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Non-Obese Type2 Diabetes Animals ModelsYukihito Ishii, Takeshi Ohta and Tomohiko Sasase[1] Japan Tobacco Inc., Central Pharmaceutical Research Institute, Murasaki-cho, Takatsuki, Osaka, Japan1. Y Goto, K-I Suzuki, M Sasaki, T Ono, S Abe, GK rats as amodel of nonobese, noninsulin-dependent diabetes. Y Goto, M Kakizaki, N Masaki, Spontaneous diabetes produced by selective breeding of normal Wistar rats.
Y Tsuura, H Ishida, Y Okamoto, S Kato, K Sakamoto, M Horie, et alGlucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat.
K Ueta, T Ishihara, Y Matsumoto, A Oku, M Nawano, T Fujita, et alLong-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats. H Yamamoto, Y Uchigata, H Okamoto, Streptozotocin and alloxan induce DNA strand breaks and poly(ADP-ribose) synthetase in pancreatic islets.
M Kergoat, B Portha, In vivo hepatic and peripheral insulin sensitivity in rats with non-insulin-dependent diabetes induced by streptozocin. An entire medical industry has grown up around diagnosing and treating gestational diabetes (GD) in the belief that doing so prevents perinatal deaths, congenital anomalies, neonatal complications, macrosomic babies, and because of fetal macrosomia, birth injuries and excessive cesarean rates. Since insulin-dependent diabetes was known to threaten the fetus, researchers extrapolated that sub-diabetic glucose elevations might also do harm. Logic notwithstanding, these concerns launched a series of studies into the risks of mild glucose elevations. Nonetheless, researchers concluded that mildly deviant glucose values in pregnancy constituted a new form of diabetes that required diagnosis, surveillance, and treatment. Obstetricians adopted O'Sullivan and Mahan's curve as the normative curve for all pregnant women, but it is not representative.
Worse yet, studies show that when pregnant women undergo two OGTTs a week or so apart, test results disagree 22 percent to 24 percent of the time (Catalano et al. More importantly, no threshold has ever been demonstrated for onset or marked increase in fetal complications below levels diagnostic of true diabetes. A test with arbitrary diagnostic thresholds is akin to claiming that all people over six feet tall have a growth abnormality or all people with a cough and a fever have pneumonia. The original intent of treating GD was preventing excess perinatal mortality and congenital anomalies. As for congenital anomalies, GD cannot cause congenital anomalies because glucose metabolism is normal in the first trimester.
The main rationale for current GD management is to reduce the incidence of birth injuries and cesarean section by reducing the incidence of macrosomia. Santini and Ales report results from a national trial that occurred in the early 1980's when some doctors at Cornell University Medical Center screened women for GD routinely and others did not.
Non-randomized trials show that diet modification rarely works without severely limiting calories or the liberal or universal use of insulin. As Santini and Ales' study suggests, not only does GD management offer little benefit, it confers risks, the gravest being a marked increase in cesarean section. Many doctors view high cesarean rates as a reasonable trade-off for preventing shoulder dystocia. Henci Goer was a doula (labor support professional) for over 20 years and a Lamaze educator for ten.
Effect of DPPIV-i on blood glucose (A) and insulin (B) levels in glucose-loaded SDT fatty rats. IntroductionDiabetes mellitus has become a global health problem, and the incidence of the disease is increasing rapidly in all regions of the world.
H Giroix, B Portha, M Kergoat, D Bailbe, L Picon, Glucose insensitivity and amino-acid hypersensitivity of insulin release in rats with non-insulin-dependent diabetes. However, diagnosis and treatment of gestational diabetes don't fulfill any of the above criteria.
GD as a concept began in 1964 when O'Sullivan and Mahan performed a 100g 3- hour oral glucose tolerance test (OGTT) on 752 pregnant women and tracked all women with at least two values above two standard deviations beyond the mean to see if hyperglycemic women were predisposed to develop diabetes down the road (O'Sullivan 1964).
This leap in logic was faulty on its face because GD does not share the risk factors of either type of true diabetes. Hunter and Keirse observe that according to Sutherland and Stowers' 1975 edition of CARBOHYDRATE METABOLISM IN PREGNANCY AND THE NEWBORN, the rate of fetal loss increases eightfold as the number of indications for glucose tolerance testing increasing from one to four. Other factors such as race, age, parity, sex, and especially maternal weight, far outweighed glucose intolerance in determining birth weight. Researchers have gone on adding rooms and stories to the GD edifice, never noticing that they have built a house on sand.
A diagnostic test should be reproducible, its thresholds should be values at which morbidity either first appears or incidence greatly increases, and normal ranges should apply to the population undergoing testing.
For one thing, O'Sullivan and Mahan tested women without regard to length of gestation, whereas today, women are typically tested at the beginning of the third trimester.
O'Sullivan and Mahan chose their cutoffs for convenience in follow-up, but all studies since then have used their criteria or some modification thereof as a threshold for pathology in the current pregnancy.
The authors of A GUIDE TO EFFECTIVE CARE IN PREGNANCY AND CHILDBIRTH relegate "screening for gestational diabetes" to "Forms of Care Unlikely to be Beneficial" (Enkin 1995).
As mentioned above, macrosomia associates with maternal weight, age, race, parity, and male fetus. No differences in perinatal mortality, morbidity, LGA or macrosomia rates were found between screened and unscreened populations, but women in the screened population were more likely to have primary cesarean sections (19 percent versus 12 percent), more clinic visits, more fetal surveillance tests, and more prenatal hospitalization (Santini et al. Even where it does work, only two studies of GD management reduced operative delivery or cesarean rates to reasonable levels, the main point of preventing macrosomia (Langer et al. The cesarean rate in a population of gestational diabetics cared for by midwives was 9 percent to 11 percent including women transferred to obstetric management, or about half the primary cesarean rate reported in populations managed by obstetricians in the same or an earlier time period (O'Brien et al. This ignores that many shoulder dystocias occur in non-macrosomic infants (Keller 1991) and that the increase in cesarean rate for infants weighing over 4000 g has not improved outcomes (Boyd et al.
Insulin increases the risk of small-for-gestational-age babies and causes symptomatic hypoglycemic episodes (Langer et al. A review article analyzes the OGTT, finds it worthless, and recommends continuing to use it to diagnose GD (Nelson 1988).
Maternal weight has the strongest correlation with macrosomia rate; it makes sense to advise heavily overweight women to lose weight before becoming pregnant.
She is now an award-winning medical writer and internationally known speaker, as well as the author of The Thinking Woman's Guide to a Better Birth. Effect of varying degrees of "normal" glucose metabolism on maternal and perinatal outcome. They were, leading the two researchers to conclude that the metabolic stress of pregnancy revealed a woman's "pre-diabetic status." This should not surprise anyone since overweight women are more likely to have hyperglycemia in pregnancy and to develop diabetes later in life.
In Type I diabetes, extremes of low and high blood glucose early in pregnancy can cause congenital anomalies or kill the forming embryo.
Hunter and Keirse observed that GD mothers had a 3-fold risk of giving birth to a baby weighing over 4500 g compared with normoglycemic women.
Glucose values rise linearly throughout pregnancy, but no corrections have been made for this. Numerous studies since have documented that birth weights and other outcomes fail to correlate with O'Sullivan's or anybody else's thresholds. O'Sullivan and colleagues randomly assigned gestational diabetics to treatment with diet and insulin and compared outcomes among treated diabetics, untreated diabetics, and a normoglycemic control population.
As with glucose values, doctors are defining deviation beyond an arbitrary point as inherently pathological.
Maternal overweight cannot be rectified during pregnancy; the rest cannot be altered at all.
1983); not to mention the role typical obstetric management plays in causing shoulder dystocia. After showing that current cutoffs fail to discriminate a group of women at high risk for macrosomia, obstetricians conclude in defiance of logic that they should lower the values or that insulin should be given to more women or that cutoffs should be chosen by fiat (Sacks et al. Pregnancy makes extra demands on insulin production; to minimize the pressure, pregnant women should eat a diet low in simple sugars, high in complex carbohydrates and fiber, and moderate in fat. Her previous book, Obstetric Myths Versus Research Realities, is a highly-acclaimed resource for childbirth professionals, and a new edition is in press.
Assessors of fetal perinatal mortality in diabetic pregnancy: analysis of 1,322 pregnancies in the Copenhagen series 1946-1972. The impact of universal screening for gestational glucose intolerance on outcome of pregnancy. Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery, and birth trauma.
Tight glucose control results in normal perinatal outcome in 150 patients with gestational diabetes. Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes.
Toward universal criteria for gestational diabetes: the 75-gram glucose tolerance test in pregnancy.
Elective induction versus spontaneous labor after sonographic diagnosis of fetal macrosomia.
The glucose and the insulin levels were examined at immediately before glucose-loading, 30, 60, and 120 min after glucose-loading. The glucose (A) and the insulin (B) levels were examined at immediately before glucose-loading, 30, 60, and 120 min after glucose-loading. For example, prevalence of diabetes across the world is forecast to increase from 171 million in 2000 to 366 million in 2030 [1].Diabetes mellitus is classified into two categories, type 1 and type 2.
Gestationally diabetic women make normal or above-normal amounts of insulin and have normal blood sugar metabolism in the first trimester. However, a woman weighing over 90 kg had a 26-fold risk of having a baby this heavy compared with normal weight women (Hunter and Keirse 1989). For another thing, O'Sullivan and Mahan studied a population that was 60 percent white and 40 percent black. An individual's blood sugar values after ingesting glucose (or food) vary widely depending on many factors. Moreover, can we justify manipulating the growth mechanism of a group of babies roughly 75 percent to 80 percent of whom will fall below the 90th percentile for weight if left alone? Goldman and colleagues reported that gestational diabetics had one-third more cesareans compared with a matched population with normal glucose tolerance, although birth weights were similar (Goldman et al. Type 1 diabetes mellitus (T1D or IDDM; Insulin Dependent Diabetes Mellitus) is characterized by a loss of insulin secretion due to pancreatic ?-cell degeneration, leading to autoimmune attack.
With either Types I or II, diabetes of long standing may damage maternal blood vessels and kidneys, causing hypertension or kidney complications.
Oats and colleagues could not find a significant association between glucose levels and birth weight until birth weight exceeded the 90th percentile. Hispanics, Native Americans, and Asian women average higher blood sugars than black or white women. For this reason, the OGTT has been abandoned as a diagnostic test for true diabetes in favor of excessive fasting glucose values, which show much greater consistency, or postprandial values of 200 mg.dl or more, which are rare.
Reducing calories by more than one-third in overweight gestational diabetics causes ketosis (Knopp et al. Within the GD population lurk a few women who were either undiagnosed pregestational diabetics or who were tipped into true diabetes by the metabolic stress of pregnancy; a fasting glucose to screen for them might be prudent. Goer has written consumer education pamphlets and numerous articles for magazines as diverse as Reader's Digest and the Journal of Perinatal and Neonatal Nursing.

Since diagnostic thresholds are set at two standard deviations beyond the mean, values for O'Sullivan and Mahan's population have arbitrarily been established as the norms for all women. Perinatal mortality statistics among non-insulin dependent diabetics remained unchanged between 1946 and 1972 in a Copenhagen study despite aggressive treatment throughout the timespan (Pedersen, JL et al. All were flawed and taken together achieved a reduction in birth weight of 87 g, a benefit "of questionable clinical significance" (Stephenson 1993). If they believed their therapy prevented macrosomia, which other work shows they did, this belief could well have influenced management decisions. In another study, gestational diabetics were randomly assigned to insulin or standard treatment in the third trimester in an effort to minimize macrosomia. And, of course, midwives already use strategies that help women minimize the likelihood of operative delivery or birth injury. Because glucose levels rise linearly throughout pregnancy, a woman could "pass" a test in gestational week 24 and "fail" it in week 28. A third study also reported similar cesarean rates in GD women and the total hospital population, but these were 27 percent and 25 percent respectively (Thompson et al. Insulin reduced LGA rates to 13 percent compared with LGA rates of 45 percent in the diet group and 38 percent in the group that refused randomization.
Finally, the poor predictability of the fetal weight estimates and surveillance tests doctors feel obliged to order, even the belief that GD is a high-risk condition, undoubtedly lead to countless unnecessary inductions and operative deliveries.
Researchers take note that sonography to estimate fetal weight did no better than a coin toss at predicting macrosomia and recommended it anyway (Combs et al. Finally, to reduce the chance of neonatal hypoglycemia, the baby should be put to breast soon after the birth, especially if the baby is big, small, or the labor has been difficult. Development of T2D is usually caused by several factors, which are combined with lifestyle, genetic defects, virus infection, and drugs [3, 4].
The one problem GD shares with both types is that chronic hyperglycemia can overfeed the fetus, resulting in macrosomia (generally defined as birth weight greater than 4000 g) or large-for- gestational-age (LGA) (greater than the 90th percentile) babies. These same problems hold true for the glucose screening test that precedes the OGTT (Sacks et al.
Conversely, a Swedish study showed a marked reduction in perinatal mortality rates between 1961 and 1971, also while treating vigorously (Karlsson et al. Despite this, cesarean rates were 14 percent and 21 percent in the diet-treated groups versus 43 percent in the insulin-treated group, a difference attributed to transferring women on insulin to the high-risk service (Buchanan 1994). Sustained hyperglycemia causes severe diabetic microvascular complications, such as retinopathy, peripheral neuropathy, and nephropathy.
Doctors find that rigid glycemic control did not improve infant outcomes and assume that means they should try harder (Hod et al.
In the diabetic states, multiple mechanisms have been implicated in glucose-mediated vascular damage and contribute to diabetic microvascular complications. In addition, postprandial state is also an important factor in the development of macroangiopathy.
Goldman and colleagues, with similar birth weights but one-third more cesareans in the GD group, congratulated themselves on the success of their management (Goldman et al. In diabetes, the postprandial phase is characterized by an exaggerated rise in blood glucose levels. It has recently been shown that postprandial hyperglycemia is relevant to onset of cardiovascular complications. From this evidence, treatment of diabetes has become a part of the strategies for the prevention of diabetic vascular complications.To help develop new diabetic treatments, it is important to reveal the complex mechanisms of diabetes. In particular, studies using diabetic animal models are essential to aid in clarification of the pathogenesis and progression in human disease course.
In this chapter, we review these three types of T2D animal models with respect to characteristic features, including impaired glucose tolerance.2.
Non-obese type 2 diabetic animal modelsCertain non-obese diabetic models are used in the investigation of T2D in humans. Since the GK rat is generally considered as one of the best models of T2D, many researchers have used this animal model to study the physiology of diabetes and its complications, and to evaluate anti-diabetes drugs. In 1973, Goto and Kakizaki of Tohoku University (Japan) started selection of this substrain from Wistar rats by mating pairs with glucose intolerance.
Since F8, sister-brother mating has been repeated, and were established as an SPF animal at F29. Today, many colonies of the GK rat exist and the rats are available for purchase from several breeders.The major quantitative trait locus (QTL) for impaired glucose tolerance is Niddm1, identified in chromosome 1.
Several loci linked to pathophysiologic characteristics was observed on chromosomes 2, 4, 5, 8, 10, and 17, indicating that the diabetic features in GK rats are inherited as polygenic traits and that GK rats would provide insights into genetics of human T2D [7]. Glucose tolerance and insulin sensitivityNon-fasting blood insulin levels in GK rats are slightly higher than in age-matched Wistar rats.
Impaired glucose-stimulated insulin secretion has been reported in GK rat in vivo [8], in the isolated pancreas [9], and in isolated pancreatic islets [10]. Perfusion experiments using isolated pancreas showed that the first phase of insulin secretion by glucose stimulation was impaired in GK rats, although the response to arginine was preserved [9].“Starfish-shaped” islets are a morphological feature of GK rat. The number of enlarged islets with irregular shape, ill-defined borders, and fibrous strands of endocrine cells is increased in aged GK rats.
These islets showed similar or moderately decreased insulin content compared with control rats. Pancreatic glucagon content is at almost the same level as in Wistar rats, and somatostatin content is slightly higher in GK rats [11]. The defective insulin response to glucose in ?-cells is due to abnormalities in the function of K+ATP channels and L-type Ca2+ channels [12].The GK rats show mild insulin resistance, mainly considered to be due to increased hepatic glucose production [8]. Drug treatment and diabetic complicationsGK rats have been widely used for evaluating anti-diabetic drugs. Almost all types of such drugs have been tested with GK rats, including sulfonylureas [13], an ?-glucosidase inhibitor [14], a thiazolidinedione derivative (troglitazone) [15], a biguanide (metformin) and a gluconeogenesis inhibitor [16], a GLP-1 analog and a dipeptidyl peptidase-4 inhibitor (DPPIV-i) [17], and an SGLT2 inhibitor [18].In addition to its useful features as a T2D model, GK rat has been used as model of diabetic complications.
Reduced motor nerve conduction velocity (MNCV) in the caudal nerve is reported in 2-month-old GK rats [19]. BackgroundStreptozotocin (STZ) is an antibiotic derived from Streptomyces achromogenes that has selective toxicity to pancreatic ?-cells.
STZ induces DNA strand breaks and a consequent excess activation of poly (ADP-ribose) synthetase, an enzyme that repairs DNA, depleting NAD in cells, which leads to energy depletion and finally causes ?-cell death [22]. Neonatal rats treated with STZ at birth (nSTZ rat) revealed acute insulin deficient diabetes at 3-5 days after birth [23]. Their pancreatic insulin contents reduced to 7% that of normal rats, and showed hyperglycemia in this period.
However, after this period, blood glucose and insulin levels in nSTZ rats were almost the same as in control rats at 3 weeks of age. At eight weeks of age, nSTZ rats showed mild hyperglycemia and impaired glucose tolerance with a 50% decrease in pancreatic insulin content [24].Recently, Masiello et al. When given a calorie-controlled high fat diet, hyperlipidemia and insulin resistance without obesity were observed [26].
Glucose toleranceThe reduction of ?-cell number and insulin content in the pancreas leads to defective insulin response in vivo.
An isolated pancreas perfusion study using adult nSTZ rats showed lack of insulin response to glucose stimulation, indicating loss of ?-cell function [27]. LGA babies happen all too often in our junk food laden culture, and it it not just a problem with GD. Reduction of GLUT2 expression in ?-cells may attribute to impaired glucose entry into ?-cells and the following insulin secretion [28]. Reduced sensitivity of KATP channel to extracellular glucose has also been suggested by the patch-clamp technique [29]. Furthermore, an in vivo study has indicated that the hepatic glucose production (HGP) in the basal state is higher in adult nSTZ rats than in control animals [30]. Ghrelin, the hunger-stimulating peptide produced in stomach, also promotes regeneration of ?-cells in nSTZ rats. When looking THAT up you realize that almost all women have a placenta on the cervix in the very early weeks. Treatment with ghrelin increased pancreatic expression of insulin and Pdx1 mRNA with a consequent improvement of hyperglycemia in nSTZ rats [38].3. But what is common knowledge in online med journals must have completely escaped all the practicing doctors, oh well. Obese type 2 diabetes animal modelsObesity is a well-established risk factor for many chronic disorders, such as T2D [39].
To understand the complicated features of the disease, spontaneously T2D models provide important knowledge. In particular, the development of diabetic animal models and pathophysiological analyses of the models are very important to aid in clarification of the pathogenesis and the patterns of progression in the human disease course.
The ob still insisted on the 24 week GD screening which clearly states that it is not accurate in the third trimester. BackgroundZucker diabetic fatty (ZDF) rat is an obese animal associated with hyperphagia, hyperglycemia, hyperinsulinemia, and hyperlipidemia.
Insulin resistance is caused by age-dependent degeneration in pancreatic ?-cells that trigger hyperglycemia. Thus, ZDF rat is a widely studied model of obesity and insulin resistance and is used for evaluation of anti-diabetic drugs.
ZDF rat was discovered in a colony of outbred Zucker fatty (ZF) rat in the laboratory of Dr. Richard Peterson at Indiana University Medical School (IUMS) started selection of this rederivation, and established an inbred line of ZDF rat in 1985. It is well known that sexual differences exist in the incidence and progression of diabetes mellitus in ZDF rat [41].
Diabetes mellitus has developed in more 90% of the males, whereas the blood glucose level remains normal in most females. However, female ZDF rat became diabetic on high-fat diet, and it was shown that the dietary fat content affected development of diabetes in females [41]. Glucose tolerance and insulin sensitivitySerum glucose levels in ZDF rat are usually elevated from 7-10 weeks of age.
ZDF rats showed hyperinsulinemia from 6 to 12 weeks, but after about 14 weeks of age their insulin levels showed a tendency to decrease.
Glucose intolerance at 12 weeks becomes more severe than that at 5-7 weeks of age [42, 43].
Age-dependent degenerative changes of pancreatic islets showed decreased production and secretion of insulin, and atrophy of islets.
Early pathological changes of the pancreatic islets, such as hypertrophy, disarray of islet architecture, and irregular islet boundaries, were observed by 10-12 weeks of age [44, 45]. The specific factor that causes deterioration of pancreatic ?-cells has not been identified, but changes in ?-cell structure and function have been well studied. It was reported that lipotoxicity based on high plasma free fatty acid could attribute to ?-cell dysfunction [46]. Reduction of islet mRNAs in ?-cells, such as those for insulin, GLUT2, and glucokinase, contributes to the ?-cell deterioration [42].
Furthermore, decrease in GLUT4 expression is also observed in skeletal muscle and adipose tissue of ZDF rat [47]. Drug treatment and diabetic complicationsIt is well known that ZDF rat is a useful model for evaluating anti-diabetic compounds. Other compounds also have been evaluated in ZDF rat, including a sulfonylurea [48], ?-glucosidase inhibitors [49], a thiazolidinedione (pioglitazone) [50], a biguanide (metformin) [51], a GLP-1 analog [52], an SGLT2 inhibitor [53], a ?3-andrenergic receptor agonist [54], and a variety of other compounds [55-58].A number of studies demonstrated that ZDF rat can be used as model of diabetic complications.

Blood urea nitrogen (BUN) levels and urinary protein excretion in ZDF rat were elevated from about 40-50 weeks of age.
Reduced MNCV in the sciatic nerve is observed from 12–14 weeks of age in ZDF rats, and endoneurial blood flow (EBF) in the sciatic nerve is also decreased after 24 weeks of age [60].
The degeneration and swelling of fibrae lentis, formation of Morgagnian globules, and stratification of epithelium lentis cells is observed in ZDF rat at 21 weeks of age [61, 62].
BackgroundOtsuka-Long-Evans-Tokushima-Fatty (OLETF) rat is a mildly obese animal associated with polydipsia, polyuria, polyphagia, hyperglycemia, and hyperlipidemia. OLETF rat is considered to be a suitable model for understanding the properties of T2D with mild obesity. The spontaneously obese rat with T2D was obtained from a colony of outbred Long-Evans rat, available for purchase from Charles River, in 1984 at laboratory of Otsuka pharmaceuticals, Tokushima [63]. A strain of this rat was established by sister-brother mating with obesity and glucose intolerance. According to the results of a study by Takiguchi [64, 65], a disrupted cholecystokinin-A (CCK-A) receptor gene in peripheral tissues and central nervous system is found in the OLETF rats [64]. Meanwhile, in peripheral tissues, CCK-A also controls satiety signals through the vagal afferent neurons [67]. Thus, dysfunctional signal of CCK may cause obese T2D, leading to hyperphagia in OLETF rats.
Glucose tolerance and insulin sensitivityNon-fasting plasma glucose levels in OLETF rats were elevated from 18 weeks of age, and the increase was sustained until 40 weeks of age.
Diabetes mellitus developed in about 90% of OLETF rats at 30 weeks of age, whereas the plasma glucose level remained normal in most females at 24 weeks of age [63, 68].
Sexual differences exit in the incidence and progression of diabetes mellitus in OLETF rats [69].
In glucose tolerance test, marked elevation of plasma glucose and insulin level responses to glucose are observed at 24 weeks of age [63]. Age-dependent degenerative changes of pancreatic islets are observed from 16 weeks of age [70]. The pathological changes of the pancreatic islets, such as hypertrophy, atrophy of insulin positive-?-cells, fibrosis, and indistinct, irregular islet boundaries, were observed by 30 weeks of age [71]. These dysfunctions of ?-cells seem to cause the development of glucose intolerance in OLETF rats.
Insulin resistance has been reported in OLETF rats at 16 weeks of age, as measured by hyperinsulinemic euglycemic clamp technique [70].
In adipocytes, the GLUT4 protein expression considerably decreased in OLETF rats at 30 weeks of age. The decrease in GLUT4 protein in muscles is also observed in OLETF rats at 30 weeks of age [72]. Drug treatment and diabetic complicationsOLETF rats have been widely used for pharmacological evaluation while testing for many anti-diabetic drugs, including a Ca2+ antagonist [73], sulfonylureas [74], an ?-glucosidase inhibitor [75], a thiazolidinedione [76], a biguanide (metformin) and a gluconeogenesis inhibitor [77], and a GLP-1 analog [78].OLETF rats are also used as a model for assessment of diabetic complications. It was reported that histopathological changes in the kidney were observed after 23 weeks of age. OLETF rats at 55 weeks of age showed an expansion of the mesangial matrix and aneurismal dilatation of intraglomerular vessels [63].
It is known that lenticular sorbitol level increases in OLETF rats from 40 weeks of age [79]. OLETF rats show swelling and liquefaction of lens fibers in the subcapsular and supranuclear region at 60 weeks of age. BackgroundWistar fatty rat develops obesity with hyperphagia, hyperglycemia, hyperinsulinemia, hyperlipidemia, and glucose intolerance. Wistar fatty rat is a good model for studying obesity and insulin resistance, and for evaluation of anti-diabetic drugs. Wistar fatty rat was established as a congenic line of the insulin resistance of the Wistar Kyoto strain (WKY) rat by introducing the fa allele of the ZF rat for obesity into the WKY rat genome in the laboratory of Dr. At 5th generation of backcrossing, male obese animals exhibit hyperglycemia, and were established as Wistar fatty rat at 10th generation.
Glucose tolerance and insulin sensitivityNonfasting plasma glucose levels in Wistar fatty rats were elevated until 8 weeks of age, and this level was sustained until 24 weeks of age. Wistar fatty rat is a widely studied model used to investigate the pathogenesis of obesity and insulin resistance, and for evaluation of anti-diabetic drugs.
In glucose tolerance test conducted at 12 weeks of age, Wistar fatty rat showed higher serum glucose and insulin levels after glucose loading compared with WKY rat, and glucose intolerance became more severe age-dependently. Hypertrophied pancreatic islets in Wistar fatty rat were increased in pancreas compared with WKY rat [80].
Insulin resistance has been reported in Wistar fatty rats, confirmed by glucose clamp technique [82]. Decreased insulin-stimulated glycogen synthesis and glycolysis in the isolated soleus muscles, and insulin-stimulated glucose oxidation and lipogenesis in adipocytes were observed in Wistar fatty rats [83]. Drug treatment and diabetic complicationsWistar fatty rats have been used as a good model for evaluation of a number of anti-diabetic drugs, including a biguanide [84], an ?-glucosidase inhibitor [75], a thiazolidinedione [85], and an DPPIV-i [86].Wistar fatty rats are also used as a model of diabetic complications. It was reported that age-related increases in urinary NAG (N-acetyl-beta-D-glucosaminidase) and urinary protein and albumin excretion in Wistar fatty rat were elevated from 5-11 weeks of age.
Wistar fatty rats at 26 weeks of age showed an expansion of the glomerular mesangial matrix and local formation of a nodular-like lesion. Reduced MNCV in the fibula nerve and histopathological changes, such as demyelination and axonal degeneration, were observed in Wistar fatty rats [88]. BackgroundThe Spontaneously Diabetic Torii (SDT) rat is a new inbred strain of Sprague-Dawley (SD) rat established as a non-obese model of type 2 diabetes mellitus. The cumulative incidence of diabetes was 100% by 32 weeks in male SDT rats, while it was only 33% in females even at 65 weeks. As a result of chronic severe hyperglycemia, the SDT rats developed severe complications in eyes, peripheral nerves, and kidneys. Especially, ocular complications including the diabetic retinopathy in SDT rats is noteworthy [90].
Of many diabetic ocular complications, cataract, retinopathy, and neovascular glaucoma (hemorrhagic glaucoma) are the most important clinically. Glucose tolerance and insulin sensitivityIn SDT rats, development of hyperglycemia may be more dependent on decreased insulin secretion than insulin resistance, as shown by the fact that the blood insulin concentration tended to be lower than in normal SD rats even before the onset of diabetes, and marked hypoinsulinemia developed after the onset of hyperglycemia [91-93], indicating that this strain of rat is a model of non-obese T2D associated with impaired insulin secretion.
In oral glucose tolerance test in SDT rats, glucose tolerance markedly decreased at least 3 months before manifestation of hyperglycemia (around 16 weeks old), and the rate of rise in blood glucose level after glucose-loading increased with age. We examined the glucose tolerance periodically at 5, 9, and 13 weeks of age in SDT rats (Figure 1.). Figure 1.Glucose tolerance test (GTT) at 5, 9, and 13 weeks of age in SD rats and SDT rats. The blood glucose level before glucose-loading and the level at 120 min after glucose-loading in SDT rats significantly decreased as compared with those in SD rats. The blood insulin level at 30 min after glucose-loading was not different from that in SD rats, but the insulin levels at the other points significantly decreased as compared with those in SD rats (Figure 1B.).
The insulin levels at points except for 120 min after glucose-loading in SDT rats was comparable with those in SD rats (Figure 1D.), but the insulinogenic index showed a lower level than SD rats (Figure. In male rats, the severity of impaired glucose tolerance before the onset of diabetes was closely correlated with the age. In addition, the insulin secretion level in pancreatic islets of Langerhans from SDT rats after glucose treatment markedly decreased at 12 weeks of age and thereafter compared with normal SD rats. Likewise, the mRNA expression levels for GLUT2 and glucokinase (GK) in the isolated pancreatic islets of Langerhans markedly decreased at 12 weeks and thereafter in SDT rats [94].
In female rats, glucose tolerance also decreased, at 25 weeks and thereafter, but insulin was secreted after glucose-loading, indicating that some factors cause insulin resistance or insulin requirement in the females, unlike in the males [95].It is reported that the pancreatic insulin content in SDT rats at 7 weeks of age decreased as compared with that in SD rats [96]. In human, ? cell mass in impaired fasting glucose (IFG) subjects significantly decreased as compared with that in nondiabetic subjects [97]. Other non-obese type 2 diabetic models, such as GK rats and the nSTZ rats, did not show a pre-diabetic state. Drug treatmentIn previous study, ?-glucosidase inhibitor voglibose was administered to male SDT rats in a pre-diabetic stage, and the effects of voglibose on the glucose intolerance and the development of diabetes were investigated [98].
Moreover, voglibose was administered as a dietary mixture to SDT rats from 10 to 20 weeks of age. In clinical study, ?-glucosidase inhibitor, such as voglibose and acarbose, showed a prevention of type 2 diabetes mellitus [99, 100]. The results showed that pharmacological intervention with voglibose in SDT rats with IGT can delay progression to T2D.
The decreased sensitivity to insulin leads to an increased requirement for insulin, and is often associated with obesity in which metabolic disturbances are marked in insulin-target organs, such as the liver, muscle and adipose tissues [102]. Obesity plays key roles in the pathophysiology of several metabolic diseases and is a risk factor for diabetes mellitus and dyslipidemia. Based on the above concept, a novel model of obesity-related diabetes was established by Masuyama et al.
They established a congenic line of the Spontaneously Diabetic Torii (SDT) rat by introducing the fa allele of the ZF rat into the SDT rat genome via the Speed Congenic Method using a PCR technique with DNA markers. This congenic strain has been maintained by inter-crossing between fa-heterozygous littermates.
Glucose tolerance, insulin sensitivity and drug treatmentMetabolic disorder in SDT fatty rats was obviously promoted as compared with SDT rats [104, 105]. Serum glucose levels in SDT fatty rats of both sexes were elevated from 6 weeks, and lipid parameters such as serum triglyceride and total cholesterol levels in the rats were elevated from 4 weeks of age. With early incidence of diabetes mellitus, diabetes-associated complications in SDT fatty rats were seen at younger ages than those in the SDT rats. SDT fatty rats did not almost show a pre-diabetic state, since the rats showed a hyperglycemia from a young age.
However, the glucose intolerance in SDT fatty rats is considered to exist with the progression of diabetes mellitus.We evaluated the pharmacological effects of an anti-diabetic drug, DPPIV-i on SDT fatty rats. DPPIV-i is expected to control postprandial hyperglycemia in patients with type 2 diabetes mellitus without increasing body weight.
SDT fatty rats at 9 weeks of age showed a prominent hyperglycemia after glucose-loading (Figure 4A.). The glucose levels at 30 and 60 min after glucose-loading in the SDT fatty rats significantly increased as compared with those in SD rats. Moreover, the insulin levels at 30 and 120 min after glucose-loading in the SDT fatty rats increased as compared with those in SD rats (Figure 4B.).
The GSIS in SDT fatty rats was accelerated as compared with SD rats, suggesting that hyperinsulinemia (insulin resistance) exists in the SDT fatty rats at 9 weeks of age. Glucose intolerance in SDT fatty rats is considered to be related with both the insulin resistance and the impaired insulin secretion.
Each of these models has different features as described above (Table 1.), and each model acts as an important tool for revealing the complex mechanisms of diabetes and developing new anti-diabetic drugs. Studies using diabetic animal models are especially essential to aid in clarification of the pathogenetic development in human T2D.

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