Potential of Birds to Serve as a Pathology-Free Model of Type 2 Diabetes,Part 1: Is the Apparent Absence of the RAGE Gene a Factor in the Resistance of Avian Organisms to Chronic Hyperglycemia?

Abstract

Diabetes mellitus is a global pandemic that accounts for ever-increasing rates of morbidity and mortality and consumes a growing share of national health care budgets. In spite of concerted efforts, a solution to this problem has not yet been found. One reason for this situation is lack of good animal models. Such models have been used successfully in many areas of biomedical research, but they have proven less than satisfactory in studies on diabetic complications. In this article, we propose to supplement traditional animal models of diabetes that use longitudinal, prospective studies of sick animals (mammals) with retrospective/comparative investigations of healthy animals (birds). Avians are promising models for such studies because they live healthy lives with chronic hyperglycemia that would be fatal to humans. We outline the advantages of the new perspective and show how, by implementing this approach, we observed that birds appear to be missing an important gene linked to diabetic complications. The protein encoded by this gene is a receptor for advanced glycation end products (RAGEs). Although the absence of RAGEs from birds has yet to be confirmed at the protein level, other differences between humans and birds may also be important in accounting for the ability of birds to live with chronic hyperglycemia. Two such additional such characteristics are currently being explored, and it is probable that more will emerge in time. We believe that the proposed perspective may improve the understanding of diabetes mellitus and may help in developing new means for controlling and preventing diabetic complications.

Introduction

Diabetes mellitus is characterized by chronically elevated concentrations of blood glucose. In a well-controlled, fasted, diabetic patient, these concentrations should be than be less than 8.5 mM as compared to the normal value of about 5 mM.^1,2 There are two types of diabetes. In type 1 diabetes mellitus (T1DM), elevated glucose is a consequence of the loss the insulin-secreting β-cells in the islets of Langerhans in the pancreas.³ Type 2 diabetes mellitus (T2DM) is due to the inability of skeletal muscles to absorb glucose from blood in response to the insulin signal.⁴ While the global incidence of T1DM is about 1/300 and increasing at about 3%/ per year,³ the vast majority of diabetes cases are T2DM and are closely correlated with unhealthy diets, sedentary lifestyle, and obesity.⁴ The annual global rate of increase of T2DM is also estimated to be between 2%–3%.⁴

Diabetic Complications and Their Management

Regardless of the cause, chronically elevated levels of blood glucose lead over time (years and decades) to pathophysiological changes collectively known as diabetic complications. These complications include retinopathy, nephropathy neuropathy, microvascular damage, and macrovascular damage.^5,6

These complications constitute a global challenge that increases significantly with each passing year.^4
–6 Although it is clear that diabetic pathologies are ultimately a result of chronic hyperglycemia, our understanding of mechanisms linking hyperglycemia to these complications is incomplete.⁶ Consequently, the only clinically reliable method of preventing or slowing down the evolution of diabetic complications is through maintenance of tight glucose control by frequent monitoring and intervention.² However, this approach is limited in practice by many factors, including cost⁵ and patient compliance.⁷ Medically, perhaps the most demanding among the challenges of this approach is how to normalize levels of blood glucose of diabetic patients without risking hypoglycemia or other adverse consequences.⁸ The seriousness of this latter problem has been emphasized by recent studies in which intensive glucose control of diabetics actually led to increased patient mortality.⁹

Once complications develop, they are treated using variety of pharmacological, surgical and other interventions, including laser photocoagulation treatment of the retina,¹⁰ dialysis,¹¹ kidney transplants,¹¹ cardiovascular surgery,¹² and lower-limb amputations.¹³ While these interventions are effective in prolonging life and improving its quality, they are cumbersome, expensive, and have limited effectiveness. It would be far better to prevent these complications from developing in the first instance.

This situation is frustrating because, compared to many other medical conditions, the etiology of diabetic complications is relatively straightforward; chronically high concentrations of blood glucose lead, over time, to cellular, organ, and systemic damage. However, the slow progression of these conditions and lack of adequate animal models have made this problem nearly intractable.

Animal Models in Biomedical Research

The use of animal model systems is one of the most productive methods for the study of human disease. Historically, the first extensive and systematic use of this methodology evolved in the context of investigations on infectious bacterial diseases and methods for their control.¹⁴ Another area where this approach proved very productive was in the discovery and characterization of vitamins.¹⁵

Paradoxically, in the context of this article, the most spectacular example of the utility of animal models occurred in diabetes research with the discovery of insulin. Following a long series of animal experiments starting in late 1800s, the final stage of research occurred very rapidly with the purification of insulin in 1921–1922. Less than 3 years later, insulin became part of medical practice and eliminated T1DM as a cause of death due to acute decompensated hyperglycemia and ketoacidosis.¹⁶ However, after this initial spectacular success, animal models proved much less useful in the study of the other aspects of diabetes, namely its long-term complications.^5,6

There are at least three reasons why use of traditional animal models has proven problematic in this research. The first is a dearth of animals with sufficient longevity to develop pathologies analogous to those found in diabetic humans. Because symptoms of diabetic complication take anywhere from 2 to 20 years to manifest,^5,6 one would want to use animals with a comparable (or longer) life span. However, commonly used laboratory animals such as mice and rats simply do not live long enough to develop many of the complications.¹⁷

A second reason is that, even if longer-lived animals are used, it is exceedingly difficult to design and carry out of studies of sufficient duration with enough animals for meaningful statistical analyses due to the slow evolution of the complications. This is especially true for larger animals such as pigs and monkeys that are more difficult and expensive to maintain than rodents. Even if these logistical difficulties are overcome, this approach is still very expensive. Given the vagaries of funding for scientific research, it is difficult to envision how such effort could be sustained.

A third, and perhaps the most important, factor hindering the use of animal models in the study of diabetic complications are the inherent differences in the biochemistry and physiology between humans and animals. As detailed in previous reviews of this subject,¹⁸ due to different biology and life histories, the relevance of animal model studies to human diseases is often questionable.

Birds As a Model of T2DM

Fortuitously in the case of T2DM, nature has provided us with potentially very useful animal models. These are birds where, due to apparent insulin resistance,¹⁹ blood glucose concentrations are chronically at levels that would be pathological for humans. Overall, avian blood glucose concentrations average about 15 mM and range from 10 mM to over 20 mM, or higher.²⁰ However, even in birds, glucose is not benign and when these animals become diabetic they become quite ill and often die due to this condition.²¹

These facts have led us to propose several hypotheses:

1. Although glucose is essential for life, it also has the intrinsic potential to cause, directly or indirectly, serious pathological dysfunctions and life-threatening problems.

2. Because of this toxic potential, all living organisms must have defenses against the damaging side effects of this essential nutrient. (A prominent example of another such “Janus-like” molecule is oxygen. Although its presence is essential for aerobic organisms, oxygen also has a well-documented potential to cause damage due to free radicals reactions.²² Consequently, all aerobic organisms have a vast array of anti-oxidant systems that allows them to cope with oxidative stress.)

3. Because plasma glucose concentrations in birds are higher than those in humans, their defense mechanism against glucose toxicity are proportionately more robust to deal with the increased stress.

4. If any of the avian defense mechanisms against glucose toxicity are applicable or transferable to humans, we may be able to find new ways of controlling, or perhaps even preventing, diabetic complications in humans.

Unfortunately, although birds have been studied quite extensively as models of aging,^23,24 relatively few investigations have been conducted to understand avian resistance to hyperglycemia.^25,26 These studies were done almost exclusively on commercial breeds of chickens and were focused on oxidative stress and the main plasma anti-oxidant uric acid. This approach has two serious weaknesses.

First of all, commercial breeds of poultry are not likely to be good models of healthy avian organisms. This is due to the fact these birds were bred for maximal production of meat and eggs at the expense of their overall health and welfare. Two known problems associated with this selective breeding are musculoskeletal abnormalities²⁷ and ascites.²⁸ It is likely that, in addition to these issues about which we do know, there are others that have not been identified or studied.

Second, oxidative stress accounts for only a part of the spectrum of hyperglycemia-associated stress. For instance, there is a large and convincing body of research showing that a large fraction of advanced glycation end product (AGE) formation in vivo is independent of oxygen.^29,30 Thus, oxidative stress is only part of the story and may not even be its most important aspect. This is further suggested by the fact that uric acid, the preeminent anti-oxidant in blood plasma, is present in humans at levels that are comparable with birds.^31,32 Thus, if oxidative stress was the primary hyperglycemia-associated stressor, human beings should be just as tolerant of chronic hyperglycemia as are birds.

This article is intended to be the first in a series attempting to examine avian defenses against chronic hyperglycemia that are largely separate and independent of oxidative stress. This is being done through a systematic meta-analysis of published data and synthesis of information that has not hitherto been considered together. As a consequence of this investigation, we propose here a new approach to the study of T2DM that could overcome many of the problems associated with traditional animal models.

Briefly, we suggest that in addition to investigating diabetic complications in prospective studies of sick animals we should also study diabetes in birds in retrospective-comparative studies of healthy animals. This is possible because birds mimic the salient pathological feature of T2DM, hyperglycemia, without the attendant complications. Thus, in this new approach, we are dealing with animals that have, over about 100 million years, evolved ways to deal successfully with chronic hyperglycemia.³³ The advantages (and some limitations) of the proposed new methodology are enumerated below and summarized in Table 1.

Table 1.

A Comparison of a Traditional Animal Model of T2DM with the Proposed Model

	Category	Traditional prospective model of pathology	Proposed new retrospective model of health
A	Effect of interspecies differences	A liability: Generates doubts about validity of animal studies	An asset: Identification of differences is key focus and goal of the studies
B	Health status of animals	Sick and difficult to maintain	Healthy and less susceptible to problems.
C	Longevity of model animals	A major obstacle	Not a problem
D	Duration of the experiments protocol and costs	Long: As long as needed to observe complications; very high costs	Short: Only as long as needed to perform the analyses; low costs
E	Continuity in protocols and personnel	Continuity in personnel essential; protocols inflexible.	Continuity of personnel relatively unimportant; protocols flexible
F	Hypothesis dependence	Experimental set-up and type of data collected crucially dependent on a hypothesis being tested	Largely hypothesis independent

Advantages and Issues Related to the Use of Birds As Models of T2DM

Effect of interspecies differences on validity of experimental results

Conventional model

In the conventional animal model of T2DM, animals are studied by following, over time, the development of hyperglycemia-induced pathologies and testing the effectiveness of interventions. Findings from such studies, no matter how rigorous and unequivocal, always carry the caveat that they may or may not be applicable to humans because of interspecies differences in biochemistry and physiology.¹⁸ Two notable diabetes-related examples of such problems have been chronicled in the scientific literature. One is the general inapplicability of aldose reductase inhibitors to human diabetes in spite of their clear benefits to rodents.³⁴ Similarly. aminoguanidine (AG) treatments to prevent non-enzymatic glycation were quite successful in rodents.^35,36 However, when attempts were made to use AG in humans, problems arose that caused this compound to be withdrawn from further clinical trials.³⁷

The new model

Because in the proposed new model the focus is on mechanisms that protect birds form chronic hyperglycemia, differences in biochemistry and physiology that in the conventional approach are serious and sometimes “fatal” liabilities actually become assets. In fact, in this new approach, we are actively seeking to find such differences. Once they have been identified, the main issues that remain to be settled are to determine which observed differences are important for protection against hyperglycemia and which may be applicable to the human system.

Due to advances in bioanalytical techniques and an improved understanding of receptors and signal transduction pathways, this comparative approach has a very good chance of providing us with new findings and insights. A brief illustration of this potential, involving AGEs and RAGEs, is given in the last section of this article.

Health status of the animals studied

Conventional model

Because spontaneous T2DM does not occur frequently or predictably in the laboratory animals, one must use inbred strains that have been altered to express the disease.⁶ Subsequently, prolonged and careful care has to be taken of sick animals, which presents many problems, not the least being a probability of losing some of them due to accidents or disease. Furthermore, while in many cases such “engineered” animals have served their purposes admirably, there is a good chance that the inbreeding and selection has produced pathological and abnormal organisms that further aggravate the problem of differences between humans and the animal models.

New model

Because normal healthy birds are intrinsically hyperglycemic, our ability to study them is limited only by our ability to obtain adequate access to them. Their maintenance in captivity is also much less of an issue because their resilience is greater and their time in captivity will be much shorter.

Longevity

Conventional model

Because diabetic complications take many years or decades to develop, most laboratory animals such as rodents with a maximum life span (MLS) of up to 4 years are less than optimal subjects for such studies. Although other, longer-lived animals, such as monkeys and pigs, have been proposed for studies of diabetes,^38,39 their use presents many serious logistical difficulties.

New model

Birds are among the longest-living vertebrates, so the most serious challenge in investigating them is ascertaining their age. This is a especially true in studies of wild birds because the known techniques of age determination such as banding,⁴⁰ and pentosidine measurements^41,42 present methodological problems^43,44 that severely limit their utility.

Fortunately, however, determining the ages of captive or domesticated birds is not a serious issue, so studies of such birds should be reasonably straightforward. Several reports on such investigations have already been published.^45
–47 An especially promising example of a resource for such studies facilities such as the one described by Dr. Prinizinger at the University of Frankfurt.⁴⁷ This is an outdoor aviary for pigeons that has been maintained for over 40 years. Newborn chicks are banded immediately after hatching so their ages are known precisely. The birds are free to come and go as they choose and they are accustomed to being handled by humans, thereby minimizing the probabilities of generating experimental artifacts due to stress.⁴⁸

It should be noted here again that other domesticated birds, such as chickens or turkeys bred for commercial meat and egg production, should be avoided because they are, in all likelihood, pathologically affected by the selective breeding.

Duration of the protocol and costs

Conventional model

Using the traditional animal model and working with laboratory animals that live for 20 or more years, special efforts are required to maintain the sick animals long enough to develop symptoms of complications. Even for the most rapidly progressing, most widespread, and most easily assessed pathology, such as retinopathy, this requires at least several years.⁴⁹ For other complications, the time for development of ascertainable symptoms is even longer.^5,6

Because of the investment of time and money, as the prospective protocols progress, the value of the experimental animals increases (both scientifically and financially) and error margins for any protocol decrease significantly. These animals simply become too valuable not to do everything as perfectly as possible. And, even if all goes well and no animals are lost or compromised, the costs of their maintenance are very large and ultimately such experiments may still produce disappointing results.

A dramatic recent illustration of problems associated with conducting long-term animal studies are publications regarding the effect of caloric restriction (CR) on life span. Basically, after 20–25 years of careful, intensive, and expensive studies to evaluate the effect of CR on rhesus monkeys, the results are definitively inconclusive.^50,51 In addition to pointing out the issues of duration and costs, this episode also illustrates the importance of interspecies differences since CR has proven effective in a variety of other organisms ranging from yeast to mice.⁵²

New model

Because elevated blood glucose is the natural state of birds, the duration of avian hyperglycemia is simply equivalent to the age of the bird. Moreover, animals that would be most suitable for these studies (such as zoo or pet animals) do not have to be maintained in special facilities. They do quite well with standard and time-tested husbandry routines practiced in their various captive environments. Thus, if one wants to investigate the effects of 10 years of hyperglycemia in a bird, one simply needs to find and study 10-year-old animals.

In studying birds, the expenses and effort of long-term maintenance are eliminated. In addition, the costs of mistakes and mishaps remain invariant, and relatively low. In addition, procedural errors can always be corrected by repetition of experiments, and the number of experimental subjects is relatively large.

Continuity of protocols and personnel

Conventional model

For a prospective study to be valid, the protocols employed over the duration of the experiment have to remain consistent even as the technology and knowledge change. This fact, by itself, may make the study out of date and irrelevant even before it is completed. For instance, even routine measurements of analytes such as glycosylated hemoglobin (HbA1c) have evolved over time, and methodologies that were routine 10 years ago are no longer considered reliable.⁵³ For many other analytes, storage of frozen samples alters their composition and properties and creates uncertainty about validity of analytical results.⁵⁴ Another requirement for consistency in prospective long-term animal studies is maintenance of a personnel core that is familiar with the study and competent to carry out its procedures consistently over time.

New model

By contrast, in the proposed approach, the numbers of experimental subjects is unlimited, samples can be collected and analyzed rapidly, and as technology evolves, new techniques and procedures can be easily applied to these fresh samples.

In terms of personnel for studying birds, the only requirement is that people involved in these projects should be scientifically knowledgeable and competent. As long as these requirements are met, different individuals can carry out the experimental procedures over time.

Hypothesis dependence

Conventional model

Most previous studies on diabetic complications using the traditional animal models were designed to test specific hypotheses. Although some of these investigations produced promising leads, they did not have a major impact on treatment of the human disease, due primarily to interspecies differences.

New model

In contrast to the traditional approach, the new methodology depends only minimally on any particular hypothesis. The only two postulates underpinning our approach are: (1) Diabetic complications are ultimately caused (either directly or indirectly) by glucose and (2) living systems have mechanisms to defend themselves against adverse effects of glucose.

Thus, rather than being bound by rigid theoretical frameworks, this methodology is relatively doctrine free and allows for the facts “to speak for themselves.” Subsequently, from analysis of results obtained in one set of experiments, testable hypotheses can be developed and evaluated for validation (or invalidation) using the traditional animal model system If warranted, then they can then examined for possible applicability to the human disease.

An Example of the New Approach: RAGEs In Birds

Advanced glycation end products

As described in an essay by Baynes in 2000,⁵⁵ life is a constant struggle between chemistry and biology. One important aspect of this dynamic balance are Maillard reactions (a.k.a., non-enzymatic glycation) between reducing sugars and amines. Since both types of compounds are indispensable for life and have to co-exist in cells and organisms, Maillard reactions are unavoidable and lead to the formation of AGEs that are almost invariably deleterious to cell and organism function.⁵⁶

Receptor for Advanced Glycation Endoproducts (RAGEs)

One way by which AGEs exert their damaging effects is through interaction with specific receptors known as receptors for advanced glycation end products (RAGEs). These molecules were discovered in 1992⁵⁷ and have been detected in the membranes of endothelial cells, lungs, vascular smooth muscle, myocytes, and neural tissue.⁵⁸ They are a part of the inflammatory system and appear to be inappropriately and excessively activated in diabetes. This hyperactivation contributes significantly to AGE-mediated damage by amplifying glycoxidative stress and contributing to deposition of AGEs in sites such as atherosclerotic plaques and kidneys.⁵⁹

In support of the proposed role of RAGEs in the etiology of diabetic complications a number of studies have shown that RAGE ^−/− mice were protected from hyperglycemia-induced damage in the myocardium,⁶⁰ renal tissues,⁶¹ and neurons.⁶²

In addition to the membrane-anchored RAGEs, two soluble forms of this protein were identified—sRAGE and esRAGE. Although work on these molecules is still ongoing, they show promise to act as prospective markers of diabetic complications.^63,64 Even more significantly, some animal experiments suggest that sRAGEs have the potential to act as therapeutic tools that would scavenge AGEs, thereby preventing damage caused by the activation of the membrane-bound RAGEs.⁶⁵

Apparent absence of RAGE genes in birds

To date birds have been not been thoroughly examined for the presence of the RAGE genes or RAGE proteins. There are only two preliminary reports addressing this issue and, while they are fragmentary and somewhat ambiguous, they do suggest that RAGE proteins are absent from birds.^66,67 Unfortunately, these findings were not widely disseminated and are virtually unknown in the diabetes research community. However, it should be noted that the authors of these studies are quite cognizant of the potential importance of their findings, as indicated by the concluding sentence of the second publication: “…further investigation of the RAGE will lead the scientific and medical communities to some profound discoveries.” ⁶⁷

Our survey of DNA sequence data confirms this assessment that birds do not possess homologs to the mammalian RAGE gene. Specifically, using the mRNA sequence (M91211.1) of Neeper et al.,⁵⁷ we conducted a BLAST homology search on the completed vertebrate genomes available at the National Center for Biotechnology Information (NCBI) website as of October, 2013. We examined 35 organisms including 22 mammals, four rodents, and nine other vertebrates for RAGE homologs at the genomic level.

RAGE homologs were found in all mammals and in none of the other vertebrates. Significantly, this latter category includes three bird species (chicken, turkey, and zebra finch). An illustration of these results is presented in Fig. 1 that shows definitive homologies for RAGE in human, mouse, rat, cattle, opossum, and platypus, while such alignments are absent from the bird genomes.

FIG. 1.

Alignment of mRNA sequence of the receptor for advanced glycation end product (RAGE) (M91211.1) with homologous sequences in selected completed vertebrate genomes. In all mammals, the RAGE sequence maps to only one location and in five out of six the relevant chromosomes has been identified. These locations and accession numbers are as follows: Human chromosome 6, NG 029868.1; mouse chromosome 17, NC000083.6; rat chromosome 20, NC 005119.1; cattle chromosome 23, AC 000180.1; opossum chromosome 2, NW 001581878.1; platypus an unknown chromosome, AC 001606835.1. In birds, the RAGE sequences map to three different locations on different chromosomes with E values that higher than mammalian matches by at least three orders of magnitude. The best matches are in the chicken (NC006107.3), turkey (NW 003434953.1), and zebra finch (NW 002198120.1).

Discussion

The idea of using birds or avian tissues to study some aspects of diabetes has been raised from time to time in the past. The most recent and most comprehensive such proposal was made by Datar and Bhonde in 2011.⁶⁸ This article, however, focused almost exclusively on the use of chick embryo to study pancreatic islets, diabetic malformations, and hyperglycemia-induced damage to endothelial cells of chorioallantoic membrane. The authors did not propose any studies on older animals.

Our proposal is a more radical attempt to effect a change of perspective in studies of diabetic complications. As shown by the observation of the apparent absence of RAGEs in birds, this re-orientation holds out a promise of providing new insights into this insidious and thus far intractable disease. The validity of this approach, however, is not dependent on the correctness of our RAGE hypothesis. We believe that addressing the questions of how birds live long and healthy lives with chronic hyperglycemia is important, regardless of the correctness of any particular answer to this question.

This new animal model paradigm cannot and will not substitute traditional animal model studies and certainly will not eliminate the need for human studies; however, it does have the potential to provide new data that can inform and direct future studies. For instance, should our finding on the absence of the RAGE gene from the avian genome prove correct, it could have some potentially important implications. Two, among the more obvious ones are:

1. The absence of RAGE in birds will lend major support to he hypothesis that RAGEs play a significant role in the development of diabetic complications.

2. In the event that RAGEs do play such a role, therapy with soluble RAGEs could potentially evolve into a viable and valuable preventative or interventional treatment for diabetic complications.

Finally, beyond diabetes, the proposed new approach may also be applicable to the study of other chronic diseases provided that one can identify animals that have the predisposing conditions of such diseases but do not succumb to them.

Footnotes

Acknowledgment

We would like to thank Dr. Karen Sweazea of Arizona State University for her support and advice.

Author Disclosure Statement

No competing financial interests exist.

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