animal models of type 2 diabetes
(T2D) mellitus are needed. However, for an animal model
to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model
should develop complications of diabetes with an etiology
similar to that of the human condition. There appears to be
no single animal model that encompasses all of these characteristics, but there are many that provide very similar
characteristics in one or more aspects of T2D in humans.
Use of the appropriate animal model based on these similarities can provide much needed data on pathophysiological mechanisms operative in human T2D.
Key Words: animal models; felines; glucose; insulin; primates; rodents; swine
Rationale for Use of Animal Models for
Diabetes Mellitus
T
he two major forms of diabetes are type 1 (formerly
termed juvenile-onset diabetes) and type 2 (formerly
termed adult-onset diabetes). Type 2 diabetes (T2D1) is
the most common form, which represents more than 90% of
William T. Cefalu, M.D., is Professor and Chief, Division of Nutrition and
Chronic Diseases, Pennington Biomedical Research Center, Louisiana
State University System, Baton Rouge, Louisiana.
1
Abbreviations used in this article: CHD, coronary heart disease; CVD,
cardiovascular disease; DCCT, Diabetes Control and Complications Trial;
GK rat, Goto-Katazaki rat; HIP rat, H-IAPP transgenic rat; IA, islet amyloidosis; IAPP, islet amyloid polypeptide; MHC, major histocompatibility
186
all cases. Regardless of the classification, the resulting
metabolic abnormalities that characterize diabetes contribute greatly to the clinical complications, and the major clinical strategy is aimed at restoring metabolic balance.
However, a major concern in testing potential and successful interventions in humans is that due to the natural history
of T2D, it takes years for the complications to develop.
Thus, it also takes years and is very costly to assess the
effect of interventions to modulate development of diabetes
or its complications. To address this concern, it is incredibly
valuable to develop and use representative animal models,
for which interventions can be assessed in much shorter
time spans. Animal models of T2D mellitus provide the
opportunity to investigate the pathophysiology as well as
evaluate potential strategies for treatment and prevention of
the disease and related complications. However, for an animal model to have relevance to the study of T2D in humans,
either the characteristics of the animal model should mirror
the pathophysiology and natural history of diabetes or the
model should develop complications of diabetes with an
etiology similar to that of the human condition. Although
there is no single animal model that encompasses all of
these characteristics, there are animal models in use that
mirror specific conditions as seen in humans and in this
context are extremely valuable.
To appreciate the value of a specific animal model for
human T2D, it is important to understand the natural history
of the human condition. The corresponding purpose of this
article is first, to provide a comprehensive overview of diabetes in humans and second, to compare and contrast the
relevant animal models. The discussion of the animal models begins with a description of diabetes in lower species,
and it concludes with relevant discussion of the value in
higher species such as the nonhuman primate. The value of
each animal model for the study of specific conditions in
humans is discussed in each section.
Economic Costs of Diabetes in Humans
The prevalence of diabetes is increasing worldwide, with an
approximate doubling of new cases predicted to occur by
complex; NSY mouse, Negoya-Shibata-Yasuda mouse; T1D, type 1 diabetes; T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study;
WHO, World Health Organization; ZDF rat, Zucker diabetic fatty rat.
ILAR Journal
the year 2025 (Zimmet et al. 2001). Many factors contribute
to this growing epidemic including the alarming increase in
obesity, sedentary lifestyles, and an aging population. The
major concern with diabetes clearly relates to the morbidity
and mortality resulting from complications of the disease.
Primarily, the complications of diabetes have been classified as microvascular (i.e., retinopathy, nephropathy, and
neuropathy) and macrovascular (i.e., cardiovascular disease). The economic costs of caring for individuals who
have diabetes and related complications are staggering. In
the year 2002, it was estimated that direct medical and
indirect expenditures attributable to diabetes were 132 billion US dollars (Hogan et al. 2003). Direct medical expenditures alone totaled 91.8 billion US dollars and comprised
23.2 billion US dollars for diabetes care, 24.6 billion US
dollars for chronic complications attributable to diabetes,
and 44.1 billion US dollars for excess prevalence of general
medical conditions. Inpatient days (43.9%), nursing home
care (15.1%), and office visits (10.9%) constituted the major
expenditure groups by service settings. In addition, 51.8%
of direct medical expenditures were incurred by people
>65 yr old. Thus, with the increasing number of new cases
of diabetes combined with the cost of caring for the disease,
new strategies are direly needed to address this global
problem.
Classification and Pathophysiology of
Diabetes Mellitus
Type 1 Diabetes
Type 1 diabetes (T1D1) represents approximately 10% of all
cases of diabetes and develops secondary to autoimmune
destruction of the insulin-producing ␤-cells of the pancreas
(Mathis et al. 2001). Because insulin is a major regulatory
hormone for both glucose and lipid metabolism, it was not
unusual in the past for individuals with T1D to present
initially in a decompensated metabolic state, or ketoacidosis. Due to the pathophysiology, insulin therapy is indicated
at the onset of this disease. It is also recognized that development of T1D involves several years of a “prediabetic”
state associated with gradual worsening in glucose regulation. There is also evidence that T1D is associated with
other common autoimmune diseases such as thyroid disease, celiac disease, and Addison’s disease (Barker 2006).
These diseases can occur together in defined syndromes
with distinct pathophysiology and characteristics, and they
are referred to as autoimmune polyendocrine syndrome I,
autoimmune polyendocrine syndrome II, and the immunodysregulation-polyendocrinopathy-enteropathy-X-linked
syndrome (Barker 2006). Genetic risk for these conditions
overlaps and includes genes within the major histocompatibility complex (MHC1) such as the human leukocyte antigens DR and DQ alleles and the major histocompatibility
complex I-related gene A (MIC-A). Other genes outside the
MHC have been associated with these autoimmune diseases
and include the gene encoding the lymphoid tyrosine phosVolume 47, Number 3
2006
phatase (PTPN22) and the cytotoxic T lymphocyteassociated antigen-4 (CTLA-4) gene (Barker 2006). Thus, it
appears that genetic risk for T1D overlaps with other autoimmune disorders and that disease risk is associated with
organ-specific autoantibodies, which can be used to screen
subjects with T1D (Barker 2006).
Type 2 Diabetes
Unlike T1D, T2D can be associated with elevated, normal, or low insulin levels, depending on the stage at which
the levels are measured. T2D is recognized as a progressive
disorder, which is associated with diminishing pancreatic
function over time. Recognition of the phase is important in
the clinical management of the disorder because depending
on the stage, effective control may require lifestyle modification, oral agent therapy, oral agents combined with insulin, or insulin alone. T2D is clearly associated with other
associated risk factors that have been described as defining
a specific syndrome (e.g., “syndrome X,” “metabolic syndrome”). These syndromes have described the human condition as characterized by the presence of coexisting
traditional risk factors for cardiovascular disease (CVD1)
such as hypertension, dyslipidemia, glucose intolerance,
obesity, and insulin resistance in addition to nontraditional
CVD risk factors such as inflammatory processes and abnormalities of the blood coagulation system (DeFronzo
1992; Haffner 1996; Isomaa et al. 2001; Liese et al. 1998;
Reaven 1988). Although the etiology for the development
of metabolic syndrome is not specifically known, it is well
established that obesity and insulin resistance are generally
present. Insulin resistance, defined as a clinical state in
which a normal or elevated insulin level produces an inadequate biological response, is considered to be a hallmark
for the presence of metabolic syndrome and T2D (Hunter
and Garvey 1998). Insulin resistance can be secondary to
rare conditions such as abnormal insulin molecules or circulating insulin antagonists (e.g., glucocorticoids, growth
hormone, anti-insulin antibodies), or even secondary to genetic syndromes such as the muscular dystrophies (Hunter
and Garvey 1998). However, the insulin resistance considered to be part of the metabolic syndrome and T2D essentially represents a skeletal muscle defect in insulin action
and accounts for the overwhelming majority of cases of
insulin resistance reported for the human condition (DeFronzo 1992; Haffner 1996; Hunter and Garvey 1998; Isomaa et al. 2001; Liese et al. 1998; Reaven 1988). The
cellular mechanisms that contribute to insulin resistance are
not fully understood.
The presence of metabolic syndrome and T2D contributes greatly to increased morbidity and mortality in humans
on several levels. As discussed below, chronic hyperglycemia results in the development of microvascular complications. It is recognized that T2D is associated with a
significant period of prediabetes characterized by the presence of insulin resistance. It is at this time that cardiovascular disease appears to begin, as shown in Figure 1. It is
187
now well accepted that the presence of insulin resistance in
an individual must be compensated by hyperinsulinemia to
maintain normal glucose tolerance (Buchanan 2003; Kahn
2000). It has also been observed that in those individuals
who develop diabetes, a progressive loss of the insulin secretory capacity of ␤-cells appears to begin years before the
clinical diagnosis of diabetes (Buchanaan 2003; Weyer et al.
1999, 2001). The pancreatic dysfunction fails to compensate
for the insulin resistance and results in a state of relative
“insulin deficiency” leading to hyperglycemia. It is at this
stage that impaired glucose tolerance and impaired fasting
glucose may be present (Cefalu 2000). With worsening islet
dysfunction and the inability to compensate fully for the
degree of insulin resistance, clinically overt T2D develops
(Buchanaan 2003; Weyer et al. 1999, 2001).
The concept described above was well appreciated in a
study designed to evaluate the natural history of T2D in the
Pima Indians. In this study, subjects who did not develop
diabetes, when followed over time, were able to secrete
enough insulin to compensate for any given degree of insulin resistance and thereby maintain carbohydrate tolerance and avoid diabetes (Weyer et al. 1999). Essentially,
individuals who were able to compensate for the increased
insulin resistance with a higher insulin response maintained
a euglycemic and nondiabetic state. Therefore, individuals
who are observed to develop clinical diabetes, at any given
level of insulin resistance, may be described as having an
insulin response that does not fully or adequately compensate to maintain euglycemia (Kahn et al. 1993; Weyer et al.
1999). Thus, the presence of metabolic syndrome and the
associated insulin resistance are prominently involved in the
natural history of T2D (Figure 1).
Another major reason that T2D contributes to increased
morbidity and mortality in humans is the association with
CVD, which appears to begin long before the presence of
hyperglycemia and during the stage of prediabetes (i.e.,
metabolic syndrome). Coexisting cardiovascular risk factors
such as dyslipidemia, hypertension, inflammatory markers,
and coagulopathy are closely associated with the prediabetic
state as defined by obesity and insulin resistance (Cefalu
2000; Isomaa et al. 2001; McLaughlin et al. 2004; Shirai
2004). Each risk factor, when considered alone, increases
CVD risk; but more importantly, in combination they provide an additive or even synergistic effect (Adult Treatment
Panel III 2001). For example, Lakka and colleagues (2002)
used definitions of metabolic syndrome based on criteria
established by the National Cholesterol Education Program
and the World Health Organization (WHO1) and evaluated
relative risk of death from coronary heart disease (CHD1)
during an 11-yr follow-up in 1209 middle-aged men. After
correcting for multiple factors, the presence of the metabolic
syndrome resulted in a 2.5- to 4-fold increase in relative risk
for CVD death regardless of what criteria for metabolic
syndrome were used (Figure 2). With the understanding that
metabolic syndrome may precede the development of diabetes by many years, the presence of this condition may
partially explain the increase in CVD risk observed years
before the diagnosis of diabetes, as outlined schematically
in Figure 3. Specifically, Hu and coworkers (2002) reported
that the relative risk for CVD was significantly increased
beginning as early as 15 yr before the diagnosis of diabetes,
and the CVD risk increased significantly in the years closer
to the actual time the clinical diagnosis of diabetes was
made (Figure 3).
Thus, given the CVD significance of insulin resistance
and metabolic syndrome, the fact that metabolic syndrome
may be three to four times as common as diabetes, and the
observation that obesity and other components of metabolic
syndrome (i.e., dyslipidemia and diabetes) have become
global health epidemics, these co-existing disorders repre-
Figure 1 Natural history of type 2 diabetes, reflecting the importance of metabolic syndrome in the genesis of the disease. The shaded area
signifies the presence of the metabolic syndrome. Copyright © 2000 from Insulin resistance, by Cefalu WT. In: Leahy J, Clark N, Cefalu
WT, eds. The Medical Management of Diabetes Mellitus. New York: Marcel Dekker, Inc. p 57-75. Reproduced by permission of
Routledge/Taylor & Francis Group, LLC.
188
ILAR Journal
Figure 2 Relative risk of death from congenital heart disease
(CHD) for metabolic syndrome during 11-yr follow-up of 1209
middle-aged men. WHO, World Health Organization; WHR,
waist:hip ratio; BMI, body mass index; LDL, low-density lipoprotein; NCEP, National Cholesterol Education Program; SES, socioeconomic status. Adapted from data in the text and Table 3 of
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo
E, Tuomilehto J, Salonen JT. 2002. The metabolic syndrome and
total and cardiovascular disease mortality in middle-aged men.
JAMA 288:2709-2716.
sent a serious public health concern. It is currently estimated
that approximately 7 to 8% of the population in the United
States suffers from the complications of T2D, and it has
been estimated that approximately 40% are obese and may
have the metabolic syndrome (CDC 2003; Ford et al. 2002;
Mokdad et al. 2003). Minority ethnic groups are at even
greater risk. Therefore, it is not surprising that the World
Health Organization has listed these conditions as primary
global health problems in Western cultures (WHO 2000),
and in some reports (e.g., Evans et al. 2004) these conditions
are described as the most dangerous diseases in the world.
Development of Complications in Diabetes
Regardless of the classification, the presence of a chronically elevated blood glucose level is implicated in the com-
plications of diabetes, whether due to T1D or T2D. For this
reason, the primary goal of therapy is to reduce hyperglycemia. The benefits of glycemic control in patients with
diabetes have been well documented inasmuch as the results
from major trials have demonstrated conclusively that glycemic control can prevent or delay the progression of diabetic microvascular complications such as retinopathy,
nephropathy, and neuropathy. These findings were initially
reported for patients with T1D, comparing intensive insulin
therapy with conventional insulin dosing in the Diabetes
Control and Complications Trial (DCCT1) (DCCT Research
Group 1993; Reichard et al. 1993). However, these observations also have been shown to apply to patients with T2D,
as documented by the UK Prospective Diabetes Study
(UKPDS1) Group (UKPDS 1998) and others (Ohkubo et al.
1995). Additional evidence from the landmark study in T2D
(i.e., the UKPDS) suggests that the risk of complications
may be decreased further if glycated hemoglobin is reduced
below levels currently accepted as clinical goals (e.g., 7%)
(Stratton et al. 2000).
Although the DCCT and UKPDS proved conclusively
that glucose control reduces microvascular complications,
there is evidence that glycemic control may also reduce
cardiovascular disease. In support of this possibility, the
EPIC-Norfolk trial demonstrated that a reduced glycated
hemoglobin level is associated with a lower rate of cardiovascular disease, even in nondiabetic subjects (Khaw et al.
2001). The most conclusive evidence, however, has been
reported from results of the follow-up study of patients with
T1D in the DCCT, the observational Epidemiology of Diabetes Interventions and Complications study (Nathan et al.
2005). During the mean 17 yr of follow-up, intensive treatment reduced the risk of any cardiovascular disease event
by 42%, and the risk of nonfatal myocardial infarction,
stroke, or death from cardiovascular disease by 57%. The
decrease in glycosylated hemoglobin values during the
DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. The favorable findings of these studies have
prompted suggestions for lowered glycemic goals as assessed with the “gold standard” test, the A1c. To achieve
optimal glycemic control, the use of insulin in a more intensive physiological replacement regimen, in addition to
the use of insulin earlier in the course of management for
patients with T2D, has gained considerable support.
Animal Models of Diabetes
Rodent Models
Figure 3 Relative risk of myocardial infarction (MI) or stroke in
prediabetes. Modified from Figures 1 and 2 of Hu FB, Stampfer
MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. 2002.
Elevated risk of cardiovascular disease prior to clinical diagnosis
of type 2 diabetes. Diabetes Care 25:1129-1134. Modified printing
with permission from The American Diabetes Association.
Volume 47, Number 3
2006
Mouse Models
In the next article in this issue, Neubauer and Kulkarni
(2006) elegantly outline the benefit of creating and studying
animal models that mimic the human disease. Because
many of the mouse models have characteristics similar to
189
those of the human condition, mouse models provide a
unique opportunity to study the onset, development, and
course of the disease as well as a unique opportunity to
study the molecular mechanisms that lead to diabetes. The
advantages of mouse models include a complete knowledge
of the genome, ease of genetic manipulation, a relatively
short breeding span, and access to physiological and invasive testing.
The use of mouse models has included the study of mice
with naturally occurring mutations, inbred mouse models,
genetically engineered mouse models, global and tissuespecific knockouts, and transgenics. Details of the genetically engineered and knockout models are outlined in detail
by Neubauer and Kulkarni (2006). However, mice with
naturally occurring mutations have been used for years by
researchers to study diabetes and obesity (Leiter and Reifsnyder 2004; Loskutoff et al. 2000). Based on the pathophysiology of T1D, a mouse model that develops ␤-cell
destruction secondary to autoimmunity would be invaluable. Although it appears that there is no single mouse
model for which all of the characteristics of T1D are present, the nonobese diabetic (NOD) mouse, which develops
diabetes spontaneously, has been used as an model (Anderson and Bluestone 2005). Other attempts to create models of
T1D have used streptozotocin to impair pancreatic cell
function. The use of streptozotocin to achieve total destruction of the pancreatic ␤-cells can result in a phenotype that
resembles insulin-dependent T1D such that hyperglycemia
is present and may even require exogenous insulin. However, although the endpoint of ␤-cell destruction is similar
to T1D in humans, the mechanism responsible for the ␤-cell
destruction is not autoimmune, therefore the etiology for the
insulin deficiency differs greatly from the human condition.
Traditionally, however, these models are invaluable when
studying the mechanisms by which hyperglycemia may
contribute to microvascular complications such as neuropathy, nephropathy, and retinopathy (Obrosova et al. 2003,
2005; Wei et al. 2003).
For the study of T2D, a mouse model that develops
insulin resistance, obesity, and pancreatic dysfunction in
addition to developing cardiovascular disease would mirror
those conditions seen in the human condition. As in T1D,
there appears to be no single mouse model for T2D that
encompasses all conditions observed in the human condition. Yet, there appear to be very appropriate mouse models
relevant to the human disease (e.g., the ob/ob [obese] and
db/db [diabetes] mice). As outlined by Neubauer and
Kulkarni (2006), these models have mutations either in the
leptin gene (ob/ob) or in the leptin receptor (db/db), and the
mice develop severe obesity (Chung et al. 1996; Zhang et
al. 1994). The db/db mouse can be considered as having a
natural history that closely parallels that of humans. In humans, however, it is difficult to separate whether insulin
resistance precedes or is secondary to the development of
obesity. With the mouse models, it appears that the obesity
predisposes these mice to diabetes, and this evidence is
incredibly valuable when assessing the effect of obesity on
190
the development of diabetes. The db/db mouse becomes
hyperinsulinemic early in life (within 2 wk of age) and
develops obesity by 3 to 4 wk. The hyperglycemia becomes
manifest at age 4 to 8 wk following ␤-cell failure (Bates et
al. 2005). Thus, the sequence of events in this model appears to mimic human T2D. In the ob/ob model, hyperinsulinemia manifests at 3 to 4 wk of age together with
hyperphagia and insulin resistance.
Another similarity between the diabetic condition observed in humans and in mouse models is that the phenotype
of the mouse model also depends on the genetic background, sex, and age of the mice (Neubauer and Kulkarni
2006). Even though the genes affected are not specifically
known for the overwhelming majority of T2D in humans,
the strong familial association is well appreciated. This increased propensity to develop diabetes for a specific genetic
background is recognized in mouse models. For example, it
has been demonstrated that mice on the C57BL/6 background appear to be more susceptible to obesity and diabetes (Black et al. 1998). In contrast, mice on the DBA
background appear to manifest islet failure earlier than other
strains (Kulkarni et al. 2003). The benefit of knowing both
the clinical presentation and the genetic background makes
these animal models particularly attractive when assessing
and evaluating candidate genes postulated to contribute to
the disease state. As outlined by Neubauer and Kulkarni
(2006), selected inbreeding has yielded additional mouse
models that mimic the human condition. The KK mouse is
observed to have moderate obesity, hyperinsulinemia, and
hyperglycemia (Reddi and Camerini-Davalos 1988)
whereas the Nagoya-Shibata-Yasuda (NSY1) mouse has
been shown to develop diabetes in an age-dependent manner. Specifically, the NSY mouse develops diabetes at a
much slower rate with insulin resistance not manifesting
until after 12 wk of age (Ueda et al. 2000). As observed in
the human condition, dietary intake contributes to the disease state, and a high-fat diet and sucrose administration
appear to accelerate the development of the disease in these
mice. Impaired insulin secretion as well as impaired insulin
action, the major pathophysiological factors contributing to
diabetes in humans, also contribute to the phenotype for
these mice (Ikegami et al. 2004).
Despite the obvious advantages of using mouse models
compared with other species (e.g., much lower cost and
feasibility of conducting longitudinal studies using larger
numbers of animals), a significant limitation is that mouse
models of diabetes do not demonstrate the similarities for
islet pathology observed in humans with T2D. Diabetes
appears to develop in these models as a consequence of a
failure to adequately increase ␤-cell mass in response to
obesity-induced insulin resistance (Baetens et al. 1978; Shafrir et al. 1999). The cellular mechanism responsible for
failure of ␤-cell mass expansion is not specifically known
but has been postulated to be secondary to acquired metabolic abnormalities (i.e., gluco- and lipotoxicity) (Harmon
et al. 2001; Lee et al. 1994). The mouse models are observed to develop diabetes in relation to profound obesity
ILAR Journal
and do not display the same islet pathology as humans with
T2D (islet amyloid).
Thus, it appears that there is no mouse model that has all
of the characteristics of T2D in humans. However, it is
apparent that there are specific mouse models that mimic
several of the pathophysiological conditions seen in humans. For this reason, mouse models remain as a major
animal model for the study of T2D.
Rat Models
The Zucker diabetic fatty rat (ZDF1) is commonly used as a
model for the study of T2D. Like the db/db/ mouse model,
the ZDF rat harbors mutations on leptin receptors, becomes
obese, and presents with hyperglycemia within the first few
months of age (Chen et al. 1996; Kawasaki et al. 2005; Lee
et al. 1994; Phillips et al. 1996). Also similar to the mouse
models, the ZDF rat appears to develop diabetes because of
an inability to increase ␤-cell mass. The ZDF rat therefore
lacks sufficient insulin secretion required to compensate for
the insulin resistance as part of the obesity (Baetens et al.
1978; Finegood et al. 2001; Shafrir et al. 1999; Tomita et al.
1992). The mechanism that is responsible for the failure of
␤-cell mass expansion is not fully understood but as is postulated in mouse models, may be secondary to gluco- and
lipotoxicity (Harmon et al. 2001; Lee et al. 1994). The ZDF
rat does not display the same islet pathology as humans with
T2D (islet amyloid).
The Goto-Katazaki (GK1) rat is another model used for
the study of T2D. The GK rat is nonobese and has a decreased ␤-cell mass. Although the decreased ␤-cell mass is
noted at birth, it is believed to be secondary to defective
␤-cell proliferation (Movassat et al. 1997; Portha et al.
2001). The GK rat displays abnormalities characteristic of
human T2D in the presentation of liver and skeletal muscle
insulin resistance. Due to impaired insulin secretion, fasting
blood glucose levels appear to be only slightly increased
(Picarel-Blanchot et al. 1996). Therefore, although there are
similarities between the characteristics of the ZDF rat and
the human condition, the overwhelming majority of humans
with T2D do not have inadequate ␤-cell proliferation in
early life. Thus, this characteristic of the GK rat model is a
limitation as it relates to the human condition.
Other Rodent Models
In the fourth article in this issue, Shafir and colleagues
(2006) describe nutritionally induced diabetes in two species of desert rodents, specifically spiny mice (Acomys cahirinus) and the desert gerbil (Psammomys obesus). The
importance of these findings cannot be overstated given the
observation that the prevalence of T2D for humans is definitely related to lifestyle and caloric intake. Thus, these
models are of special interest when assessing the impact of
increased energy intake on the development of T2D.
Volume 47, Number 3
2006
Spiny Mice (A. cahirinus)
Spiny mice live in the arid areas of eastern Mediterranean
countries and in North Africa. Due to these living conditions, it would not be surprising for these animals to have
metabolic responses under their “normal” living conditions
that would be aimed at protecting the pancreas from overstimulation. However, when studied under various dietary
conditions, these animals demonstrate interesting metabolic
responses (see Shafrir et al. 2006). Specifically, when subjected to a high-energy diet, they gain weight markedly and
manifest glucose intolerance. In addition, their weight gain
is associated with ␤-cell hyperplasia and hypertrophy, and
they do not respond readily to stimulation of insulin secretion. The accompanying hyperglycemia and hyperinsulinemia are observed to be mild and intermittent.
Overnutrition in this animal model primarily affects ␤-cells
causing hypertrophy and proliferation with a propensity toward islet cell disintegration (Shafrir et al. 2006). It is clear
that this progression of events leading to diabetes differs
from ␤-cell apoptosis caused by excessive insulin secretion
pressure to compensate for the peripheral resistance. Thus,
this animal model represents another model of nutritional
diabetes development, even though it may not be totally
representative of the events in humans. Diabetes occurs only
in old animals, after spontaneous islet rupture that is accompanied by a loss of the rich insulin content.
Desert Gerbil (P. obesus)
The “sand rats” also discussed by Shafrir and colleagues
(2006) are another interesting model for the study of diabetes. As described, P. obesus is characterized by muscle
insulin resistance and the inability of insulin to activate the
insulin signaling on a high-energy diet. Insulin resistance
imposes a vicious cycle of hyperglycemia and compensatory hyperinsulinemia, which leads to ␤-cell failure and
increased secretion of proinsulin. On the surface, this series
of events appears to be similar to that seen in the human
condition, but the progression from one stage to the next is
still not clear. To better understand this model, Adler and
colleagues (1976) established a colony and identified three
main groups during the more than 20 yr of the colony’s
existence. Specifically, the groups were classified as
normoglycemic-normoinsulinemic, normoglycemic-hyperinsulinemic, and hyperglycemic-hyperinsulinemic. The proportion of animals among these groups remained stable and
predictable. In an experiment that lasted 1 yr during which
100 animals were removed at random from the colony, Kalderon and coworkers (1986) reported that approximately
32% of the animals were normoglycemic-normoinsulinemic
(Group A) and 26% were hyperinsulinemic but normoglycemic, with some gain in adipose tissue weight (Group B).
Group C was described as having hyperglycemia in the
presence of remarkable hyperinsulinemia. The very high
level of insulin secretion in this group of Psammomys failed
to promote peripheral glucose uptake, as determined by
191
2-deoxyglucose uptake. It also failed to restrain hepatic gluconeogenesis, as indicated by increased alanine conversion
to glucose by isolated hepatocytes and the elevated activity
of phosphoenolpyruvate carboxykinase (Shafrir and Ziv
1998). The presence of skeletal muscle insulin resistance
and the increase in hepatic glucose production are very
similar to the abnormalities observed in humans. The last
group (D) of Psammomys on a relatively high energy diet
was hyperglycemic and inulinopenic and comprised only
∼6% of the colony sample. All of these animals were lean,
and their low plasma insulin levels indicated an exhaustion
of insulin secretion.
Shafrir and coauthors (2006) stress that the distribution
in the colony described above does not necessarily represent
gradual stages of diabetes progression from stages A to D.
Some animals apparently lived for a long period of time as
stage B, whereas others directly lapsed from stage A to C.
Adler and colleagues (1988) also reported an inverted “U”
shape of the curve of plasma insulin levels, in correlation
with glucose levels. In these animals, a definite gradual and
irreversible shift occurs from hyperinsulinemia with obesity
to hypoinsulinemia with weight loss and fatal ketoacidosis.
An interesting observation in these animals, which is very
relevant to the human condition, is that the progression from
normoglycemia/normoinsulinemia to hyperglycemia/
hyperinsulinemia may be halted or reversed by reduction in
food intake. This attenuation in the development of insulin
resistance secondary to reduction in dietary intake mimics
the response in the human condition quite well. However,
the major limitation of this model compared with the human
condition is that the development of diabetes in this model
has been observed to be characterized by a gradual loss of
␤-cell mass due to increased ␤-cell apoptosis and decreased
␤-cell proliferation (Donath et al. 1999). Research has suggested that ␤-cell apoptosis in P. obesus is mediated by the
IL1␤/Nf/␬B pathway and does not contain amyloid deposits
characteristic of humans with T2D (Maedler et al. 2002).
Thus, P. obesus shares many of the clinical and metabolic
characteristics of T2D observed in humans such as the presence of insulin resistance, increased hepatic glucose production, and the ability to attenuate progression based on
reduction in energy intake. However, there appear to be
significant differences in etiology for ␤-cell failure in this
model compared with humans, which may limit the usefulness of this model for pancreatic pathology.
Transgenic Models for ␤-Cell Pathology
One of the limitations of the rodent models, as discussed, is
that the models of diabetes do not demonstrate the similarities for islet pathology observed in humans with T2D. The
fifth article in this issue (Matveyenko and Butler 2006)
provides a detailed discussion of islet amyloid polypeptide
(IAPP1) transgenic rodents. The rationale for developing
such models is clear when considering the natural history,
pathophysiology, and islet pathology in humans with T2D.
As described above, prediabetes in humans is clearly asso192
ciated in most cases with insulin resistance. However, as is
also discussed, compensatory insulin secretion is generally
observed in these states maintaining nearly normal glycemia. The progression to T2D then occurs in those individuals who are genetically predisposed to develop the
pancreatic dysfunction. In T2D, the pancreatic islets are
characterized by an approximately 70% decrease in the
number of insulin-secreting ␤-cells, increased ␤-cell apoptosis, and islet amyloid (Butler et al. 2003). The amyloid
found in the pancreatic islets in T2D has been reported to be
composed of extracellular fibrils of IAPP, a 37 amino acid
protein that is coexpressed and cosecreted by ␤-cells (Butler
et al. 1990). It appears that the sequence of IAPP displays
close homology in its amino and carboxy terminal residues.
However, between species, there appears to be variance for
residues 20 through 29 (see Matveyenko and Butler 2006).
It is also suggested that IAPP20-29 confers IAPP its amyloidogenic properties. This observation is important because
it appears that human, nonhuman primate, and feline IAPP
are amyloidogenic, but that rodent IAPP is not (Betsholtz et
al. 1989; Westermark et al. 1990). This distinction may
explain the observation that the spontaneous development
of T2D in humans, monkeys, and cats is characterized by
islet amyloid whereas this is not the case for rodents
(O’Brien et al. 1993).
Thus, despite the usefulness of rodent models as discussed above to study the role of increased food consumption on the development of obesity and diabetes, the finding
that rodents may not share the specific islet pathology seen
in other species may limit their usefulness. To overcome
these difficulties, transgenic rodent models for human IAPP
have been developed with the overall aim of investigating
the possible adverse effects of amyloidogenic IAPP on
␤-cell destruction. In this endeavor, the development of the
h-IAPP (HIP1) transgenic rat represents an exciting advance
(see Matveyenko and Butler 2006). The HIP rat is h-IAPP
transgenic on the Sprague-Dawley background (Butler et al.
2004). Homozygous HIP rats developed diabetes rapidly
within the first 2 mo of life, whereas hemizygous HIP rats
spontaneously developed mid-life diabetes (6-12 mo) associated with islet amyloid (Butler et al. 2004). The latter have
been studied in more detail. In these prospective studies, the
HIP rat develops islet pathology closely related to that in
humans (progressive loss of ␤-cell mass, islet amyloid, and
increased ␤-cell apoptosis), and these abnormalities appear
to precede the development of hyperglycemia (Butler et al.
2004). Once hyperglycemia develops in the HIP rat, ␤-cell
apoptosis increases further and is correlated with blood glucose concentration, implying glucose toxicity. The HIP rat
model will provide an opportunity to evaluate the progression of abnormalities in insulin secretion and action in relation to changes in ␤-cell mass.
Feline Models
Investigators have evaluated the development of diabetes in
the domestic cat in numerous studies, and the similarities to
ILAR Journal
the human condition are striking, as reviewed in detail by
Henson and O’Brien (2006) in this issue. First, as observed
in humans, more than 80% of cats with diabetes have clinical characteristics and abnormalities consistent with T2D,
and the typical onset for diabetes also appears to be in
middle age or later (Johnson et al. 1986; Panciera et al.
1990). Second, the domestic cat shares with humans the
same environment and has many of the same risk factors for
diabetes such as physical inactivity and obesity. Given that
lifestyle and dietary intake play such a major role in the
human condition, the relevance of this finding is noted because there is evidence that the incidence of diabetes in cats
is increasing for the same reasons it is increasing in humans
(Prahl et al. 2003). Third, T2D in cats, as in humans, appears to be associated with diseases, pharmacological
agents, and hormones that impair peripheral tissue insulin
sensitivity such as acromegaly or hyperadrenocorticism or
treatment with corticosteroids or progestins (Rand et al.
2004).
A central feature in the development of diabetes in humans is the presence of insulin resistance and obesity as
observed in the prediabetic state. The failure to compensate
for insulin resistance secondary to ␤-cell dysfunction and
loss dictates the progression to overt diabetes. It is now
apparent that the factors that contribute to insulin resistance
in humans (e.g., obesity) are similar to the corresponding
factors in cats. Diabetic cats are insulin resistant, and it has
been reported that insulin sensitivity values may be six-fold
lower than normal cats (Feldhahn et al. 1999). Similar to
data related to humans (Appleton et al. 2001; Fettman et al.
1998), significant weight gain in cats (∼44%) was reported
to result in a 52% decrease in insulin sensitivity, and
subsequent weight loss was shown to improve glucose
tolerance.
Thus, the clinical presentation for diabetes in cats appears to closely parallel that seen for human T2D. Furthermore, the most important characteristics noted in feline
diabetes that are similar to humans are the pancreatic pathology and physiology (e.g., islet amyloidosis and partial
loss of ␤-cells) (Johnson et al. 1986, 1989; O’Brien et al.
1985, 1986, 1993). As reported, islet amyloidosis (IA1) has
been detected in more than 90% of humans with T2D, and
it appears to occur in nearly all cases of spontaneous diabetes in cats (Johnson et al. 1986, 1989; O’Brien et al.
1993). The deposition of IA in diabetic cats is associated
with an approximately 50% loss of ␤-cell mass, which is
similar to findings in human T2D (Butler et al. 2003;
O’Brien et al. 1986). In addition to providing a model to
evaluate pancreatic mechanisms involved in diabetes as it
relates to humans, cats with diabetes appear to share many
similarities related to the complications of diabetes, particularly diabetic complications such as diabetic neuropathy and
retinopathy (Henson and O’Brien 2006).
Based on the data cited above, diabetes in cats resembles
human T2D mellitus in many respects including clinical and
physiological features of the disease. These features include
age of onset in middle age, association with obesity, reVolume 47, Number 3
2006
sidual insulin secretion, development of IA deposits, loss of
approximately 50% of ␤-cell mass, and development of
complications in several organ systems including peripheral
polyneuropathy and retinopathy. These characteristics of feline diabetes make the cat a very appropriate model when
evaluating the pathogenesis of human T2D.
Swine Models
The rationale for the appropriateness of swine as models for
human diabetes is based on several observations. Humans
and pigs appear to have very similar gastrointestinal structure and function, pancreas morphology, and overall metabolic status (Larsen and Rolin 2004). In addition, the
pharmacokinetic values after subcutaneous drug administration are similar for humans and pigs. As outlined in detail by
Bellinger and colleagues (2006) in this issue, many species
of pigs share several of the clinical characteristics of human
diabetes. For example, two lines of Yucatan minipigs with
altered glucose tolerance have been described. One is reported with impaired tolerance and the other with enhanced
tolerance (Phillips and Panepinto 1986; Phillips et al. 1982).
The impaired glucose tolerance was due to a decrease in
peripheral insulin concentration resulting from decreased
insulin secretion in response to a glucose challenge. The low
serum insulin levels in this line did not appear to be due to
impaired synthesis and storage of insulin but were consistent with a modified pancreatic receptor or postreceptor response as suggested by the finding that these pigs had
normal insulin release in response to isoproterenol challenge. In addition, the Göttingen minipig was suggested as
a valuable model for metabolic syndrome based on its response to a high-fat high-energy diet (Johansen et al. 2001).
For example, female Göttingen minipigs fed a high-fat
high-energy diet to induce obesity had increased body
weight and fat content. Although preprandial plasma glucose and insulin concentrations were not altered, insulin
response to intravenous glucose was increased (Johansen et
al. 2001). Male Göttingen minipigs fed a high-fat highenergy diet also became obese (had increased weight and
body fat) and had increased fasting blood glucose and insulin levels compared with normal-fed controls (Larsen et
al. 2001).
Although there appear to be spontaneous swine models
of T2D, the use of swine models has been very beneficial in
the specific studies of complications of streptozotocininduced diabetes mellitus, particularly for cardiovascular,
renal, and ophthalmic complications (Askari et al. 2002;
Gerrity et al. 2001; Hainsworth et al. 2002; Natarajan et al.
2002). One of the most important aspects of using pigs as a
model for the human condition is in the study of diabetic
vascular disease. These models allow investigators to define
the precise biochemical changes and mechanisms that initiate and perpetuate atherosclerotic lesion progression. In this
research, streptozotocin and alloxan have been used to create
insulin-deficient diabetes in pigs to create hyperglycemic
193
states. Insulin-deficient pigs are reported to develop more
severe coronary atherosclerosis than nondiabetic controls.
Pigs fed a high-fat high-cholesterol diet develop coronary,
aortic, iliac, and carotid atherosclerotic lesions in anatomical locations extremely relevant to the human condition.
Most importantly, these lesions recapitulate the histopathology seen in humans. For example, the swine models for
cardiovascular disease develop proliferative lesions that
consist of smooth muscle cells, macrophages, lymphocytes,
foam cells, calcification, fibrous caps, necrotic and apoptotic cells, plaque hemorrhage, and expanded extracellular
matrices (Brodala et al. 2005; Nichols et al. 1992; Prescott
et al. 1995, 1991). Based on the studies described above, it
appears that swine models are relevant animal models for
the study of cardiovascular complications and the contribution of metabolic abnormalities to the process.
Primate Models
Of all the animal models proposed, the abnormalities that
are observed for glucoregulation in primates, and particularly the clinical presentation, appear to correspond quite
well to those observed in humans. Spontaneous diabetes has
been reported in cynomolgus, rhesus, bonnet, Formosan
rock, pig-tailed, and celebes macaques, in addition to African green monkeys and baboons (Bodkin 2000; Clarkson et
al. 1985; Cromeens and Stephens 1985; de Koning et al.
1993; Hansen and Bodkin 1986; Howard 1986; O’Brien et
al. 1996; Ohagi et al. 1991; Tigno et al. 2004; Wagner et al.
1996; Yasuda et al. 1988). As has been observed for humans, the overwhelming majority of cases reported in primates represent T2D and are associated with both obesity
and increasing age (Wagner et al. 1996, 2001). These clinical observations that are similar to the human condition
have been noted for rhesus and cynomolgus monkeys and
for baboons (Banks et al. 2003, Cai et al. 2004; Hamilton
and Ciaccia 1978; Hotta et al. 2001; Wagner et al. 1996;
Stokes 1986). The most remarkable similarity may be in the
identification of the prediabetic phase, with the observation
of insulin resistance and compensatory hyperinsulinemia as
is well documented for the human condition (see Figure 1).
In primates, the natural history of diabetes includes a
period of insulin resistance, with compensatory hyperinsulinemia despite normal glucose tolerance. This period of
compensatory hyperinsulinemia is followed by continued
deterioration of insulin secretory capacity. As the disease
progresses, monkeys develop impaired glucose tolerance
with slight increases in fasting glucose levels before becoming overtly hyperglycemic due to a relative or absolute decrease in pancreatic insulin secretion. An important finding
that makes the primate model very relevant to the study of
human diseases is the observation of eventual pancreatic
exhaustion with replacement of normal islet architecture
with an islet-associated amyloid. Such phases for diabetes
progression have been reported for both cynomolgus and
rhesus monkeys (Bodkin 2000; Hansen and Bodkin 1986;
194
Tigno et al. 2004; Wagner et al. 1996, 2001). Much like the
human condition, glucose and triglyceride concentration
levels can be high for several years before requiring intervention. However, with continued insulin resistance and
further declining pancreatic reserves, there is generally a
sharp increase in glucose that prompts treatment to prevent
ketosis and acidosis (Wagner et al. 1996). Because obesity
and insulin resistance appear to be very prevalent in primate
models of T2D, it is not surprising that lifestyle interventions that appear to be effective in human studies appear to
be equally effective in primate studies. Specifically, reduction in energy intake (i.e., caloric restriction) can be very
effective in improving glucoregulation, most likely secondary to improved insulin sensitivity (Bodkin et al. 2003; Cefalu et al. 2004; Gresl et al. 2001; Wagner et al. 1996).
As discussed in this issue (Wagner et al. 2006) and
elsewhere in the literature (de Koning et al. 1993; O’Brien
et al. 1993, 1996; Wagner et al. 1996), one of the main
pathological findings in primates that appears very similar
to humans is that the major pancreatic lesion is islet amyloidosis. Specifically, this lesion has been reported for spontaneous cases of diabetes in Macaca mulatta, Macaca nigra,
Macaca nemestrina, Macaca fascicularis, and baboons
(Cromeens and Stephens 1985; de Koning et al. 1993; Howard 1986; Hubbard et al. 2002; O’Brien et al. 1996; Ohagi
et al. 1991). Islet amyloid is found in approximately 90% of
human T2DM. As with monkeys, the degree of islet mass
replaced by amyloid appears to correlate with increasing
insulin needs (Hoppener et al. 2000; Kahn et al. 1999). The
amyloid has since been shown to be immunoreactive for
IAPP and generally associated with a marked reduction in
insulin-immunoreactive ␤-cells, as reported for humans
with T2D (Kahn et al. 1999; Wagner et al. 2001).
One of the major advantages of using the primate model
as it relates to human health is the development of atherosclerosis (Clarkson 1998). As with swine models, nonhuman primates may be useful for determining mechanisms
whereby cardiovascular disease is increased with diabetes.
Monkeys with insulin resistance have dyslipidemia and increased inflammation similar to human diabetics. In addition, streptozotocin can be used to induce a hyperglycemic
state allowing studies that focus on interactions among lipids, oxidative stress, and atherogenesis and that likely explain a portion of the increased cardiovascular disease with
diabetes.
Summary
The incidence of T2D is increasing on a global level. The
major problems associated with diabetes relate to microand macrovascular complications, which contribute greatly
to the morbidity and mortality associated with the disease. It
is recognized that the development of such complications
and progression of the disease from prediabetic state to
overt diabetes take years. Assessment of interventions designed to delay or prevent complications or disease progresILAR Journal
sion in humans will also take years to accomplish. Such
protracted human clinical research trials can be very costly.
For these reasons, there is a well-defined need for appropriate animal models of T2D mellitus to better study both
the pathogenesis and potential therapeutic agents. However,
for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should
mirror the pathophysiology and natural history of diabetes
or the model should develop complications of diabetes with
an etiology similar to the human condition. It appears that
no single animal model encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of T2D in humans. Use of
the appropriate animal model based on these similarities can
provide much needed data on pathophysiological mechanisms operative in human T2D.
Acknowledgment
The author received no outside funding to prepare this
manuscript, nor are there any potential conflicts of information relevant to the contents of this manuscript.
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