Insulin tolerance test type 2 diabetes quiz,insulin resistance treatment type 1 diabetes symptoms,m en m personaliseren - Good Point

Type 2 Diabetes Mellitus is a metabolic disease characterized by hyperglycemia due to defective insulin secretion, insulin action or both. There is currently an epidemic of Type 2 Diabetes throughout the world that is rapidly worsening, the number of cases in Canada is expected to double between 2000 and 2010.
Insulin resistance is defined as an impaired biologic response to either exogenous or endogenous insulin (12). Initially insulin resistance is compensated by hyperinsulinism; as the beta cell becomes exhausted and can no longer keep up, we develop impaired glucose tolerance (IGT). Individuals with the metabolic (insulin resistance) syndrome are at dramatically elevated risk for diabetes, ischaemic heart disease, stroke, kidney failure, blindness and nerve disease. The goal of the metabolic process is to provide the required amounts of energy to the body. So that we don’t have to be eating constantly in order to keep on living, the body (primarily the liver) is capable of producing glucose (gluconeogenesis) from amino acids, lactate, pyruvate and glycerol. Protein metabolism consists of breakdown of protein to amino acids and synthesis of protein from amino acids. In the early stages, the decreased glucose disposal (from decreased glycogen formation) and the increased glucose production (by the liver) are compensated by increased insulin production by the pancreas so glucose levels remain normal.
This is a genetic adaptation which would enhance survival in individuals living in an environment of frequent famine. We know that the risk of microvascular disease (retinopathy, nephropathy, neuropathy) increases directly with glucose levels and this is one reason why the diagnostic levels of glycemia were changed in the 1998 CDA guidelines for diagnosis of Diabetes. What tends to be less well known is that the threshold of glycemia for development of macrovascular disease is much lower.
The major cause of death in type 2 diabetics and in people with impaired glucose tolerance is ischaemic heart disease. Individuals with insulin resistance and type 2 diabetes have abnormal lipids including elevations of triglycerides and low HDL (8). In insulin resistance and type 2 diabetes there is enhanced clotting and inhibited clot breakdown which explains the increased risk of acute coronary occlusion and myocardial infarction. Insulin resistance contributes to endothelial dysfunction by stimulating smooth muscle cell proliferation, stimulating growth factors, increasing formation and decreasing regression of lipid plaques and by stimulating connective tissue synthesis. Insulin resistance contributes to insulin induced hypertension by enhancing renal tubular reabsorption of sodium and increasing the tone of the sympathetic nervous system. The result of these lipid, glucose and hemostatic abnormalities results in increased risk of coronary heart disease and worsens the prognosis following a coronary event. Insulin resistance is the first abnormality seen in the individual who will develop type 2 diabetes. Exercise: Exercise is one of the most effective means at our disposal to increase non-insulin dependant glucose transport. Diet: Even a modest weight loss of 5% of total body weight can lead to a significant improvement in insulin resistance and glycemic control as well as improving lipid profile and lowering blood pressure. In the UKPDS, few subjects were able to maintain a HgbA1c below 7% by lifestyle measures alone and with time there was a inexorable progression to higher glucose levels as pancreatic beta cell function declined. Pharmacologic treatment: The object of pharmacologic treatment should be to improve insulin resistance and to reduce glucose levels. Drugs that increase pancreatic insulin production: Drugs such as the sulphonylureas or meglitinides that increase insulin production should be avoided unless insulin deficiency predominates. Drugs that slow intestinal absorption of carbohydrate: The alpha glucosidase inhibitors (acarbose), impair the breakdown of disaccharides and starches in the proximal portion of the small bowel. Drugs that improve glucose uptake and utilization in adipose tissue and muscle, thereby reducing insulin resistance: The thiazolidinediones or glitazones, rosoglitazone and pioglitazone. The enhanced glucose transport leads to decreased glucose levels and increased glycogen formation. UK Prospective Diabetes Study Group XI: Biochemical risk factors in type 2 diabetic subjects at diagnosis compared with age-matched normal subjects. During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. HNF-4α controlling many genes involved in liver function such as the GLUT2 and L-PK genes.
Evidence on the mode of action of metformin shows that it improves insulin sensitivity by increasing insulin receptor tyrosine kinase activity and enhancing glycogen synthesis in hepatocytes, and by increasing recruitment and transport of GLUT4 transporters to the plasma membrane in adipose tissue. In addition to its effects on hepatic glucose and lipid homeostasis and adipose tissue lipid homeostasis, metformin exerts effects in the pancreas, vascular endothelial cells, and in cancer cells. Science, Technology and Medicine open access publisher.Publish, read and share novel research.
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. I will show you an easy and safe way to assess how far down the Road to Diabetes you have already travelled. The following test is my version of the Glucose Tolerance Test which is used by doctors to determine if you are diabetic or not. If you discover you are diabetic, you should continue to take another glucose test every hour, for another four hours, or until glucose drops below 105. According to me, there is a right way and a wrong way to eat to avoid or slow down diabetes. Fortunately, I think that now I have finally learned to eat correctly because now I learned to test my glucose levels before and after most meals.
How far down that road to diabetes we have already travelled depends on the state of our pancreas, and very few people know how well their pancreas is working. The values obtained tell a lot about your body metabolizes sugar, and the state of the pancreas.
FOUR ENGINES-- You are flying high and fast, Clear weather ahead, no problems are expected.
However, now that you know that you have lost one engine it makes sense that you should do everything possible to avoid losing any other engine, which would definitely not be good for your health. Severe symptoms, including psychotic or neurotic behaviour, might occur during the traditional glucose tolerance test, but probably not with a large glass of orange juice. No part of this site or its content may be reproduced in any form or by electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the copyright holder. The information provided on this site is provided for illustration purposes only and does not represent a proposal or specific recommendation. It is the defective insulin action or Insulin Resistance that is one of the greatest challenges in Diabetes management. The cost in lives lost and the financial cost of dealing with the medical complications of diabetes is staggering. As long as the pancreatic beta cell can compensate for the insulin resistance by producing more insulin; glucose levels will remain normal. People with diabetes have up to four times the risk of developing ischaemic heart disease of age matched non diabetics.
In the fasting state when insulin levels are low, triglycerides are broken down by lipolysis to free fatty acids and glycerol. In susceptible individuals there is impaired suppression of hepatic glucose production by insulin. As the disease progresses, the pancreatic beta cell production decreases and and is unable to keep up with the body's needs in times of stress. Obesity and particularly abdominal obesity is associated with decreased levels of insulin mediated glucose uptake but is the obesity the cause or the effect of insulin resistance (3). The old fasting glucose level for diagnosis of diabetes had been 7.8 but at this level 20% of newly diagnosed diabetics already had microvascular disease. The cardiac risk of type 2 diabetes is the same as having had a previous coronary event (7). In the United Kingdom Prospective Diabetes Study (UKPDS) (9), men with diabetes had elevated triglyceride levels and lower HDL compared to control while women had the same elevated triglyceride values and low HDL but they also showed higher LDL than controls.
There are increased levels of fibrinogen, plasma activator inhibitor-1 (PAI-1), factor V and D-dimer; all of which contribute to enhanced thrombogenesis as well as decreased fibrinolysis (11). The platelets are more sensitive to aggregating agents such as epinephrine, thromboxane and thrombin as well as having increased glycoprotein receptors (11).
50% of type 2 diabetics will die from coronary ischaemic events and of those that suffer an MI, 44% will be dead in the next year.
Initially there is hyperinsulinism but as the pancreatic beta cell is no longer able to produce the increased amounts of insulin needed for glucose control; relative insulin deficiency results and glucose levels start to rise.
The sugars and starches must be broken down to monosaccharides before they can be absorbed though the bowel wall into the blood.
It is known that elevated plasma free fatty acids which are seen in insulin resistance and type 2 diabetes impair glucose transport.
The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes. Metabolic consequences of a family history of NIDDM (the Botnia Study): evidence for sex specific parental effects. Association of increased intramyocellular lipid content with insulin resistance in lean non diabetic offspring of type 2 diabetes subjects.
Mortality from coronary heart disease in subjects with type 2 diabetes and in non diabetic subjects with and without prior myocardial infarction.
Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose intolerance. Another exenatide-related drug is Bydureon® which is a once-a-week injectable form of exenatide. A more recent addition to the GLP-1 receptor agonist family of diabetes drugs is Trulicity® (dulaglutide) manufactured by Eli Lilly and Co.
Additionally, it has been shown that metformin affects mitochondrial activities dependent upon the model system studied.
The latter effects of metformin were recognized in epidemiological studies of diabetic patients taking metformin versus those who were taking another anti-hyperglycemia drug. 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.
But now that you know that you are in trouble, you should take very good care of your two remaining engines so that you won't lose another one!
As a word of caution, the information presented cannot possibly substitute for competent medical advice.
Traditionally our thinking has been that it is the chronic glucose elevation of diabetes that leads to the damage and dysfunction to the kidney, eye, nerves and blood vessels.
It is only by understanding and developing effective treatment for Insulin Resistance that we can hope to deal to this threat to our lives and health. The difficulty is that we really don’t have any easy way of identifying and measuring insulin resistance.
It is only when the beta cell becomes impaired and insulin secretion is inadequate to compensate for insulin resistance that glucose levels rise. The diagnosis of Diabetes is based on a glucose level but the disease that caused this glucose level has been present for years. The body has energy reserves of carbohydrate in the form of glycogen and fat in the form of triglycerides. Insulin inhibits protein breakdown and stimulates protein synthesis while glucagon and low insulin levels favour protein breakdown. The production of insulin cannot keep pace with acute needs and and initially early phase insulin secretion is lost. Abdominal fat tissue could provide a chain of events leading to skeletal muscle insulin resistance which appears to be the first step in the cascade leading ultimately to Type 2 Diabetes.
In times of plenty this genetic background could become detrimental, leading to increased free fatty acids and intra myocellular lipid with insulin resistance. The composition of the HDL and LDL particles is also different in subjects with insulin resistance, IGT and type 2 diabetes with a decrease in particle size of both HDL and LDL.
Treatment of insulin resistance is therefore of paramount importance in decreasing morbidity and mortality. The study of De Vegt has shown that almost 65% of patients with both IGT and IFT will progress to diabetes over a 6 yr period (14).
Metformin predominantly works by decreasing hepatic glucose production especially nocturnal gluconeogenesis.
The action of acarbose will delay but not prevent absorption, thus there is more time for glucose disposal from the blood and high post prandial glucose peaks may be avoided.

This leads to enhanced production of the target genes which are involved in carbohydrate and lipid metabolism. The glitazones impair breakdown of triglyceride leading to lowering of plasma free fatty acids and therby improving glucose transport.
In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Metformin has a mild inhibitory effect on complex I of oxidative phosphorylation, has antioxidant properties, and activates both glucose-6-phosphate dehydrogenase, G6PDH and AMP-activated protein kinase, AMPK. King, Indiana University School of Medicine and Indiana University Center for Regenerative Biology and Medicine, Terre Haute, IN. We are now realizing that the risks and damage may start years before blood glucose levels rise above normal. The only reliable measurement of insulin resistance is the hyperinsulinemic euglycemic clamp which is complex and costly. Initially there may be adequate insulin production in the fasting state but an inability for the pancreas to cope with the stress of high carbohydrate intake resulting in post prandial hyperglycemia. The first manifestation of disease has been insulin resistance and elevated serum insulin levels. Glucose production and release are stimulated by catecholamines (epinephrine & norepinephrine) and glucagons while liver glucose production is suppressed by insulin.
There are certainly genetic factors in the development of Type 2 Diabetes and the first of these may be the genetic factor for abdominal obesity (4).
Low birthweight is also a risk factor for development of insulin resistance and diabetes mellitus (6). Most people with insulin resistance already have elevated glucose levels though they may not yet be in the diabetic range, this increased level of basal glycemia increased the risk for ischaemic heart disease. The decreased particle size of the HDL confers less protection against heart disease while the smaller denser LDL particles are more easily oxidized and are more atherogenic (10). The hyperinsulinism and the cluster of related symptoms such as hyperlipidemia, obesity, hypertension, hypercoagulability and microalbuminuria lead to increased risk of death and illness. Since the sugar and starch load is carried further down the GI tract there is more time for fermentation and thus abdominal cramps and gas may limit utility. Levels of Glut-1 and Glut-4 are increased, these are glucose transporters which transport glucose across cell membranes.
Increased free fatty acids also lead to increased liver gluconeogenesis and decreased glycolysis so the decrease in FFA decreases gluconeogenesis, increases glycolysis and lowers plasma glucose. Pancreases from transgenic mice showed an increase in ?-cell mass (about 3-fold) and in insulin mRNA levels. The importance of AMPK in the actions of metformin stems from the role of AMPK in the regulation of both lipid and carbohydrate metabolism (see AMPK: Master Metabolic Regulator for more details). 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.
In order to arrive to your destination it will be very important to care for your last remaining engine. We have tried other models of measuring insulin resistance such as the HOMA-IR model which relates fasting glucose levels to fasting insulin levels but this test has considerable variability and has not been useful in clinical practice. In 1988 Gerald Reaven recognized a cluster of risk factors commonly present in individuals with high insulin levels (Reaven G. Some tissues can utilize other energy sources such as fat or protein but the brain is wholly dependant on glucose oxidation to maintain metabolic processes. It is unlikely that a single genetic variant is the cause of insulin resistance and type 2 diabetes. Metformin use is not associated with weight gain but GI side effects frequently limit the dose that may be used. This class of drugs is particularly helpful in the early stages of diabetes when HgbA1c levels are only modestly elevated and small decreases in blood glucose are needed to bring glycemia to goal levels.
By decreasing hepatic phosphenolpyruvate carboxykinase (PEPCK) the glitazones reduce hepatic insulin resistance. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. In adipose tissue, metformin inhibits lipolysis while enhancing re-esterification of fatty acids.
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.
Transfer of glucose across cell membranes is essential for providing the fuel to power the cell. The transition from normal glucose tolerance to IGT and to Type 2 Diabetes is a reflection of the deterioration of the function of the pancreatic beta cell (2). Insulin signaling is also increased by increases in IR tyrosine phosphorylation, increases in IRS-1 tyrosine phosphorylation, increases in Phosphatidylinositide 3 kinase, and decreases in Tumour Necrosis Factor alpha action. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice.
The activation of AMPK by metformin is likely related to the inhibitory effects of the drug on complex I of oxidative phosphorylation. If you have a particular question about the information presented, you can send me an e-mail and I will try my best to help you.
The glucose transporters Glut 1 in the fasting state and Glut 4 in the fed state transfer glucose across the cell membrane into the cell.
Not only elevated insulin and glucose levels but also elevated free fatty acid levels are characteristic of the insulin resistance syndrome and type 2 diabetes mellitus. If a normal fasting glucose cannot be attained using metformin alone, then another drug needs to be added. In the STOP NIDDM trial reported at the EASD meeting in September 2001, acarbose given with meals to individuals with IGT decreased the conversion to type 2 diabetes over a 5 year period. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. This would lead to a reduction in ATP production and, therefore, an increase in the level of AMP and as a result activation of AMPK. This was initially referred to as syndrome X and is characterized by hypertension, obesity (particularly abdominal), high triglyceride, low HDL and impaired glucose tolerance. There are also lipid effects with increased Lipoprotein lipase activity leading to increased triglyceride breakdown and increased Phosphodiesterase 3B leading to decreased intra-adipocyte lipolysis.
Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. Awake fed control and transgenic mice were injected intraperitoneally with 0.75 IU of a soluble insulin. In fact, since the cells of the gut will see the highest doses of metformin they will experience the greatest level of inhibited complex I which may explain the gastrointestinal side effects (nausea, diarrhea, anorexia) of the drug that limit its utility in many patients. Development of T2D is usually caused by several factors, which are combined with lifestyle, genetic defects, virus infection, and drugs [3, 4]. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.
Blood samples were taken from the tail vein of the same animals at the times indicated, and glucose concentration was determined as indicated in Methods. Sustained hyperglycemia causes severe diabetic microvascular complications, such as retinopathy, peripheral neuropathy, and nephropathy.
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. 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]. 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. Treatment with ghrelin increased pancreatic expression of insulin and Pdx1 mRNA with a consequent improvement of hyperglycemia in nSTZ rats [38].3.
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. 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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