Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological Relevance to the Human Condition
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological
Relevance to the Human Condition
William T. Cefalu
Abstract all cases. Regardless of the classification, the resulting
metabolic abnormalities that characterize diabetes contrib-
The prevalence of diabetes throughout the world has in- ute greatly to the clinical complications, and the major clini-
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
creased dramatically over the recent past, and the trend will cal strategy is aimed at restoring metabolic balance.
continue for the foreseeable future. One of the major con- However, a major concern in testing potential and success-
cerns associated with diabetes relates to the development of ful interventions in humans is that due to the natural history
micro- and macrovascular complications, which contribute of T2D, it takes years for the complications to develop.
greatly to the morbidity and mortality associated with the Thus, it also takes years and is very costly to assess the
disease. Progression of the disease from prediabetic state to effect of interventions to modulate development of diabetes
overt diabetes and the development of complications occur or its complications. To address this concern, it is incredibly
over many years. Assessment of interventions designed to valuable to develop and use representative animal models,
delay or prevent disease progression or complications in for which interventions can be assessed in much shorter
humans also takes years and requires tremendous resources. time spans. Animal models of T2D mellitus provide the
To better study both the pathogenesis and potential thera- opportunity to investigate the pathophysiology as well as
peutic agents, appropriate animal models of type 2 diabetes evaluate potential strategies for treatment and prevention of
(T2D) mellitus are needed. However, for an animal model the disease and related complications. However, for an ani-
to have relevance to the study of diabetes, either the char- mal model to have relevance to the study of T2D in humans,
acteristics of the animal model should mirror the patho- either the characteristics of the animal model should mirror
physiology and natural history of diabetes or the model the pathophysiology and natural history of diabetes or the
should develop complications of diabetes with an etiology model should develop complications of diabetes with an
similar to that of the human condition. There appears to be etiology similar to that of the human condition. Although
no single animal model that encompasses all of these char- there is no single animal model that encompasses all of
acteristics, but there are many that provide very similar these characteristics, there are animal models in use that
characteristics in one or more aspects of T2D in humans. mirror specific conditions as seen in humans and in this
Use of the appropriate animal model based on these simi- context are extremely valuable.
larities can provide much needed data on pathophysiologi- To appreciate the value of a specific animal model for
cal mechanisms operative in human T2D. human T2D, it is important to understand the natural history
of the human condition. The corresponding purpose of this
Key Words: animal models; felines; glucose; insulin; pri- article is first, to provide a comprehensive overview of dia-
mates; rodents; swine betes in humans and second, to compare and contrast the
relevant animal models. The discussion of the animal mod-
els begins with a description of diabetes in lower species,
Rationale for Use of Animal Models for and it concludes with relevant discussion of the value in
Diabetes Mellitus higher species such as the nonhuman primate. The value of
each animal model for the study of specific conditions in
T
he two major forms of diabetes are type 1 (formerly humans is discussed in each section.
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
Economic Costs of Diabetes in Humans
The prevalence of diabetes is increasing worldwide, with an
William T. Cefalu, M.D., is Professor and Chief, Division of Nutrition and
Chronic Diseases, Pennington Biomedical Research Center, Louisiana approximate doubling of new cases predicted to occur by
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; complex; NSY mouse, Negoya-Shibata-Yasuda mouse; T1D, type 1 dia-
GK rat, Goto-Katazaki rat; HIP rat, H-IAPP transgenic rat; IA, islet am- betes; T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study;
yloidosis; IAPP, islet amyloid polypeptide; MHC, major histocompatibility WHO, World Health Organization; ZDF rat, Zucker diabetic fatty rat.
186 ILAR Journalthe year 2025 (Zimmet et al. 2001). Many factors contribute phatase (PTPN22) and the cytotoxic T lymphocyte-
to this growing epidemic including the alarming increase in associated antigen-4 (CTLA-4) gene (Barker 2006). Thus, it
obesity, sedentary lifestyles, and an aging population. The appears that genetic risk for T1D overlaps with other auto-
major concern with diabetes clearly relates to the morbidity immune disorders and that disease risk is associated with
and mortality resulting from complications of the disease. organ-specific autoantibodies, which can be used to screen
Primarily, the complications of diabetes have been classi- subjects with T1D (Barker 2006).
fied as microvascular (i.e., retinopathy, nephropathy, and
neuropathy) and macrovascular (i.e., cardiovascular dis- Type 2 Diabetes
ease). The economic costs of caring for individuals who
have diabetes and related complications are staggering. In Unlike T1D, T2D can be associated with elevated, nor-
the year 2002, it was estimated that direct medical and mal, or low insulin levels, depending on the stage at which
indirect expenditures attributable to diabetes were 132 bil- the levels are measured. T2D is recognized as a progressive
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
lion US dollars (Hogan et al. 2003). Direct medical expen- disorder, which is associated with diminishing pancreatic
ditures alone totaled 91.8 billion US dollars and comprised function over time. Recognition of the phase is important in
23.2 billion US dollars for diabetes care, 24.6 billion US the clinical management of the disorder because depending
dollars for chronic complications attributable to diabetes, on the stage, effective control may require lifestyle modi-
and 44.1 billion US dollars for excess prevalence of general fication, oral agent therapy, oral agents combined with in-
medical conditions. Inpatient days (43.9%), nursing home sulin, or insulin alone. T2D is clearly associated with other
care (15.1%), and office visits (10.9%) constituted the major associated risk factors that have been described as defining
expenditure groups by service settings. In addition, 51.8% a specific syndrome (e.g., “syndrome X,” “metabolic syn-
of direct medical expenditures were incurred by people drome”). These syndromes have described the human con-
>65 yr old. Thus, with the increasing number of new cases dition as characterized by the presence of coexisting
of diabetes combined with the cost of caring for the disease, traditional risk factors for cardiovascular disease (CVD1)
new strategies are direly needed to address this global such as hypertension, dyslipidemia, glucose intolerance,
problem. obesity, and insulin resistance in addition to nontraditional
CVD risk factors such as inflammatory processes and ab-
Classification and Pathophysiology of normalities of the blood coagulation system (DeFronzo
Diabetes Mellitus 1992; Haffner 1996; Isomaa et al. 2001; Liese et al. 1998;
Reaven 1988). Although the etiology for the development
Type 1 Diabetes of metabolic syndrome is not specifically known, it is well
established that obesity and insulin resistance are generally
Type 1 diabetes (T1D1) represents approximately 10% of all present. Insulin resistance, defined as a clinical state in
cases of diabetes and develops secondary to autoimmune which a normal or elevated insulin level produces an inad-
destruction of the insulin-producing -cells of the pancreas equate biological response, is considered to be a hallmark
(Mathis et al. 2001). Because insulin is a major regulatory for the presence of metabolic syndrome and T2D (Hunter
hormone for both glucose and lipid metabolism, it was not and Garvey 1998). Insulin resistance can be secondary to
unusual in the past for individuals with T1D to present rare conditions such as abnormal insulin molecules or cir-
initially in a decompensated metabolic state, or ketoacido- culating insulin antagonists (e.g., glucocorticoids, growth
sis. Due to the pathophysiology, insulin therapy is indicated hormone, anti-insulin antibodies), or even secondary to ge-
at the onset of this disease. It is also recognized that devel- netic syndromes such as the muscular dystrophies (Hunter
opment of T1D involves several years of a “prediabetic” and Garvey 1998). However, the insulin resistance consid-
state associated with gradual worsening in glucose regula- ered to be part of the metabolic syndrome and T2D essen-
tion. There is also evidence that T1D is associated with tially represents a skeletal muscle defect in insulin action
other common autoimmune diseases such as thyroid dis- and accounts for the overwhelming majority of cases of
ease, celiac disease, and Addison’s disease (Barker 2006). insulin resistance reported for the human condition (De-
These diseases can occur together in defined syndromes Fronzo 1992; Haffner 1996; Hunter and Garvey 1998; Iso-
with distinct pathophysiology and characteristics, and they maa et al. 2001; Liese et al. 1998; Reaven 1988). The
are referred to as autoimmune polyendocrine syndrome I, cellular mechanisms that contribute to insulin resistance are
autoimmune polyendocrine syndrome II, and the immuno- not fully understood.
dysregulation-polyendocrinopathy-enteropathy-X-linked The presence of metabolic syndrome and T2D contrib-
syndrome (Barker 2006). Genetic risk for these conditions utes greatly to increased morbidity and mortality in humans
overlaps and includes genes within the major histocompat- on several levels. As discussed below, chronic hyperglyce-
ibility complex (MHC1) such as the human leukocyte anti- mia results in the development of microvascular complica-
gens DR and DQ alleles and the major histocompatibility tions. It is recognized that T2D is associated with a
complex I-related gene A (MIC-A). Other genes outside the significant period of prediabetes characterized by the pres-
MHC have been associated with these autoimmune diseases ence of insulin resistance. It is at this time that cardiovas-
and include the gene encoding the lymphoid tyrosine phos- cular disease appears to begin, as shown in Figure 1. It is
Volume 47, Number 3 2006 187now well accepted that the presence of insulin resistance in hyperglycemia and during the stage of prediabetes (i.e.,
an individual must be compensated by hyperinsulinemia to metabolic syndrome). Coexisting cardiovascular risk factors
maintain normal glucose tolerance (Buchanan 2003; Kahn such as dyslipidemia, hypertension, inflammatory markers,
2000). It has also been observed that in those individuals and coagulopathy are closely associated with the prediabetic
who develop diabetes, a progressive loss of the insulin se- state as defined by obesity and insulin resistance (Cefalu
cretory capacity of -cells appears to begin years before the 2000; Isomaa et al. 2001; McLaughlin et al. 2004; Shirai
clinical diagnosis of diabetes (Buchanaan 2003; Weyer et al. 2004). Each risk factor, when considered alone, increases
1999, 2001). The pancreatic dysfunction fails to compensate CVD risk; but more importantly, in combination they pro-
for the insulin resistance and results in a state of relative vide an additive or even synergistic effect (Adult Treatment
“insulin deficiency” leading to hyperglycemia. It is at this Panel III 2001). For example, Lakka and colleagues (2002)
stage that impaired glucose tolerance and impaired fasting used definitions of metabolic syndrome based on criteria
glucose may be present (Cefalu 2000). With worsening islet established by the National Cholesterol Education Program
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
dysfunction and the inability to compensate fully for the and the World Health Organization (WHO1) and evaluated
degree of insulin resistance, clinically overt T2D develops relative risk of death from coronary heart disease (CHD1)
(Buchanaan 2003; Weyer et al. 1999, 2001). during an 11-yr follow-up in 1209 middle-aged men. After
The concept described above was well appreciated in a correcting for multiple factors, the presence of the metabolic
study designed to evaluate the natural history of T2D in the syndrome resulted in a 2.5- to 4-fold increase in relative risk
Pima Indians. In this study, subjects who did not develop for CVD death regardless of what criteria for metabolic
diabetes, when followed over time, were able to secrete syndrome were used (Figure 2). With the understanding that
enough insulin to compensate for any given degree of in- metabolic syndrome may precede the development of dia-
sulin resistance and thereby maintain carbohydrate toler- betes by many years, the presence of this condition may
ance and avoid diabetes (Weyer et al. 1999). Essentially, partially explain the increase in CVD risk observed years
individuals who were able to compensate for the increased before the diagnosis of diabetes, as outlined schematically
insulin resistance with a higher insulin response maintained in Figure 3. Specifically, Hu and coworkers (2002) reported
a euglycemic and nondiabetic state. Therefore, individuals that the relative risk for CVD was significantly increased
who are observed to develop clinical diabetes, at any given beginning as early as 15 yr before the diagnosis of diabetes,
level of insulin resistance, may be described as having an and the CVD risk increased significantly in the years closer
insulin response that does not fully or adequately compen- to the actual time the clinical diagnosis of diabetes was
sate to maintain euglycemia (Kahn et al. 1993; Weyer et al. made (Figure 3).
1999). Thus, the presence of metabolic syndrome and the Thus, given the CVD significance of insulin resistance
associated insulin resistance are prominently involved in the and metabolic syndrome, the fact that metabolic syndrome
natural history of T2D (Figure 1). may be three to four times as common as diabetes, and the
Another major reason that T2D contributes to increased observation that obesity and other components of metabolic
morbidity and mortality in humans is the association with syndrome (i.e., dyslipidemia and diabetes) have become
CVD, which appears to begin long before the presence of 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 Journalplications of diabetes, whether due to T1D or T2D. For this
reason, the primary goal of therapy is to reduce hypergly-
cemia. The benefits of glycemic control in patients with
diabetes have been well documented inasmuch as the results
from major trials have demonstrated conclusively that gly-
cemic control can prevent or delay the progression of dia-
betic 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 obser-
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
Figure 2 Relative risk of death from congenital heart disease vations also have been shown to apply to patients with T2D,
(CHD) for metabolic syndrome during 11-yr follow-up of 1209
as documented by the UK Prospective Diabetes Study
middle-aged men. WHO, World Health Organization; WHR,
(UKPDS1) Group (UKPDS 1998) and others (Ohkubo et al.
waist:hip ratio; BMI, body mass index; LDL, low-density lipopro-
tein; NCEP, National Cholesterol Education Program; SES, socio- 1995). Additional evidence from the landmark study in T2D
economic status. Adapted from data in the text and Table 3 of (i.e., the UKPDS) suggests that the risk of complications
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo may be decreased further if glycated hemoglobin is reduced
E, Tuomilehto J, Salonen JT. 2002. The metabolic syndrome and below levels currently accepted as clinical goals (e.g., 7%)
total and cardiovascular disease mortality in middle-aged men. (Stratton et al. 2000).
JAMA 288:2709-2716. Although the DCCT and UKPDS proved conclusively
that glucose control reduces microvascular complications,
sent a serious public health concern. It is currently estimated there is evidence that glycemic control may also reduce
that approximately 7 to 8% of the population in the United cardiovascular disease. In support of this possibility, the
States suffers from the complications of T2D, and it has EPIC-Norfolk trial demonstrated that a reduced glycated
been estimated that approximately 40% are obese and may hemoglobin level is associated with a lower rate of cardio-
have the metabolic syndrome (CDC 2003; Ford et al. 2002; vascular disease, even in nondiabetic subjects (Khaw et al.
Mokdad et al. 2003). Minority ethnic groups are at even 2001). The most conclusive evidence, however, has been
greater risk. Therefore, it is not surprising that the World reported from results of the follow-up study of patients with
Health Organization has listed these conditions as primary T1D in the DCCT, the observational Epidemiology of Dia-
global health problems in Western cultures (WHO 2000), betes Interventions and Complications study (Nathan et al.
and in some reports (e.g., Evans et al. 2004) these conditions 2005). During the mean 17 yr of follow-up, intensive treat-
are described as the most dangerous diseases in the world. ment 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
Development of Complications in Diabetes decrease in glycosylated hemoglobin values during the
DCCT was significantly associated with most of the posi-
Regardless of the classification, the presence of a chroni-
tive effects of intensive treatment on the risk of cardiovas-
cally elevated blood glucose level is implicated in the com-
cular disease. The favorable findings of these studies have
prompted suggestions for lowered glycemic goals as as-
sessed with the “gold standard” test, the A1c. To achieve
optimal glycemic control, the use of insulin in a more in-
tensive 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
Mouse Models
prediabetes. Modified from Figures 1 and 2 of Hu FB, Stampfer
MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. 2002. In the next article in this issue, Neubauer and Kulkarni
Elevated risk of cardiovascular disease prior to clinical diagnosis (2006) elegantly outline the benefit of creating and studying
of type 2 diabetes. Diabetes Care 25:1129-1134. Modified printing animal models that mimic the human disease. Because
with permission from The American Diabetes Association. many of the mouse models have characteristics similar to
Volume 47, Number 3 2006 189those of the human condition, mouse models provide a the development of diabetes. The db/db mouse becomes
unique opportunity to study the onset, development, and hyperinsulinemic early in life (within 2 wk of age) and
course of the disease as well as a unique opportunity to develops obesity by 3 to 4 wk. The hyperglycemia becomes
study the molecular mechanisms that lead to diabetes. The manifest at age 4 to 8 wk following -cell failure (Bates et
advantages of mouse models include a complete knowledge al. 2005). Thus, the sequence of events in this model ap-
of the genome, ease of genetic manipulation, a relatively pears to mimic human T2D. In the ob/ob model, hyperin-
short breeding span, and access to physiological and inva- sulinemia manifests at 3 to 4 wk of age together with
sive testing. hyperphagia and insulin resistance.
The use of mouse models has included the study of mice Another similarity between the diabetic condition ob-
with naturally occurring mutations, inbred mouse models, served in humans and in mouse models is that the phenotype
genetically engineered mouse models, global and tissue- of the mouse model also depends on the genetic back-
specific knockouts, and transgenics. Details of the geneti- ground, sex, and age of the mice (Neubauer and Kulkarni
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
cally engineered and knockout models are outlined in detail 2006). Even though the genes affected are not specifically
by Neubauer and Kulkarni (2006). However, mice with known for the overwhelming majority of T2D in humans,
naturally occurring mutations have been used for years by the strong familial association is well appreciated. This in-
researchers to study diabetes and obesity (Leiter and Reif- creased propensity to develop diabetes for a specific genetic
snyder 2004; Loskutoff et al. 2000). Based on the patho- background is recognized in mouse models. For example, it
physiology of T1D, a mouse model that develops -cell has been demonstrated that mice on the C57BL/6 back-
destruction secondary to autoimmunity would be invalu- ground appear to be more susceptible to obesity and diabe-
able. Although it appears that there is no single mouse tes (Black et al. 1998). In contrast, mice on the DBA
model for which all of the characteristics of T1D are pres- background appear to manifest islet failure earlier than other
ent, the nonobese diabetic (NOD) mouse, which develops strains (Kulkarni et al. 2003). The benefit of knowing both
diabetes spontaneously, has been used as an model (Ander- the clinical presentation and the genetic background makes
son and Bluestone 2005). Other attempts to create models of these animal models particularly attractive when assessing
T1D have used streptozotocin to impair pancreatic cell and evaluating candidate genes postulated to contribute to
function. The use of streptozotocin to achieve total destruc- the disease state. As outlined by Neubauer and Kulkarni
tion of the pancreatic -cells can result in a phenotype that (2006), selected inbreeding has yielded additional mouse
resembles insulin-dependent T1D such that hyperglycemia models that mimic the human condition. The KK mouse is
is present and may even require exogenous insulin. How- observed to have moderate obesity, hyperinsulinemia, and
ever, although the endpoint of -cell destruction is similar hyperglycemia (Reddi and Camerini-Davalos 1988)
to T1D in humans, the mechanism responsible for the -cell whereas the Nagoya-Shibata-Yasuda (NSY1) mouse has
destruction is not autoimmune, therefore the etiology for the been shown to develop diabetes in an age-dependent man-
insulin deficiency differs greatly from the human condition. ner. Specifically, the NSY mouse develops diabetes at a
Traditionally, however, these models are invaluable when much slower rate with insulin resistance not manifesting
studying the mechanisms by which hyperglycemia may until after 12 wk of age (Ueda et al. 2000). As observed in
contribute to microvascular complications such as neurop- the human condition, dietary intake contributes to the dis-
athy, nephropathy, and retinopathy (Obrosova et al. 2003, ease state, and a high-fat diet and sucrose administration
2005; Wei et al. 2003). appear to accelerate the development of the disease in these
For the study of T2D, a mouse model that develops mice. Impaired insulin secretion as well as impaired insulin
insulin resistance, obesity, and pancreatic dysfunction in action, the major pathophysiological factors contributing to
addition to developing cardiovascular disease would mirror diabetes in humans, also contribute to the phenotype for
those conditions seen in the human condition. As in T1D, these mice (Ikegami et al. 2004).
there appears to be no single mouse model for T2D that Despite the obvious advantages of using mouse models
encompasses all conditions observed in the human condi- compared with other species (e.g., much lower cost and
tion. Yet, there appear to be very appropriate mouse models feasibility of conducting longitudinal studies using larger
relevant to the human disease (e.g., the ob/ob [obese] and numbers of animals), a significant limitation is that mouse
db/db [diabetes] mice). As outlined by Neubauer and models of diabetes do not demonstrate the similarities for
Kulkarni (2006), these models have mutations either in the islet pathology observed in humans with T2D. Diabetes
leptin gene (ob/ob) or in the leptin receptor (db/db), and the appears to develop in these models as a consequence of a
mice develop severe obesity (Chung et al. 1996; Zhang et failure to adequately increase -cell mass in response to
al. 1994). The db/db mouse can be considered as having a obesity-induced insulin resistance (Baetens et al. 1978; Sha-
natural history that closely parallels that of humans. In hu- frir et al. 1999). The cellular mechanism responsible for
mans, however, it is difficult to separate whether insulin failure of -cell mass expansion is not specifically known
resistance precedes or is secondary to the development of but has been postulated to be secondary to acquired meta-
obesity. With the mouse models, it appears that the obesity bolic abnormalities (i.e., gluco- and lipotoxicity) (Harmon
predisposes these mice to diabetes, and this evidence is et al. 2001; Lee et al. 1994). The mouse models are ob-
incredibly valuable when assessing the effect of obesity on served to develop diabetes in relation to profound obesity
190 ILAR Journaland do not display the same islet pathology as humans with Spiny Mice (A. cahirinus)
T2D (islet amyloid).
Thus, it appears that there is no mouse model that has all Spiny mice live in the arid areas of eastern Mediterranean
of the characteristics of T2D in humans. However, it is countries and in North Africa. Due to these living condi-
apparent that there are specific mouse models that mimic tions, it would not be surprising for these animals to have
several of the pathophysiological conditions seen in hu- metabolic responses under their “normal” living conditions
mans. For this reason, mouse models remain as a major that would be aimed at protecting the pancreas from over-
animal model for the study of T2D. stimulation. However, when studied under various dietary
conditions, these animals demonstrate interesting metabolic
responses (see Shafrir et al. 2006). Specifically, when sub-
Rat Models
jected to a high-energy diet, they gain weight markedly and
manifest glucose intolerance. In addition, their weight gain
The Zucker diabetic fatty rat (ZDF1) is commonly used as a
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
is associated with -cell hyperplasia and hypertrophy, and
model for the study of T2D. Like the db/db/ mouse model,
they do not respond readily to stimulation of insulin secre-
the ZDF rat harbors mutations on leptin receptors, becomes
tion. The accompanying hyperglycemia and hyperinsu-
obese, and presents with hyperglycemia within the first few
linemia are observed to be mild and intermittent.
months of age (Chen et al. 1996; Kawasaki et al. 2005; Lee
Overnutrition in this animal model primarily affects -cells
et al. 1994; Phillips et al. 1996). Also similar to the mouse
causing hypertrophy and proliferation with a propensity to-
models, the ZDF rat appears to develop diabetes because of
ward islet cell disintegration (Shafrir et al. 2006). It is clear
an inability to increase -cell mass. The ZDF rat therefore
that this progression of events leading to diabetes differs
lacks sufficient insulin secretion required to compensate for
from -cell apoptosis caused by excessive insulin secretion
the insulin resistance as part of the obesity (Baetens et al.
pressure to compensate for the peripheral resistance. Thus,
1978; Finegood et al. 2001; Shafrir et al. 1999; Tomita et al.
this animal model represents another model of nutritional
1992). The mechanism that is responsible for the failure of
diabetes development, even though it may not be totally
-cell mass expansion is not fully understood but as is pos-
representative of the events in humans. Diabetes occurs only
tulated in mouse models, may be secondary to gluco- and
in old animals, after spontaneous islet rupture that is ac-
lipotoxicity (Harmon et al. 2001; Lee et al. 1994). The ZDF
companied by a loss of the rich insulin content.
rat does not display the same islet pathology as humans with
T2D (islet amyloid).
Desert Gerbil (P. obesus)
The Goto-Katazaki (GK1) rat is another model used for
the study of T2D. The GK rat is nonobese and has a de-
The “sand rats” also discussed by Shafrir and colleagues
creased -cell mass. Although the decreased -cell mass is
(2006) are another interesting model for the study of dia-
noted at birth, it is believed to be secondary to defective
betes. As described, P. obesus is characterized by muscle
-cell proliferation (Movassat et al. 1997; Portha et al.
insulin resistance and the inability of insulin to activate the
2001). The GK rat displays abnormalities characteristic of
insulin signaling on a high-energy diet. Insulin resistance
human T2D in the presentation of liver and skeletal muscle
imposes a vicious cycle of hyperglycemia and compensa-
insulin resistance. Due to impaired insulin secretion, fasting
tory hyperinsulinemia, which leads to -cell failure and
blood glucose levels appear to be only slightly increased
increased secretion of proinsulin. On the surface, this series
(Picarel-Blanchot et al. 1996). Therefore, although there are
of events appears to be similar to that seen in the human
similarities between the characteristics of the ZDF rat and
condition, but the progression from one stage to the next is
the human condition, the overwhelming majority of humans
still not clear. To better understand this model, Adler and
with T2D do not have inadequate -cell proliferation in
colleagues (1976) established a colony and identified three
early life. Thus, this characteristic of the GK rat model is a
main groups during the more than 20 yr of the colony’s
limitation as it relates to the human condition.
existence. Specifically, the groups were classified as
normoglycemic-normoinsulinemic, normoglycemic-hyper-
insulinemic, and hyperglycemic-hyperinsulinemic. The pro-
Other Rodent Models portion of animals among these groups remained stable and
predictable. In an experiment that lasted 1 yr during which
In the fourth article in this issue, Shafir and colleagues 100 animals were removed at random from the colony, Kal-
(2006) describe nutritionally induced diabetes in two spe- deron and coworkers (1986) reported that approximately
cies of desert rodents, specifically spiny mice (Acomys ca- 32% of the animals were normoglycemic-normoinsulinemic
hirinus) and the desert gerbil (Psammomys obesus). The (Group A) and 26% were hyperinsulinemic but normogly-
importance of these findings cannot be overstated given the cemic, with some gain in adipose tissue weight (Group B).
observation that the prevalence of T2D for humans is defi- Group C was described as having hyperglycemia in the
nitely related to lifestyle and caloric intake. Thus, these presence of remarkable hyperinsulinemia. The very high
models are of special interest when assessing the impact of level of insulin secretion in this group of Psammomys failed
increased energy intake on the development of T2D. to promote peripheral glucose uptake, as determined by
Volume 47, Number 3 2006 1912-deoxyglucose uptake. It also failed to restrain hepatic glu- ciated in most cases with insulin resistance. However, as is
coneogenesis, as indicated by increased alanine conversion also discussed, compensatory insulin secretion is generally
to glucose by isolated hepatocytes and the elevated activity observed in these states maintaining nearly normal glyce-
of phosphoenolpyruvate carboxykinase (Shafrir and Ziv mia. The progression to T2D then occurs in those individu-
1998). The presence of skeletal muscle insulin resistance als who are genetically predisposed to develop the
and the increase in hepatic glucose production are very pancreatic dysfunction. In T2D, the pancreatic islets are
similar to the abnormalities observed in humans. The last characterized by an approximately 70% decrease in the
group (D) of Psammomys on a relatively high energy diet number of insulin-secreting -cells, increased -cell apop-
was hyperglycemic and inulinopenic and comprised only tosis, and islet amyloid (Butler et al. 2003). The amyloid
∼6% of the colony sample. All of these animals were lean, found in the pancreatic islets in T2D has been reported to be
and their low plasma insulin levels indicated an exhaustion composed of extracellular fibrils of IAPP, a 37 amino acid
of insulin secretion. protein that is coexpressed and cosecreted by -cells (Butler
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
Shafrir and coauthors (2006) stress that the distribution et al. 1990). It appears that the sequence of IAPP displays
in the colony described above does not necessarily represent close homology in its amino and carboxy terminal residues.
gradual stages of diabetes progression from stages A to D. However, between species, there appears to be variance for
Some animals apparently lived for a long period of time as residues 20 through 29 (see Matveyenko and Butler 2006).
stage B, whereas others directly lapsed from stage A to C. It is also suggested that IAPP20-29 confers IAPP its amy-
Adler and colleagues (1988) also reported an inverted “U” loidogenic properties. This observation is important because
shape of the curve of plasma insulin levels, in correlation it appears that human, nonhuman primate, and feline IAPP
with glucose levels. In these animals, a definite gradual and are amyloidogenic, but that rodent IAPP is not (Betsholtz et
irreversible shift occurs from hyperinsulinemia with obesity al. 1989; Westermark et al. 1990). This distinction may
to hypoinsulinemia with weight loss and fatal ketoacidosis. explain the observation that the spontaneous development
An interesting observation in these animals, which is very of T2D in humans, monkeys, and cats is characterized by
relevant to the human condition, is that the progression from islet amyloid whereas this is not the case for rodents
normoglycemia/normoinsulinemia to hyperglycemia/ (O’Brien et al. 1993).
hyperinsulinemia may be halted or reversed by reduction in Thus, despite the usefulness of rodent models as dis-
food intake. This attenuation in the development of insulin cussed above to study the role of increased food consump-
resistance secondary to reduction in dietary intake mimics tion on the development of obesity and diabetes, the finding
the response in the human condition quite well. However, that rodents may not share the specific islet pathology seen
the major limitation of this model compared with the human in other species may limit their usefulness. To overcome
condition is that the development of diabetes in this model these difficulties, transgenic rodent models for human IAPP
has been observed to be characterized by a gradual loss of have been developed with the overall aim of investigating
-cell mass due to increased -cell apoptosis and decreased the possible adverse effects of amyloidogenic IAPP on
-cell proliferation (Donath et al. 1999). Research has sug- -cell destruction. In this endeavor, the development of the
gested that -cell apoptosis in P. obesus is mediated by the h-IAPP (HIP1) transgenic rat represents an exciting advance
IL1/Nf/B pathway and does not contain amyloid deposits (see Matveyenko and Butler 2006). The HIP rat is h-IAPP
characteristic of humans with T2D (Maedler et al. 2002). transgenic on the Sprague-Dawley background (Butler et al.
Thus, P. obesus shares many of the clinical and metabolic 2004). Homozygous HIP rats developed diabetes rapidly
characteristics of T2D observed in humans such as the pres- within the first 2 mo of life, whereas hemizygous HIP rats
ence of insulin resistance, increased hepatic glucose pro- spontaneously developed mid-life diabetes (6-12 mo) asso-
duction, and the ability to attenuate progression based on ciated with islet amyloid (Butler et al. 2004). The latter have
reduction in energy intake. However, there appear to be been studied in more detail. In these prospective studies, the
significant differences in etiology for -cell failure in this HIP rat develops islet pathology closely related to that in
model compared with humans, which may limit the useful- humans (progressive loss of -cell mass, islet amyloid, and
ness of this model for pancreatic pathology. increased -cell apoptosis), and these abnormalities appear
to precede the development of hyperglycemia (Butler et al.
Transgenic Models for -Cell Pathology 2004). Once hyperglycemia develops in the HIP rat, -cell
apoptosis increases further and is correlated with blood glu-
One of the limitations of the rodent models, as discussed, is cose concentration, implying glucose toxicity. The HIP rat
that the models of diabetes do not demonstrate the similari- model will provide an opportunity to evaluate the progres-
ties for islet pathology observed in humans with T2D. The sion of abnormalities in insulin secretion and action in re-
fifth article in this issue (Matveyenko and Butler 2006) lation to changes in -cell mass.
provides a detailed discussion of islet amyloid polypeptide
(IAPP1) transgenic rodents. The rationale for developing Feline Models
such models is clear when considering the natural history,
pathophysiology, and islet pathology in humans with T2D. Investigators have evaluated the development of diabetes in
As described above, prediabetes in humans is clearly asso- the domestic cat in numerous studies, and the similarities to
192 ILAR Journalthe human condition are striking, as reviewed in detail by sidual insulin secretion, development of IA deposits, loss of
Henson and O’Brien (2006) in this issue. First, as observed approximately 50% of -cell mass, and development of
in humans, more than 80% of cats with diabetes have clini- complications in several organ systems including peripheral
cal characteristics and abnormalities consistent with T2D, polyneuropathy and retinopathy. These characteristics of fe-
and the typical onset for diabetes also appears to be in line diabetes make the cat a very appropriate model when
middle age or later (Johnson et al. 1986; Panciera et al. evaluating the pathogenesis of human T2D.
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 Swine Models
lifestyle and dietary intake play such a major role in the
human condition, the relevance of this finding is noted be- The rationale for the appropriateness of swine as models for
cause there is evidence that the incidence of diabetes in cats human diabetes is based on several observations. Humans
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
is increasing for the same reasons it is increasing in humans and pigs appear to have very similar gastrointestinal struc-
(Prahl et al. 2003). Third, T2D in cats, as in humans, ap- ture and function, pancreas morphology, and overall meta-
pears to be associated with diseases, pharmacological bolic status (Larsen and Rolin 2004). In addition, the
agents, and hormones that impair peripheral tissue insulin pharmacokinetic values after subcutaneous drug administra-
sensitivity such as acromegaly or hyperadrenocorticism or tion are similar for humans and pigs. As outlined in detail by
treatment with corticosteroids or progestins (Rand et al. Bellinger and colleagues (2006) in this issue, many species
2004). of pigs share several of the clinical characteristics of human
A central feature in the development of diabetes in hu- diabetes. For example, two lines of Yucatan minipigs with
mans is the presence of insulin resistance and obesity as altered glucose tolerance have been described. One is re-
observed in the prediabetic state. The failure to compensate ported with impaired tolerance and the other with enhanced
for insulin resistance secondary to -cell dysfunction and tolerance (Phillips and Panepinto 1986; Phillips et al. 1982).
loss dictates the progression to overt diabetes. It is now The impaired glucose tolerance was due to a decrease in
apparent that the factors that contribute to insulin resistance peripheral insulin concentration resulting from decreased
in humans (e.g., obesity) are similar to the corresponding insulin secretion in response to a glucose challenge. The low
factors in cats. Diabetic cats are insulin resistant, and it has serum insulin levels in this line did not appear to be due to
been reported that insulin sensitivity values may be six-fold impaired synthesis and storage of insulin but were consis-
lower than normal cats (Feldhahn et al. 1999). Similar to tent with a modified pancreatic receptor or postreceptor re-
data related to humans (Appleton et al. 2001; Fettman et al. sponse as suggested by the finding that these pigs had
1998), significant weight gain in cats (∼44%) was reported normal insulin release in response to isoproterenol chal-
to result in a 52% decrease in insulin sensitivity, and lenge. In addition, the Göttingen minipig was suggested as
subsequent weight loss was shown to improve glucose a valuable model for metabolic syndrome based on its re-
tolerance. sponse to a high-fat high-energy diet (Johansen et al. 2001).
Thus, the clinical presentation for diabetes in cats ap- For example, female Göttingen minipigs fed a high-fat
pears to closely parallel that seen for human T2D. Further- high-energy diet to induce obesity had increased body
more, the most important characteristics noted in feline weight and fat content. Although preprandial plasma glu-
diabetes that are similar to humans are the pancreatic pa- cose and insulin concentrations were not altered, insulin
thology and physiology (e.g., islet amyloidosis and partial response to intravenous glucose was increased (Johansen et
loss of -cells) (Johnson et al. 1986, 1989; O’Brien et al. al. 2001). Male Göttingen minipigs fed a high-fat high-
1985, 1986, 1993). As reported, islet amyloidosis (IA1) has energy diet also became obese (had increased weight and
been detected in more than 90% of humans with T2D, and body fat) and had increased fasting blood glucose and in-
it appears to occur in nearly all cases of spontaneous dia- sulin levels compared with normal-fed controls (Larsen et
betes in cats (Johnson et al. 1986, 1989; O’Brien et al. al. 2001).
1993). The deposition of IA in diabetic cats is associated Although there appear to be spontaneous swine models
with an approximately 50% loss of -cell mass, which is of T2D, the use of swine models has been very beneficial in
similar to findings in human T2D (Butler et al. 2003; the specific studies of complications of streptozotocin-
O’Brien et al. 1986). In addition to providing a model to induced diabetes mellitus, particularly for cardiovascular,
evaluate pancreatic mechanisms involved in diabetes as it renal, and ophthalmic complications (Askari et al. 2002;
relates to humans, cats with diabetes appear to share many Gerrity et al. 2001; Hainsworth et al. 2002; Natarajan et al.
similarities related to the complications of diabetes, particu- 2002). One of the most important aspects of using pigs as a
larly diabetic complications such as diabetic neuropathy and model for the human condition is in the study of diabetic
retinopathy (Henson and O’Brien 2006). vascular disease. These models allow investigators to define
Based on the data cited above, diabetes in cats resembles the precise biochemical changes and mechanisms that ini-
human T2D mellitus in many respects including clinical and tiate and perpetuate atherosclerotic lesion progression. In this
physiological features of the disease. These features include research, streptozotocin and alloxan have been used to create
age of onset in middle age, association with obesity, re- insulin-deficient diabetes in pigs to create hyperglycemic
Volume 47, Number 3 2006 193states. Insulin-deficient pigs are reported to develop more Tigno et al. 2004; Wagner et al. 1996, 2001). Much like the
severe coronary atherosclerosis than nondiabetic controls. human condition, glucose and triglyceride concentration
Pigs fed a high-fat high-cholesterol diet develop coronary, levels can be high for several years before requiring inter-
aortic, iliac, and carotid atherosclerotic lesions in anatomi- vention. However, with continued insulin resistance and
cal locations extremely relevant to the human condition. further declining pancreatic reserves, there is generally a
Most importantly, these lesions recapitulate the histopathol- sharp increase in glucose that prompts treatment to prevent
ogy seen in humans. For example, the swine models for ketosis and acidosis (Wagner et al. 1996). Because obesity
cardiovascular disease develop proliferative lesions that and insulin resistance appear to be very prevalent in primate
consist of smooth muscle cells, macrophages, lymphocytes, models of T2D, it is not surprising that lifestyle interven-
foam cells, calcification, fibrous caps, necrotic and apop- tions that appear to be effective in human studies appear to
totic cells, plaque hemorrhage, and expanded extracellular be equally effective in primate studies. Specifically, reduc-
matrices (Brodala et al. 2005; Nichols et al. 1992; Prescott tion in energy intake (i.e., caloric restriction) can be very
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
et al. 1995, 1991). Based on the studies described above, it effective in improving glucoregulation, most likely second-
appears that swine models are relevant animal models for ary to improved insulin sensitivity (Bodkin et al. 2003; Ce-
the study of cardiovascular complications and the contribu- falu et al. 2004; Gresl et al. 2001; Wagner et al. 1996).
tion of metabolic abnormalities to the process. 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
Primate Models pathological findings in primates that appears very similar
to humans is that the major pancreatic lesion is islet amy-
Of all the animal models proposed, the abnormalities that loidosis. Specifically, this lesion has been reported for spon-
are observed for glucoregulation in primates, and particu- taneous cases of diabetes in Macaca mulatta, Macaca nigra,
larly the clinical presentation, appear to correspond quite Macaca nemestrina, Macaca fascicularis, and baboons
well to those observed in humans. Spontaneous diabetes has (Cromeens and Stephens 1985; de Koning et al. 1993; How-
been reported in cynomolgus, rhesus, bonnet, Formosan ard 1986; Hubbard et al. 2002; O’Brien et al. 1996; Ohagi
rock, pig-tailed, and celebes macaques, in addition to Afri- et al. 1991). Islet amyloid is found in approximately 90% of
can green monkeys and baboons (Bodkin 2000; Clarkson et human T2DM. As with monkeys, the degree of islet mass
al. 1985; Cromeens and Stephens 1985; de Koning et al. replaced by amyloid appears to correlate with increasing
1993; Hansen and Bodkin 1986; Howard 1986; O’Brien et insulin needs (Hoppener et al. 2000; Kahn et al. 1999). The
al. 1996; Ohagi et al. 1991; Tigno et al. 2004; Wagner et al. amyloid has since been shown to be immunoreactive for
1996; Yasuda et al. 1988). As has been observed for hu- IAPP and generally associated with a marked reduction in
mans, the overwhelming majority of cases reported in pri- insulin-immunoreactive -cells, as reported for humans
mates represent T2D and are associated with both obesity with T2D (Kahn et al. 1999; Wagner et al. 2001).
and increasing age (Wagner et al. 1996, 2001). These clini- One of the major advantages of using the primate model
cal observations that are similar to the human condition as it relates to human health is the development of athero-
have been noted for rhesus and cynomolgus monkeys and sclerosis (Clarkson 1998). As with swine models, nonhu-
for baboons (Banks et al. 2003, Cai et al. 2004; Hamilton man primates may be useful for determining mechanisms
and Ciaccia 1978; Hotta et al. 2001; Wagner et al. 1996; whereby cardiovascular disease is increased with diabetes.
Stokes 1986). The most remarkable similarity may be in the Monkeys with insulin resistance have dyslipidemia and in-
identification of the prediabetic phase, with the observation creased inflammation similar to human diabetics. In addi-
of insulin resistance and compensatory hyperinsulinemia as tion, streptozotocin can be used to induce a hyperglycemic
is well documented for the human condition (see Figure 1). state allowing studies that focus on interactions among lip-
In primates, the natural history of diabetes includes a ids, oxidative stress, and atherogenesis and that likely ex-
period of insulin resistance, with compensatory hyperinsu- plain a portion of the increased cardiovascular disease with
linemia despite normal glucose tolerance. This period of diabetes.
compensatory hyperinsulinemia is followed by continued
deterioration of insulin secretory capacity. As the disease
progresses, monkeys develop impaired glucose tolerance Summary
with slight increases in fasting glucose levels before becom-
ing overtly hyperglycemic due to a relative or absolute de- The incidence of T2D is increasing on a global level. The
crease in pancreatic insulin secretion. An important finding major problems associated with diabetes relate to micro-
that makes the primate model very relevant to the study of and macrovascular complications, which contribute greatly
human diseases is the observation of eventual pancreatic to the morbidity and mortality associated with the disease. It
exhaustion with replacement of normal islet architecture is recognized that the development of such complications
with an islet-associated amyloid. Such phases for diabetes and progression of the disease from prediabetic state to
progression have been reported for both cynomolgus and overt diabetes take years. Assessment of interventions de-
rhesus monkeys (Bodkin 2000; Hansen and Bodkin 1986; signed to delay or prevent complications or disease progres-
194 ILAR Journalsion in humans will also take years to accomplish. Such diabetes mellitus: Insulin resistance, glucose tolerance, and cardiovas-
protracted human clinical research trials can be very costly. cular complications. ILAR J 47:243-258.
Betsholtz C, Svensson V, Rorsman F, Engstrom U, Westermark GT,
For these reasons, there is a well-defined need for appro- Wilander E, Johnson K, Westermark P. 1989. Islet amyloid polypeptide
priate animal models of T2D mellitus to better study both (IAPP):cDNA cloning and identification of an amyloidogenic region
the pathogenesis and potential therapeutic agents. However, associated with the species-specific occurrence of age-related diabetes
for an animal model to have relevance to the study of dia- mellitus. Exp Cell Res 183:484-493.
betes, either the characteristics of the animal model should Black BL, Croom J, Eisen EJ, Petro AE, Edwards CL, Surwit RS. 1998.
Differential effects of fat and sucrose on body composition in A/J and
mirror the pathophysiology and natural history of diabetes C57BL/6 mice. Metabolism 47:1354-1359.
or the model should develop complications of diabetes with Bodkin NL. 2000. The rhesus monkey (Macaca mulatta): A unique and
an etiology similar to the human condition. It appears that valuable model for the study of spontaneous diabetes mellitus and
no single animal model encompasses all of these character- associated conditions. In: Sima AF, Shafrir E, eds. Animal Models in
istics, but there are many that provide very similar charac- Diabetes: A Primer. Singapore: Taylor & Francis, Inc. p 309-325.
Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E, Hansen BC. 2003.
Downloaded from https://academic.oup.com/ilarjournal/article-abstract/47/3/186/668583 by guest on 30 January 2020
teristics in one or more aspects of T2D in humans. Use of Mortality and morbidity in laboratory-maintained rhesus monkeys and
the appropriate animal model based on these similarities can effects of long-term dietary restriction. J Gerontol 58A:212-219.
provide much needed data on pathophysiological mecha- Brodala N, Merricks EP, Bellinger DA, Damrongsri D, Offenbacher S,
nisms operative in human T2D. Beck J, Madianos P, Sotres D, Chang YL, Koch G, Nichols TC. 2005.
Porphyromonas gingivalis bacteremia induces coronary and aortic ath-
erosclerosis in normocholesterolemic and hypercholesterolemic pigs.
Arterioscler Thromb Vasc Biol 25:1456-1451.
Buchanan TA. 2003. Pancreatic beta-cell loss and preservation in type 2
Acknowledgment diabetes. Clin Ther 25(Suppl B):B32-B46.
Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC. 2004.
The author received no outside funding to prepare this Diabetes due to a progressive defect in beta-cell mass in rats transgenic
manuscript, nor are there any potential conflicts of infor- for human islet amyloid polypeptide (HIP rat): A new model for type
mation relevant to the contents of this manuscript. 2 diabetes. Diabetes 53:1509-1516.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. 2003.
Beta-cell deficit and increased beta-cell apoptosis in humans with type
2 diabetes. Diabetes 52:102-110.
References Butler PC, Chou J, Carter WB, Wang YN, Bu BH, Chang D, Chang JK,
Rizza RA. 1990. Effects of meal ingestion on plasma amylin concen-
Adler JH, Lazarovici G, Marton M, Ben-Sasson R, Ziv E, Bar-On H, tration in NIDDM and nondiabetic humans. Diabetes 39:752-756.
Rosenmann E. 1988 Patterns of hyperglycemia hyperinsulinemia and Cai G, Cole SA, Tejero E, Proffitt JM, Freeland-Graves JH, Blangero J,
pancreatic insufficiency in sand rats (Psammomys obesus). In: Lessons Comuzzie AG. 2004. Pleiotropic effects of genes for insulin resistance
from Animal Diabetes. London: J. Libbey. p 384-388. on adiposity in baboons. Obesity Res 12:1766-1772.
Adler JH, Roderig C, Gutman A. 1976. Breeding sand rats (Psammomys CDC [Centers for Disease Control and Prevention]. 2003. Diabetes preva-
obesus) with a diabetic predisposition for laboratory investigations. lence among American Indians and Alaska Natives and the overall
Refuah Vet 22:1-8. population—United States, 1994-2. MMWR 52:702-704.
Cefalu WT. 2000. Insulin resistance. In: Leahy J, Clark N, Cefalu WT, eds.
Adult Treatment Panel III [Executive Summary of the Third Report of The
The Medical Management of Diabetes Mellitus. New York: Marcel
National Cholesterol Education Program (NCEP) Expert Panel on De-
Dekker, Inc. p 57-75.
tection, Evaluation, and Treatment of High Blood Cholesterol in
Cefalu WT, Wang ZQ, Bell-Farrow AD, Collins J, Morgan T, Wagner JD.
Adults]. 2001. JAMA 285:2486-2497.
2004. Caloric restriction and cardiovascular aging in cynomolgus mon-
Anderson MS, Bluestone JA. 2005. The NOD mouse: A model of immune
keys (Macaca fascicularis): Metabolic, physiologic, and atherosclerot-
dysregulation. Annu Rev Immunol 23:447-485.
ic measures from a 4-year intervention trial. J Geronol 59A:1007-1014.
Appleton DJ, Rand JS, Sunvold GD. 2001. Insulin sensitivity decreases
Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND,
with obesity, and lean cats with low insulin sensitivity are at greatest
Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgen-
risk of glucose intolerance with weight gain. J Feline Med Surg 3:211-
stern JP. 1996. Evidence that the diabetes gene encodes the leptin
228.
receptor: Identification of a mutation in the leptin receptor gene in
Askari B, Carroll MA, Capparelli M, Kramer F, Gerrity RG, Bornfeldt KE. db/db mice. Cell 84:491-495.
2002. Oleate and linoleate enhance the growth-promoting effects of Chung WK, Power-Kehoe L, Chua M, Lee R, Leibel RL. 1996. Genomic
insulin-like growth factor-I through a phospholipase D-dependent path- structure of the human OB receptor and identification of two novel
way in arterial smooth muscle cells. J Biol Chem 277:36338-36344. intronic microsatellites. Genome Res 6:1192-1199.
Baetens D, Stefan Y, Ravazzola M, Malaisse-Lagae F, Coleman DL, Orci Clarkson TB. 1998. Nonhuman primate models of atherosclerosis. Lab
L. 1978. Alteration of islet cell populations in spontaneously diabetic Anim Sci 48:569-572.
mice. Diabetes 27:1-7. Clarkson TB, Koritnik DR, Weingand KW, Miller LC. 1985. Nonhuman
Banks WA, Altmann J, Sapolsky RM, Phillips-Conroy JE, Morley, JE. primate models of atherosclerosis: Potential for the study of diabetes
2003. Serum leptin levels as a marker for a syndrome X-like condition mellitus and hyperinsulinemia. Metabolism 34(Suppl 1):51-59.
in wild baboons. J Clin Endo Metab 88:1234-1240. Cromeens DM, Stephens LC. 1985. Insular amyloidosis and diabetes mel-
Barker JM. 2006. Type 1 diabetes associated autoimmunity: Natural his- litus in a crab-eating macaque (Macaca fascicularis). Lab Anim Sci
tory, genetic associations and screening. J Clin Endocrinol Metab 91: 35:642-645.
1210-1217. DCCT Research Group [Diabetes Control and Complications Trial Re-
Bates SH, Kulkarni RN, Seifert M, Myers MG Jr. 2005. Roles for leptin search Group]. 1993. The effect of intensive treatment of diabetes on
receptor/STAT3-dependent and -independent signals in the regulation the development and progression of long-term complications in insulin-
of glucose homeostasis. Cell Metab 1:169-178. dependent diabetes mellitus. N Engl J Med 329:977-986.
Bellinger DA, Merricks EP, Nichols TC. 2006. Swine models of type 2 de Koning EJP, Bodkin NL, Hansen BC, Clarks A. 1993. Diabetes mellitus
Volume 47, Number 3 2006 195You can also read
