Type 2 Diabetes, Obesity, and Bumblefoot: A Possible Correlation?
Debora Seifried Wind
From the RMCA web site, June 2003
Authors Note: This theory, and resulting paper, is based on empirical evidence as well as in-depth research. The rats observed were those in the author's own rattery.
empirical: (adj.) originating in, relying on, or based on factual information, observation, or direct sense experience.
In the past there has been much debate, and research, over the relationship between Type 2 Diabetes and obesity. The question raged as to whether obesity was the cause of type 2 diabetes or whether type 2 diabetes was the cause of obesity. Only within the past few decades has strong evidence been found that diabetes is, in fact, strongly genetic. With this newly acquired knowledge it has become increasingly evident that individuals who inherit certain genes will be more predisposed to developing obesity and insulin resistance, or classic Type 2 Diabetes, than individuals who do not inherited such genes.
In 1961 scientists Lois M. Zucker and Theodore F. Zucker, Ph.D., of the Laboratory of Comparative Pathology in Stow, Mass., were conducting research as to whether or not the propensity for obesity was inherited. They discovered a gene in the rats they were studying that appeared to be responsible for obesity. They labeled this gene the "fatty-gene" (fa). Because the Zuckers were first to identify this gene in rats, this strain, a very large and at times morbidly obese rat, carries their name: Zucker Fatty rat (ZFr). These rats generally did not display hyperglycemia when fed ad libitum (means free fed; food always available), although both bucks and does did have reduced glucose tolerance and other indications of insulin resistance. They were, however, able to compensate for this resistance up to a point by increasing insulin production and secretion. They did not typically develop type 2 diabetes.
From the original colony of Zucker rats in Stow, Massachusetts, a few fatty bucks were observed that had unusually high levels of blood glucose as well as intolerance to glucose. This trait proved difficult to follow in the ensuing years, yet it continued to appear in a number of fatty bucks as well as a few fatty does. Concerted effort was made to selectively inbreed for this trait. By 1985 several inbred, as well as outbred, lines of rats were established that maintained a very high level hyperglycemia, impaired glucose tolerance, and typically developed type 2 diabetes. These rats became known as Zucker Diabetic Fatty rats (ZDF/Drt-fa).
There are other strains of rats, besides the Zucker rat, that have the fa-gene in their genetic profile. Virtually all received the fa-gene via the Zucker rat. The Wister fatty rat (fa/fa), for example, was developed by taking the fatty gene from the Zucker rat and transferring it to the Wister-Kyoto rat, who is less sensitive to insulin, and less tolerant to glucose, than the lean Zucker rats. Fatty Wister-Kyoto rats also show obesity, hyperphagia, hyperlipidemia, hyperinsulinemia and peripheral insulin resistance, similar to that of Zucker rats. Hypertrophy of pancreatic islets and degranulation of beta cells have been observed in both bucks and does of Wistar fatty rats. Release of insulin from the pancreas decreases as the rat's age increases. Bucks, but not does, develop diabetic symptoms such as progressive hyperglycemia, polydipsia, and glucosuria as early as a few months of age. One study found that Wister fatty does also developed frank hyperglycemia when fed a diet high in sugar, yet apparently did not develop overt diabetes. This particular finding has not yet been reproduced and confirmed by others.
Another example of a strain of rat with the fa gene in its make-up is the Koletsky rat, or Obese Spontaneously Hypertensive rat. This particular strain was originally established in 1970 after a cross between a Wystar-Kyoto spontaneously hypertensive doe and a normotensive Sprague-Dawley buck. From this cross, a spontaneous genetic mutation appeared which resulted in obesity in the offspring. The obese phenotype was due to an autosomal recessive mutation dubbed the Corpulent gene (cp) which, turns out, is in the same gene as the fa-mutation of the Zucker rat. In 1991, using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism techniques, the fa-gene was mapped to rat chromosome number five.
The fa-gene is inherited as a simple autosomal recessive mutation of a single gene. The gene is physically quite large and has at least two mutations identified with it. One mutation encodes for a shortened leptin receptor protein which can not interact with leptin. This results in a "failure-to-function" on the part of leptin receptors. A second mutation involves encoding for the insulin receptors. In 2001 researchers found a genetic defect in the beta-cell gene expression, involving transcription, that segregated independently from the fa locus in ZDF-lean rats. The Beta-cell gene transcription is also inherited as an autosomal recessive. Because of this, type 2 diabetes is now thought to be polygentic in nature (requiring more than one impaired gene) as it results from a combination of several defects: obesity caused by the leptin receptors' failure to function, peripheral insulin resistance caused by the fa gene's faulty encoding for insulin receptors, and a defect in the Beta-cell transcription resulting in an inability to adequately compensate for insulin resistance brought about by the fa gene.
Rats who inherit one copy of the fa gene, with a genotype of FA/fa, or fa/+, where + indicates the wild type (properly functioning) Leptin receptor, are commonly referred to as Lean Zucker (or Lean Wistar) rats. They are typically, but not always, very large, remain lean, and generally stay fairly healthy. They usually do not develop frank diabetes although they still exhibit mild peripheral insulin resistance in the skeletal muscles and liver tissue as well as mild hyperglycemia.
Rats who inherit two copies of the fa gene (fa/fa), encoding for the faulty Leptin receptor, dwarf their normal (+/+) siblings from an early age and quickly become obese even when fed a lab diet ad libitum containing only 2% fat content. Because the fa gene is inherited it is present at the time of conception and begins to act in the early stages of life. It acts upon the leptin receptors (OB-R) within the capillaries of the hypothalamus, deep within the brain, by easily saturating the blood-brain barrier. Because the receptors are so easily saturated by the circulating leptin within the bloodstream, with a saturation point four times lower than that of wild types, insufficient quantities of leptin are able to cross the blood-brain barrier. This results in messages of "hunger" being continually sent out by the hypothalamus. Hunger is one of the most powerful driving forces in life. The rat feels hungry and therefore eats, and eats, and eats. This constant drive to eat results in more, and larger, adipocytes (fat cells) being produced, and as leptin is mainly secreted by adipocytes, this in turn further increases circulating levels of Leptin. These rats grow very quickly and gain weight rapidly. At six weeks of age, affected males weigh around 200 grams. By eight weeks of age they weigh around 300 + grams. By twelve weeks of age weight of fa/fa rats range from 390 grams to over 570 grams. At eighteen weeks of age weight ranges from 640 grams to over 780 grams. These rats, both males and females although females while still obese weigh less, continue to gain weight well past the age of 43 weeks, or ten months of age, when they can attain weights of up to 1,000 grams (1 Kilogram), or 2.2 pounds, and greater. Compare this to rats with properly functioning leptin receptors (+/+) who weigh between 275 grams to 600 grams for fully mature bucks, and 225 to 400 grams for fully mature does. These rats grow to become huge rats. So much so that the word "Jumbo" is often used as a term of art when referring to these rats because they truly are "Jumbo" when compared to homozygous wild types (+/+). Heterozygous (fa/+, or FA/fa) rats are approximately one third larger than wild types (+/+), with homozygous recessive (fa/fa) rats being as large or larger than fa/+ and are obese.
Homozygous fa rats exhibit insulin resistance, have high levels of circulating Leptin, and often times develop frank type 2 diabetes. Rats with this genotype also exhibit hyperphagia (overeating), hyperlipidemia (excessive fat in bloodstream in the form of excess cholesterol), excess visceral adipose tissue, and morbid obesity. Metabolic changes such as peripheral insulin resistance, hyperinsulinemia (abnormally high levels of insulin in the bloodstream), and impaired glucose tolerance are commonly observed in these rats and, particularly in males, mild to severe hyperglycemia occurs. With increasing age these obese rats spontaneously develop proteinuria (protein in the urine) and glomerulosclerosis of the kidneys which ultimately leads to renal failure if the rat does not succumb to other complications of type 2 diabetes first. These rats suffer from a profound loss of cardiac function including cardiac dysfunction, arrhythmias, cardiomyopathy, congestive heart failure (particularly left-sided), and myocardial infarction. Neuropathy occurs in approximately fifty percent of all affected fa/fa rats.
This gene affects both males and females. Bucks homozygous for the fa-gene (fa/fa), are still quite willing and fertile breeders while homozygous does are typically sterile. Only seven in twenty homozygous does are able to conceive a litter, and only one in twenty are able to bring a litter to full term. Does heterozygous for this trait (fa/+) are able to have litters, usually while still at a young age. The younger the doe, the better her chances of having a normal pregnancy. The older the doe the greater her chances of complications.
The word "diabetes" comes from the Greek word meaning "passing through" which refers specifically to the copious amounts of urine being excreted by untreated diabetics. The word "mellitus" is derived from the Latin word for "honey," in reference to the sweet characteristic of the glucose-laden urine. There are two major forms of diabetes. The first is type 1 diabetes, also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes. It is the result of too little insulin being produced either because of damage to the pancreas or damage due to the body's own immune system. The beta cells in the pancreas that produce insulin are gradually destroyed and eventually insulin deficiency becomes absolute. Without insulin to move glucose into cells, the blood glucose levels become excessively high (hyperglycemia). Since the body cannot utilize the glucose, it spills over into the urine and is lost. Affected individuals become dependent on administration of insulin for survival.
Type 2 diabetes, which is the focus of this article, is the second and by far most common form of diabetes. It is also referred to, somewhat imprecisely, as noninsulin-dependent diabetes mellitus. This type accounts for up to seventy-five percent of all cases of diabetes. Yet these two forms share a common characteristic: elevated blood glucose levels due to absolute or relative insufficiencies of insulin, a hormone produced and secreted by beta cells (located in the islets of Langerhans in the pancreas). Most individuals with type 2 diabetes produce variable, sometimes even normal, amounts of insulin, yet when insulin attaches to the receptor cells, if it is able to attach to the receptor, glucose still cannot enter the cell. The resulting condition is known as insulin resistance.
Before one can identify "abnormalities" in rats, one must first be familiar with what constitutes "normalcy" in rats. Size is a good first indicator for "normalcy" in our fancy rats. Normal values for weight range between 225 grams and 400 grams for mature (ten month old) does, and between 275 grams and 600 grams for mature bucks. Does should be lean and racy in appearance, bucks should be lean and muscular. A "normal" rat should show a healthy flight response and is easily startled by unknown, or unexpected, objects. They should also exhibit an uncertainty of new, or unfamiliar, foods taking only a small taste at first before deciding whether or not to eat it. When genetically "normal" rats feel hungry, they eat, get full after a short time, and show no further interest in consuming any more (although they will snatch the proffered morsel and go hide it to eat at a later time). A "normal" rat should sleep for the better part of the day, only waking and becoming active during the evening hours, as well as in the early morning hours. Healthy, "normal" rats are quite dexterous, active, and enjoy climbing. Typical water intake should range between one and two fluid ounces per twenty-four hour period per individual rat. To put some perspective on this, two rats should drink between two and four ounces of water per twenty-four hour period, three rats should drink three to six ounces of water per day, while four rats should drink between four and eight ounces of water per day, etc.
"Abnormal" rats, on the other hand, are very, very, large with males weighing in at 2.2 pounds and over (or greater than one kilogram) and females weighing in at a pound and over. They do not have a healthy "flight" response and do not startle easily. They are extraordinarily laid back rats. They are always hungry and will eagerly wolf down even the most unfamiliar foods. They do not sleep for longer than about four hours at a time as the driving force of hunger awakens them. They are not as active and playful as "normal" rats. After the age of four months they rarely romp, play, or climb about their cage. They are content solely to recline and eat. They can be unusually clumsy. They drink more than two ounces of water per day. They are very prone to abscesses. One particular peculiarity, which made it into several researchers' field notes and was also observed by this author, is these rats' propensity to lay or sleep all sprawled out, on their backs with all four feet up in the air, rather than in a typical "rat ball." They have even been seen drinking, as well as eating, while reclining on their backs. Is it physically uncomfortable for them to sleep in a typical "rat ball"? Possibly. Are they so obese that they are more comfortable eating and drinking while laying on their backs? Quite likely. One can only speculate as to other reasons why.
Detection and Treatment In Rats
Type 2 diabetes in rats begins gradually and progresses slowly. In the early stages (three to seven months of age) there are very few, if any, outward symptoms present besides obesity. Onset usually does not become evident until a rat reaches middle age, usually around eight to ten months, and older. Symptoms in the rat include excessive thirst (drinking more than 2 ounces of water per day), increased urination (large amounts of very clear, diluted, urine), dry "crispy" haircoat if kidney damage is occurring or if there is left-sided congestive heart failure present, a fine, glossy haircoat if kidney damage is not yet occurring, constipation, urine retention, fatigue, unexplained weakness in the rear legs, unusual clumsiness, paw shaking which can include almost frantic shaking and licking of fingers and palm on the affected paw or paws, unexplained itching, sterility in females, failure to bring litters to term, birth defects, failure of even simple wounds to heal, foot ulcerations including ulcerative pododermatitis (bumblefoot), unexplained weight loss, spontaneous interoccular hemorrhages (bleeding within the eye due to microscopic vascular ruptures within the retina), recurrent abscesses, recurrent respiratory infections that either do not respond to antibiotics or reoccur immediately after antibiotic treatment has been terminated, and pneumonia are all indications of possible type 2 diabetes.
The major complications in diabetes are due to vascular (blood vessel) abnormalities and nerve damage (neuropathy). The profound loss of cardiac function in these rats results in heart attacks accounting for 60%, and strokes for 25%, of all deaths in affected individuals. Diabetes also accelerates the progression of atherosclerosis, where layers of plaque made up of cholesterol, fats, and other particles, build up within the walls of arteries. As this process progresses, the internal diameter of the affected arteries narrow, blood flow slows, and the blood vessels may become blocked. This can lead to coronary artery disease, heart attacks, and strokes. High blood pressure is also a major cause of heart attack, stoke, and heart failure. Insulin resistance is often accompanied by high blood pressure. All these, combined, can result in "unexplained," unexpected, sudden deaths in affected rats.
Neuropathy is decreased, or distorted, nerve function particularly in the nerves responsible for sensation. Approximately fifty percent of all fa/fa rats have, or exhibit, neuropathy. Symptoms include unexplained itching, numbness, tingling, weakness, and burning sensations, usually starting in the fingers and toes and moving up the arms and legs. This manifests itself in rats by the rat suddenly, for no apparent reason, shaking and/or licking the affected paw, specifically the fingers and palm. They may be perched at their food dish happily eating away, when all of a sudden they drop their food as if it has burned them, and begin shaking and almost frantically licking the fingers and palm of the affected paw. The rat may also have periods where their arm, or leg, seems to "fall asleep." The rat stumbles, become unduly clumsy for a "normal" rat, and carries the affected leg as if it were literally "asleep." A few minutes later the rat appears to be just fine. Rats may repeatedly get toenails caught on parts of the cage or furniture, rip off the toenail, and then appear as if nothing has happened. They have even been seen to be sleeping soundly, then suddenly wake up and begin licking and shaking a paw, as if the paw were tingling or burning. These various types of "episodes" do not seem to last long, but they do reoccur.
If nerves become damaged as a result of the disease, it is possible that even a minor wound can become infected. The problem is compounded in diabetes because of circulatory problems. Minor infections can develop into deep tissue injury. Abscesses are commonplace. Foot ulcerations, in particular, are very common in type 2 diabetics. This is not only because of the weight factor involved, but also because of the vascular changes that have occurred as a result of the disease. It is this author's opinion that Bumblefoot (Ulcerative pododermatitis) especially bumblefoot that does not heal when treated with Blu-Kote, or given other appropriate medical care, is another indication of type 2 diabetes in our large and/or obese fancy rat population.
Kidney failure, or nephropathy, is a very serious complication of type 2 diabetes. Unfortunately, progressive kidney failure is also very prevalent in fa/fa rats. The risk for developing this complication is significantly compounded by high blood pressure, the profound loss of cardiac function in these rats, and urinary tract problems. Nephropathy in rats is manifested by polydipsia (excessive thirst - drinking more than two ounces of water in any given 24 hour period); excreting copious amounts of clear, dilute urine; urine that dries to leave a hard-to-remove whitish film; a harsh, almost crispy haircoat; kidney stones; bladder stones; and foul smelling urine. Polyurea (excessive urination) can be difficult to determine if there are no solid balconies in the cage, or if there is no solid surface such as linoleum flooring, laid down on the wire mid-floor of the cage for the urine to puddle on. Without a solid surface in the cage the urine passes through the wire floor and falls into the litter below. The litter absorbs the urine, and polyurea goes undetected.
Gestational diabetes, also referred to at times as "transient diabetes," increases the risk of birth defects. Often times the doe will have an abnormally long gestation (i.e. 21 to 28 days as compared to 21 to 23 days) and give birth to either a single, monstrously huge, rat pup, or a small litter of very large pups. Because glucose crosses the placenta, a female with diabetes can pass high levels of blood glucose to the fetus. In response, the fetus secretes large amounts of insulin. This combination of high fetal blood levels of glucose and insulin leads to excessive fetal growth. It may also contribute to delayed maturation of the rat fetus' lungs, and even death of the fetus. Blocked birthing passages during labor are also common. Along with the dangers to the developing fetus, there are also risks to the pregnant doe, particularly preeclampsia, a potentially dangerous and life threatening condition involving abnormally high blood pressure.
Respiratory problems that either don't respond to antibiotics, or seem to clear up only to come back quickly, is another indication of type 2 diabetes in rats. This susceptibility to respiratory weakness is due not only to a slight change in a protein molecule on the surface of the lungs, which results in susceptibility to pneumonia and respiratory infections, but also from left-sided congestive heart failure and stenosis of the left ventricle chamber, which causes fluid build-up in the lungs, hence, pneumonia.
Diagnostic tests that can determine whether a rat is positive for type 2 diabetes includes the Fasting Plasma Glucose test, as well as the Glucose Tolerance Test. Tests which check for glucose in the urine are unreliable at best. They often give false negative results, and can miss up to eighty percent of all type 2 diabetics. The most reliable test is a Fasting Plasma Glucose test which can be done on rats after five hours of fasting. The test needs to be done twice, once on two different days. Fasting Plasma Glucose levels of 135 or higher indicates positive for Type 2 diabetes. A non-fasting plasma glucose greater than 175 is also indicative of type 2 diabetes. Depending on the results of the FPG tests, the vet may decide to do an Oral Glucose Tolerance Test to gain more specific information.
These rats are by no means "doomed." There are many things that can be done to help these rats live a more normal and healthy life. Type of cage doesn't really matter. Both types, those with solid balconies as well as those with wire midfloors and balconies, have their advantages and disadvantages. The important thing is to make sure there is plenty of soft cushioning on all the walking surfaces of the cage for the rats to walk on and snuggle in. They need the cushioned walking surface in order to keep tissue breakdown, particularly of the feet, at a minimum. Several layers of T-shirts can be used for this, as can layers of old sweatshirts or sweatpants. "Vetbed" is an excellent source of padding and can be purchased on the web, however it is expensive. Towels are advised against as rats who suffer from neuropathy can get toenails caught in the fabric loops of the towels and torn off. It is imperative to keep the rats' living area as clean as possible. Change the "rat linens" daily and replace with clean laundered ones.
To help minimize the effects of type 2 diabetes, try to have the rat do some sort of aerobic exercise for at least twenty to forty minutes a day, every day. Exercise is very important, in the big scheme of things, because it increases the sensitivity of insulin receptors in the skeletal muscles as well as liver cells to the insulin that is already circulating in the system. This, in turn, helps reduce blood glucose levels. Rat treadmills are commonly used in laboratories for this exact purpose. Wodent Wheels are an excellent alternative to rat treadmills. They are an easily accessible source for aerobic exercise, especially if the rat is raised with access to one since puphood. Make sure to get the Wobust Wodent wheel with the three hole faceplate as these large, obese, rats are physically unable to fit through the openings in the standard five hole faceplate. Any size Wodent Wheel smaller than the Wobust is too small for these large rats to use properly, even for the females. Other sorts of aerobic exercise include play time with owners with such cat toys as "Feather On a Stick," "Hanging Balls" glove, or other interactive toy. However, this is a double edged sword. Because of the profound loss of cardiac function, due to stenosis of the left ventricle chamber and the propensity for left sided congestive heart failure, these rats tend not to tolerate strenuous exercise well. They are "not into" activity and would much rather recline and eat than play. Use moderation.
If any treats are being given, Stop! Only basic, high quality rat lab block or, what the author had success with, Nutro Natural Lite Dog Food and supplements. Do not give veggies, yogies, fruits, popcorn, dried pasta, potatoes, or other leftovers (besides bones). Keep protein intake below eighteen percent as higher levels of protein are hard on already stressed kidneys. Each day, without fail, give each affected rat a tiny piece of whole wheat bread, about the size of one's thumb nail, with the following supplements: at least four drops of Flax seed oil, four to six drops of Garlic Extract (like Kyolic Liquid garlic extract), a small amount of fresh or dried ground sage, and every other week, with the first week being "two-a-days," add four to five drops of Echinacea tincture. Glycerin based Echinacea may be substituted for tincture. The author only chose Echinacea in tincture form as it remained stable and active for longer periods of time, therefor allowing for a greater shelf life. Both are equally as good.
Flax Seed Oil is given because it is rich in Omega-3, 6, and 9 Fatty Acids, known as "Essential Fatty Acids," and has been shown to significantly aid the body in utilizing the insulin that it has already produced. Flax Seed Oil was chosen as it is one of the best, and highest, sources of Essential Fatty Acids. EFA's can also be found, but to a lesser extent, in walnuts, sunflower seed oil, cod liver oil, and Extra Virgin Olive Oil. Do not cook the oil before giving it to your rats. Cooking changes the essential nature of the oil and reduces the oil's effectiveness with regards to sensitizing insulin receptors (which is why it's being given in the first place!). Garlic Extract helps clear out excess cholesterol and fat from the bloodstream, prevents platelets from sticking together, increases "good" HDL cholesterol, promotes the breakdown of certain types of blood clots, lowers blood pressure, also helps to sensitize insulin receptors in both the liver and muscle tissues, and helps strengthen cardiac output and rhythm. The Echinacea tincture helps to stimulate the rat's own immune system. Echinacea is an immunostimulant, and functions by activating certain white blood cells, t-cells, increases cellular respiration, and also increases the production of Interferon. Sage has also been found to help sensitize the body's insulin receptors to the insulin that has already produced.
If the above dietary supplements fail to work, the herb Gymnema sylvestre, or Gurmar, may be used with caution as it will decrease plasma glucose levels. This herb has been shown to stimulate insulin secretion while lowering cholesterol and triacylglycerols. Dosage is one-tenth that recommended for humans, or 40 mg of standardized Gurmar extract daily per each affected rat. This can also be given on a twice a day basis, with 20 mg to be given in the morning with a second 20 mg given in the evening.
In the end stages of type 2 diabetes insulin may need to be administered. Should this be required it is imperative that the insulin be given at the same time, usually early evening, every day. One's vet can determine the proper dosage, depending on the weight of the affected rat as well as results obtained from tests such as the Oral Glucose Tolerance test. In the Rat Health Care booklet, by Debbie Ducommun, Debbie advises to use the U40 strength insulin. Starting dosage is one unit of U40 strength, or 0.01 ml, per 50 grams of body weight. A rat which weighs in at 1 kilo would initially receive 0.20 ml of U40 insulin once every day. If U40 strength is unavailable, U100 can be diluted to the appropriate strength by one's vet. Dosage may be increased to as much as 2 units per 50 grams of body weight. Administration is by subcutaneous injection using a tuberculin syringe and 25 gauge needle.
Other medications which can be prescribed by one's veterinarian that may be of help include: Troglitazone (TGZ) 200 mg/kg per day, as well as Enalapril which can be used to ameliorate proteinuria as well as treat congestive heart failure.
Although fa/fa rats can have profound health problems they are not necessarily "bad" rats. As long as owners, or potential owners, are fully aware of the potential for required supplementation and medical care, these rats can make truly special pets. Their huge size and extremely laid back nature make them more than just easily tractable. These gentle giants are "Lap-Rats to the Max," and "Snugglers Extraodinaire." Simply make sure that adequate health support be given to these rats. This is treatable! Although these rats may have a shorter natural life span than those with wild type leptin receptors there are cases of affected rats living up to two years and slightly over. Be observant and begin supplementation as soon as a rat becomes suspect. If the rat is not a type 2 diabetic the supplements will do him, or her, no harm and, indeed, can help the rats' overall health in the long run.
These rats are, however, absolutely unacceptable as "Breeder Quality" rats. It is strongly advised that affected rats never be bred. Tragedy and heartache may well be the result. It is better to simply enjoy and care for these laid back behemoths while they're here. They can bring much happiness to their owners and will forever hold a special place in anyone's heart who's ever owned one (or several).
IMPORTANT UPDATE from the author (10/9/03)Since that article was written, there have been at least two (2) reported and verified cases, to me, of Zucker rats being born to normal sized, normal weight rats. Although in the article I spoke of heterozygous rats being "very large but lean rats," THIS IS NOT ALWAYS GOING TO BE THE CASE anymore! There are now verified cases of diabetic rats coming from apparently "normal" rats (here within the U.S.). Not all rats carrying the genes for Zucker (heterozygous for the trait) will be large and/or lean.
As was explained to me by the head geneticist at Harlan Teklad:
"Fatty Zucker- These rats will be obviously obese, and both chromosomes carry the mutation. This animal will be diabetic, but depending on age can be sub-divided into obese, mildly diabetic (blood glucose <11 mM) and obese severely diabetic (blood glucose >20 mM) groups. The origins of you rat will determine which type of model you will have. For example, Harlan carries the obese, non-diabetic model, and Charles River carries the obese severely diabetic model. If your rats have been bred for many generations without selecting for any of these phenotypes, then most likely will will see a mix of all three" (emphasis added).
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