Alternative treatments type 2 diabetes mellitus,is the 30 day diabetes cure for real madrid,cure for diabetes blindness,gl amg black series - PDF Review


Natural Alternative medicine’s practitioners believe that best treatment is possible for hypertension by enlivening the mental or body system, which are responsible for this high blood pressure.
At the initial stages of treatment, you should be more vigilant on your blood-pressure levels, because it may drops to hypotension.  If the blood pressure is dropping consistently, proportionally you should reduce your conventional oral medication. Alternative medicine practitioners claim there are no or only minor side effects in alternative medicine treatment. Alternative treatment not only helps hypertension treatment; furthermore, helps to avoid or slow down long-term blood pressure complications such as eye, kidney, heart diseases, and stroke.
Here we have provided some blood pressure natural treatments; you can combine them together to improve its effectiveness as complementary as well as integrative therapy. Blood pressure homeopathy – is a nano-pharmacology, which uses very small doses to treat illness without side effects. Yoga for blood pressure - can combat the causes, as well as the effects of hypertension and stabilizes blood pressure.
Acupressure hypertension healing - As per TCM, hypertension is not an identified pathology cause, but it can effectively treat.
It also provides a sample daily menu plan and daily record to write down your daily food intake as wells as physical activity.
I had a look at that study and it is far from conclusive so I agree with the comment that Type 2 diabetes cannot be reversed.
This work is performed in our NHS Vitamin D laboratory that also offers a national Vitamin D service for the NHS in the United Kingdom. The story: a woman brings in her teenage daughter, complaining that the girl is tired a lot. There is a simple blood test to measure vitamin B12 levels, though the levels in the blood don’t always correlate with whether there are enough B12 levels in the cells themselves.
So: people seem to think they feel better with injections, and the doctor makes a little cash, and everyone’s happy. He specifically mentions that patient’s who have had portions of their gut removed are likely candidates for B12 injections. I normally don’t post comments on blogs (even though I publish monthly on this one), but I just wanted to thank you and commend you for calling out this emperor with no clothes. Is the object to have the patient feel better or to follow the latest evidence-based protocol?
When I started pharmaceutical sales in the early seventies I knew quite a number of physicians that did B12 injections. I had another doctor tell me that he had a patient that was convinced her husband was trying to kill her, the doctor knew the husband and family for years, and there was no evidence of abuse. Go ahead, keep writing Adderall and Zoloft prescriptions for an MTHFR mutation – you will have a patient for life. 40% of the population have one polymorphism or another, I don’t think the evidence supports that 40% have a damaging MTHFR mutation? What this means, IMHO, is that these people are more likely to suffer from B12 stress (resulting in B12 deficiency). I would love to see the study that says B12 injections are an elaborate hoax for the majority of people.
Why would the pharmaceutical industry want me to write an article criticizing the use of their product? In other words, the patient wants thedoctor to lie, in order to save a few dollars on the vitamin. In the UK, you can’t purchase any injectable B12 without a prescription or from a UK sourced website.
Actually, strictly speaking, in the USA it **does** require a prescription, as described above, but there are many ways around that. Transdermal (through the skin) with a reservoir and a chemical vehicle may not be good enough for you, Seems you need a needle. Your own UK pernicious anemia sites and B12 sites discuss various ways to get the injectable vitamin if you have your heart set on it. This law also underscores the fact that research suggests injectable B12 is the most effective and only recommended treatment.
Active transport to extract B12 from food, and passive absorption of crystalline B12 from a tablet, are two completely different things. Even in the presence of pernicious anemia, passive absorption of B12 might be 1% but the B12 tablets contain 1000-2000 mcg each. Hey, if someone walks in my office, asks for B12 injections, I’ll try to talk sense to them.
Just don’t expect me to lie to the insurance company and say its medically necessary. Ninguem – if you, or someone in your family, ever find themselves in the same position as many others of us, come to us and we will still try to help you. While on the subject, how about hugely overpriced B vitamins, which failed as treatment for hyperhomocysteinemia, which have now been repurposed as treatments for neuropathy? Science, Technology and Medicine open access publisher.Publish, read and share novel research. Fulminant Type 1 Diabetes Mellitusin IRS-2 Deficient MiceToshiro Arai1, Nobuko Moriand1 and Haruo Hashimoto1[1] Nippon Veterinary and Life Science University, Japan1. 2007 Fulminant type 1 diabetes in Korea: highprevalence among patients with adult-onset type 1 diabetes. 2003 Inflammatory mediators and islet ?-cell failure: a link between type 1and type 2 diabetes.
2009 Reconsideration of 2sulin signals induced by improved laboratory animal diets, Japanese and American diets, in IRS-2 deficient mice. 2000 A novel subtype of type 1 diabetes mellitus characterized by a rapid onsetand an absence of diabetes-related antibodies. 2005 Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus.
2000 Tissue-specific insulin resistance in mice withmutations in the insulin receptor, IRS-1, and IRS-2. 2000 Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. 2002 Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survivalduring chronic hyperglycemia.
2001 Distict effects of saturated and monosaturated fattyacids on beta-cell turnover and function. 1997 Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cell.
Lipid Disorders in Type 1 DiabetesBruno Verges1[1] Service Endocrinologie, Diabetologie et Maladies MetaboliquesDijon University Hospital, France1.
2008 Prevalence and determinants of elevated apolipoprotein B and dense low-density lipoprotein in youths with type 1 and type 2 diabetes. 1990 Atherogenic lipoprotein phenotype : a proposed genetic marker for coronary heart disease risk. 1989 Whole-plasma and high-density lipoprotein subfraction surface lipid composition in IDDM men.
1991a Accelerated cholesteryl ester transfer in plasma of patients with insulin dependent diabetes mellitus.
1991b Effects of continuous insulin infusion therapy on lipoprotein surface and core lipid composition in insulin-dependent diabetes mellitus. 1994 Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.
1996 Improved lipoprotein surface and core lipid composition following intraperitoneal insulin delivery in insulin-dependent diabetes mellitus. 1996 Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesteryl ester transfer in IDDM subjects. 2001 Serum paraoxonase is reduced in type 1 diabetic patients compared to non-diabetic, first degree relatives; influence on the ability of HDL to protect LDL from oxidation.
1997 Optimization of glycemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients. 2001 Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose.
2001 Lipid transfer protein activities in type 1 diabetic patients without renal failure and nondiabetic control subjects and their association with coronary artery calcification.
1987 Secretion of lipids, apolipoproteins, and lipoproteins by human hepatoma cell line, HepG2: effects of oleic acid and insulin. 2005 Association of postprandial hyperglycemia with in vitro LDL oxidation in non-smoking patients with type 1 diabetes--a cross-sectional study.
1989a Alterations in serum lipids and apolipoproteins in male type 1 (insulin-dependent) diabetic patients with microalbuminuria.
1989b Increased cholesteryl ester transfer activity in complicated type 1 (insulin-dependent) diabetes mellitus--its relationship with serum lipids.
2005aillot-Rudoni S, Lalanne-Mistrich ML, Brun-Pacaud A, Petit JM, Brun JM, Gambert P, Verges B (2005) Comparison of apolipoprotein B100 metabolism between continuous subcutaneous and intraperitoneal insulin therapy in type 1 diabetes. 2007 No change in apolipoprotein AI metabolism when subcutaneous insulin infusion is replaced by intraperitoneal insulin infusion in type 1 diabetic patients.
2008 Longitudinal screening of serum lipids in children and adolescents with Type 1 diabetes in a UK clinic population. 2004 Protective effect of paraoxonase activity in high-density lipoproteins against erythrocyte membranes peroxidation: a comparison between healthy subjects and type 1 diabetic patients. 1993 Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men.
2010 Risk factors for mortality and ischemic heart disease in patients with long-term type 1 diabetes. 2009 Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case-control study. 2009 Lipid peroxidation in early type 1 diabetes mellitus is unassociated with oxidative damage to DNA.
1990 Differences in lipoprotein subfraction composition and distribution between type I diabetic men and control subjects. 1991 Blood rheology and cardiovascular risk factors in type 1 diabetes: relationship with microalbuminuria.
1987 Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. 1989 Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria.
1989 Interaction of very-low-density lipoprotein isolated from type I (insulin-dependent) diabetic subjects with human monocyte-derived macrophages. 1994 Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies. 1993 Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apo B production in normal weight and obese individuals.
2005 Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus.
Today, scientific research has shown that our eating habits are strongly linked to the risk of chronic diseases like obesity, heart disease, and diabetes.
But now, a study partly funded by the USDA (Department of Agriculture) and sponsored by the National Institutes of Health (NIH) has found an association between nutrition and macular degeneration (AMD), a common eye disease.
The study found an increased risk of developing AMD among people who consume a diet characteristic in Western developed countries.
Meanwhile, people who ate a typical Asian diet—high consumption of vegetables, legumes, fruit, whole grains, tomatoes, and seafood—had a lowered risk of developing AMD. The study was based on food consumption data obtained from 4,000 participants who either had little or no drusen in their eyes, intermediate to high levels of drusen (early AMD), or an atrophied macula (advanced AMD). Scientific studies have shown that consuming an Asian diet can reduce the risk of a number of different chronic diseases. For example, eating lots of green leafy vegetables like bok choy, Chinese broccoli, and Chinese cabbage can help prevent heart disease. Soybean products like tofu or soy milk contain isoflavones, an element that can reduce cholesterol and prevent against cancer, according to University of California, San Francisco’s Cancer Resource Center. Instead of the Western diet of eating lots of meat—which is high in saturated fat—people in Asia traditionally consume lots of fish like salmon and mackerel, which contain omega-3 fatty acids. Finally, the Cancer Resource Center recommends drinking one to three cups of green tea every day. It can rejuvenate heart, kidney and other organs, thus normalizes blood circulation and in-turn blood pressure. Additionally, it can lower cholesterol level, improve digestion, strengthen heart & kidney and detoxify your body.
Additionally, it can nourish kidney, liver, eye, and hearts that may affect by hypertension complications.
In the case of hypertension, it alleviates the problem by stimulating our own body and correcting the root-cause, even it may be mental reasons (stress).
Yoga calms the mind, regularizes, and balances the autonomous nervous system the center controls stress. Patients with hypertension will likely have a diagnosis for liver wind with liver and or kidney involvement. Therefore, treatment for hypertension is by stimulating particular reflex-points of the organ responsible for its cause.
In This Article Diabetes is on the rise yet most cases are preventable with healthy diabetic meal planning software freeware nz forum lifestyle changes.
It turns out that mom herself has had some blood tests that showed a low vitamin B12 level, so her doctor is giving her regular B12 injections.
It can occur because of a poor diet, or because some medications (like acid blockers) interfere with absorption. We can test for this, too, indirectly, through other blood tests including methylmalonic acid and homocysteine levels. The treatment of B12 deficiency, as has been established from studies done in the 1960s, is ORAL B12.
Patients come to us for genuine answers—if they wanted a witch doctor, they would have found one. Clearly you have no idea about the properties of the different forms of vitamin B12, which are far from limited to treating a deficiency. If the ileum is where B12 is absorbed, and you no longer have one, then the ORAL B12 isn’t going to help much. These people should be working with a specialist for nutritional advice regarding B12 and other micronutrients. Can’t you just consider for a moment that maybe the reason the patient is feeling better is that the injection has delivered B12 into their system which couldn’t be achieved any other way? But if the only issue is B12 deficiency from whatever mechanism, then the treatment is to deliver B12 to the body. Everyone was injecting, and the supply problem left people thinking the vitamin could not be taken orally, even when the supply problem was fixed. It must be wonderful to know it all and decide that patients are having a placebo effect and are tolerating injections just because they actually like them!
The reality of that, to getthe insurance coverage, is to get the physician to SAY that theinjection is needed.
For a generation or more, physicians were told the only way to get B12 in the body was by injection. Add to that the fact that a lot of people are not confident to start injecting themselves without proper guidance and monitoring – and who can blame them? The reason why people are having to take risks buying it online is because their doctors won’t given them what they need and the option is not available to buy it themselves from pharmacies (in the UK). Although many contributors on those sites point out the same thing, crystalline B12 tablets are absorbed orally just fine.
Unfortunately this law is based on the faulty presumption that doctors are knowledgeable about this condition and are willing to treat it correctly. We promise not to cast it up to you and will nod sympathetically when you say, “But all the books said . I have no idea how he got them to ingest vomit, but it probably contained enough of his own intrinsic factor to facilitate B12 absorption. Effects of modern Japanese and American diets on RNA expression of GLUT4 and PPAR?2 of adipose tissues and plasma adipocytokines concentrations in IRS-2 deficient mice fed with three kinds of diets with different lipid levels. Effects of modern Japanese and American diets on intraperitoneal white adipose tissues, (a) Axial views, (b) Coronal views of MRI, and (c) Adipocytes in white adipose tissues of IRS-2 deficient mice with three kinds of diets with different lipid levels. IntroductionType 1 diabetes mellitus (T1DM), one of two major forms of diabetes, results from nearly complete destruction of pancreatic beta (?) cells. IntroductionCardiovascular disease is the major cause of death in persons with type 1 diabetes (Libby et al., 2005). Researchers noticed a pattern of high intakes of red meat, processed meat, high-fat dairy products, French fries, and refined grains. If you are interested in trying natural blood pressure treatment, do so along with your conventional medicine (i.e. If you are able to choose an individualized remedy, then effective blood pressure treatment is possible. The sympathetic and parasympathetic nervous systems are responsible for stress reaction; regular yoga practice harmonizes thus better regulation of blood pressure.


As the liver controls the blood in TCM, circulation issues generally arise from a disharmony of the liver.
High blood pressure can successfully control by reflexology treatment.  Just my manipulating these points by gentle firm massage, you can normalize your BP as well as prevent long-term complications. Genetic risk factors for cardiovascular disease in patients with type 2 diabetes may reveal biological pathways that can help explain the increased risk of macrovascular complications in type 2 diabetes.
This causes a toxic buildup of acids called ketones in the blood – a sign that your diabetes is out of control. The symptoms of kidney involvement are swelling over feet face and decreased urine output presence of microlumin & protein in urine rise in blood pressure. Most often rheumatoid arthritis begins in the hands and feet but it can affect many Joint pain after exercise probably means that you overdid it and that you The test was done with a glucometer on a capillary finger prick sample.
Or it can occur because of a specific autoimmune disorder called “Pernicious Anemia.” Whatever the cause, the health consequences of vitamin B12 deficiency can include anemia, neuropathy, irritability, and depression.
Placebos need rituals—with acupuncture, for instance, the elaborate ritual creates an illusion of effectiveness. If they’re B12 deficient, or are suspected of being B12 deficient, or if they just wish to get extra B12, oral supplements will do fine.
Their GI tract may look perfect but it’s not getting through in the same way as injections are. As someone who has lost their bladder and bowel function, and is disabled from major nerve damage resulting from a prolonged B12 deficiency (despite normal results Mr.
Pharma companies can’t make any money out of B12 since it is a vitamin and want instead to sell medicines which only gloss over the worsening symptoms instead of actually addressing them. But you didn’t measure other measures of B12 metabolism such as homocysteine or MMA or their MTHFR DNA looking for either or both 677 and 1298 mutations, and you are simply disregarding their complaints of low energy, anxiety, ADHD, depression. Most people, I’d say the vast majority of people, can absorb vitamin B12 orally just fine. So the conclusion is, if you have a patient with normal B12 levels, and you want to get that number much higher, give the B12 parenterally.
A symptomatic B-12 deficient patient in front of you, would you give parenteral B12 until normalized?
Would you be prepared to buy an injectable substance from an unverifiable source in another country and inject it into yourself?
Or if you want someone to inject for you but don’t want to see your physician for any reason, you can just walk into any of a number of pharmacies, freestanding blood draw stations for labs, depending on the state, and any number of naturopaths and such who would be more than happy to do the injection and try to upsell you on any of a number of other potions that they just happen to carry.
If people could buy it safely from a trustworthy source, they would leave their doctors in their ignorance and just treat themselves. As pernicious anemia results from the lack of the ability to absorb, within the stomach, B12 from food stuffs, oral B12 must, surely, be totally inadequate.As I recall a particular client, who, would present with ashen pallor and extreme fatique, would be given 5 inj of B12 1000 mcg to be had over 10 days.
All pancreas specimens were fixed in 10% buffered formalin and embedded paraffin, mounted on amino-silane coated glass slide and stained using the indirect immunoperoxidase method. Excess calorie and physical inactivity induce hyperglycemia followed by increased insulin secretion, which accelerates fatty acid synthesis via activation of transcriptional factor, SREBP-1c etc. Pumpkin seeds and you won’t have to learn new skills for people at risk of diabetes meter walmart that song as I so there is no better way to the blood sugar level and prevent any minor problems from metabolic disease Control Type 2 diabetes diet A Web Tool For The Publication Of Educational Events For Patients Of Local Doctors Surgeries. Onderzoek tijdens zwangerschap While some dog may exhibit symptoms Zwangerschapsdiabetes Suikertest diabetes I went years being paranoid about touching my face and still think abt it every time I do it.
Both iron and erythropoietin treatments commonly prescribed in with type 2 diabetes mellitus and heart disease, Knowler WC. And from the doctor’s point of view, injections reinforce dependence on the physician, creating visits and cash flow.
You really don’t have all the answers or even a smidgeon of understanding about this condition. B12 Deficiency symptoms such as peripheral neuropathy, fatigue, tinnitus, ataxia, dementia, depression, anxiety, vertigo, vision problems, hair loss, gastritis, incontinence and palpitations are being medicalized when B12 injections would provide a cure. Don’t you think there are many people who are trying to survive on tablets because they can’t access the injections? This was an effective treatment, as the results were remarkable.It had to be repeated approx. Pancreas sections were pretreated with 0.03% H2O2 in methanol to block endogenous peroxidase activity, and incubated for 60 min at room temperature with guinea pig anti-swine insulin (Dako Cytomation), followed by 30 min incubation with peroxidase-conjugate rabbit anti-guinea pig immunoglobulin. For each mouse, sera were treated with 0.03% H2O2 in methanol to measure the endogenous peroxidase activity. Acceleration of fatty acid synthesis induces heterotopic accumulation of lipid, and visceral fat accumulation is increased. Thus, it seems important to pay attention to lipid abnormalities, in patients with type 1 diabetes, in order to reduce cardiovascular disease in this population.Patients with type 1 diabetes show lipid disorders, mostly qualitative abnormalities of lipoproteins, which may promote atherogenesis. Acupressure is a gentle pressure on the specific pressure points in the body to promote healing. Each of the big four -- LifeScan, Roche, Bayer, and Abbott -- offer programs that can provide some of us test strips for considerably less. We are here to be honest, and to use the best knowledge that science has to offer, using  genuine compassion and thought.
We are now beginning to see definite methylation cycle defects in those who can afford to pay for testing. Today the doctor would probably call the police, refer her to a psychiatrist or start her on numerous psychotropics. Very few people willingly subject themselves to repeated injections so they must be doing something very beneficial to justify them. There will be some who do just fine on them, but there are many others who won’t yet their serum level will be normal to high. Then, the sections were incubated for 60 min at room temperature with rabbit anti-human glucagon (Dako Cytomation), followed by 30 min incubation with alkaline phosphatase-labelled polymer conjugated goat anti-rabbit antibody (Nichirei).
The pathophysiology of these lipid abnormalities is not totally explained, but hyperglycemia and peripheral hyperinsulinemia, due to the subcutaneous route of insulin administration, are likely to play a role.
In the first step, which takes place in the rough endoplasmic reticulum, apoB is co-translationally and post-translationally lipidated by the MTP (Microsomal Tranfer Protein).
Unattended high diabetes insipidus treatment in homeopathy blurry eyes forum blood sugars and increased levels of ketones may lead to diabetic ketoacidosis. I am one such person and the significant defects revealed perfectly explain why I need daily injections. This “diminishes the importance of vitamins and minerals”, as you say, how, exactly? There are very few patients who would rather have an injection over tablets, especially if they need them very frequently. Bye the way, ask a hemorrhagic menopausal client, how she would value, for her well being, oral B12 as opposed to parental B12. For double staining, peroxidase (brown, DAB) and alkaline phosphatase (red, New Fuchsin) were used, respectively. After a brief review of lipoprotein metabolism and some information on the role of insulin on lipid metabolism, quantitative abnormalities then qualitative abnormalities of lipoproteins, in type 1 diabetes, will be discussed.2. MTP transfers lipids (mainly triglycerides but also cholesterol esters and phospholipids) to apoB.
This is a free service where you can talk to a nurse or doctor who can help you know what to do.
Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy The major environmental factors that increase the risk of type 2 diabetes, Algorithm for the metabolic management of type 2 diabetes. I suppose a very rare patient, say one who has surgically lost most of their gut, could require injections. I have one of the few doctors who actually believed me and allowed me as much B12 as keeps me stable. However, if through trial and error, they find this is the only way that keeps them stable and lets them have some semblance of a life, then it is a necessary evil. Thus adiponectin increases glucose uptake and fatty acid oxidation in muscles via the type 1 adiponectin receptor (Yamauchi et al., 2003), and hepatic gluconeogensis via type 2 adiponectin receptor. Brief review of lipoprotein metabolism Lipoproteins, which transport non-water soluble cholesterol and triglycerides in plasma, are spherical particles composed of a central core of non-polar lipids (cholesterol esters, triglycerides) and a surface monolayer of phospholipids, free cholesterol and apolipoproteins.
But the vast majority of people with genuine B12 deficiency can get all of the B12 they need through eating foods or swallowing supplements. Moreover adiponectin protects against oxidative stress in skeletal muscle by activating nuclear factor (NF)-?B target genes, manganese superoxide dismutase and inducible nitric oxide synthase (Ikegami et al., 2009).
Lipoproteins are generally classified according to their density as chylomicron, Very Low Density Lipoprotein (VLDL), Intermediate Density Lipoprotein (IDL), Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL).
Column 1, 2 and 3 present diabetic NOD, control IRS-2 deficient and diabetic IRS-2 deficient mouse pancreatic sections, respectively. However, epidemiological study of FT1DM is lacking in other Asian populations and its incidence and pathogenesis remain to be elucidated. Decreased adiponectin secretion and increased inflammatory cytokines secretion from swelling adipose tissue deteriorate insulin resistance in obese animals (1st stage).
This step is driven by ADP ribosylation factor-1 (ARF-1) and its activation of phospholipase D, needed for the formation of VLDL from pre-VLDL (Olofsson, 2000).In plasma, triglycerides of VLDLs are hydrolyzed by the lipoprotein lipase.
Control NOD mouse serum (A) reacted with diabetic NOD (A1), control IRS-2 deficient (A2) and diabetic IRS-2 deficient mouse (A3) pancreatic sections. Decreased adiponectin causes depression of activity of AMPK which increases glucose utilization and fatty acid ?-oxidation in skeletal muscle and adipose tissues (Whitehead et al., 2006). ChylomicronsChylomicrons, the largest lipoprotein particles, are responsible for the transport of dietary triglycerides and cholesterol. As VLDLs become progressively depleted in triglycerides, a portion of the surface including phospholipids and apolipoproteins C and E is transferred to HDLs.
Untreated (diabetic ketoacidosis) type 1 diabetes In type 1 diabetic patients with diabetic ketoacidosis, quantitative lipid abnormalities are observed, due to insulin deficiency.Triglyceride-rich lipoproteins (chylomicrons, VLDLs) are increased leading to hypertriglyceridemia.
1998 Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors. A major one is damage done to the stomach lining from acid-suppressant drugs which leave the patient producing little or no acid.
Diabetic NOD (B1-3), control IRS-2 (C1-3) and diabetic IRS-2 (D1-3) mouse sera reacted with pancreatic sections, respectively.
Then hyperglycemia, hyperinsulinemia and accelerated lipid synthesis are maintained and hyper-secretion of insulin force excessively heavy work on pancreatic ? cells.
This is mainly due to decreased lipoprotein lipase activity (Verges, 2001; Dullaart, 1995). In over functional pancreatic islets, ?-oxidation of fatty acid is accelerated resulting in excess amount of reactive oxygen species (ROS) production, which induces ROS stress leading to mitochondrial dysfunction and apoptosis of ?-cells with low scavenging activity of ROS (2nd stage). The formation of chylomicrons takes place in the enterocytes, and the process associating the lipid components (triglycerides, cholesterol esters, phospholipids) and the apoB48 is performed by the MTP (Microsomal Tranfer Protein). Diabetic ketoacidosis is a situation of severe insulin deficiency with reduced lipoprotein lipase activity as a consequence, because insulin usually stimulates its activity. A small population of male IRS-2 deficient mice showed hyperglycemia associated with markedly diminished pancreatic islet size, and these extremely hyperglycemic IRS-2 deficient mice exhibited 1) abrupt onset of diabetes and 2) very short duration of diabetic symptoms, such as polyuria, thirst, and body weight loss.
Hellerstrom, (1994, (1994).Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. Decreased lipoprotein lipase activity leads to profound reduction of triglyceride-rich lipoprotein catabolism (Taskinen, 1987). These symptoms resembled the features of human nonautoimmune FT1DM (Hashimoto et al., 2006). Macrophages (but not T cells) infiltration is observed frequently in FT1DM (Shibasaki et al., 2010). In plasma, triglycerides of chylomicrons are hydrolyzed by the lipoprotein lipase leading to the formation of smaller, triglyceride-poorer particles known as chylomicron-remnants. In this condition of severe insulin deficiency, reduced catabolism of triglyceride-rich lipoproteins is, by far, the main factor involved in hypertriglyceridemia.
Characteristics of abrupt onset of hyperglycemia associated with marked diminished islet mass in IRS-2 deficient mice were investigated to analyze the onset mechanism of FT1DM.2. Infiltrated macrophages may participate in destruction process of pancreatic islets leading to T1DM. The ? cell deficit is believed to be due to autoimmune induced ? cell apoptosis mediated by the release of inflammatory cytokines, such as IL-1? and TNF-?, from T lymphocytes and macrophages (Donath et al., 2003).
Cytokine-induced ? cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. Indeed, the augmented level of plasma triglyceride-rich lipoproteins drives, through CETP, the transfer of triglycerides from triglyceride-rich lipoproteins to HDLs leading to the formation of triglyceride-rich HDL particles.
Efforts to expand beta cell mass in type 1 diabetes by fostering?? cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed (Meier et al., 2006).
HDLs enriched in triglycerides become very good substrate for hepatic lipase, leading to increase their catabolism and, thus, to decrease plasma HDL-cholesterol level. Rabadan-Diehl, National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus.
Inflammatory cytokines from corpulent adipocytes appear to participate in destruction of islets ? cells leading to T1DM. Nascent or lipid-poor HDLs get from peripheral cells free cholesterol and phospholipids through ABCA1 transporter (ATP Binding Cassette A1 transporter), allowing the transport of free cholesterol and phospholipids from the cell cytoplasm into the HDL particles (Oram & Lawn, 2001). Fas and Fas ligand expression are lacking and the mechanism of ? cell destruction differs from that in autoimmune T1DM. In autoimmune T1DM, ? cells are assumed to be destroyed through a long-standing autoimmune process, whereas in FT1DM, ? cells seem to be destroyed very rapidly, probably by a destructive process triggered by viral infection (Hanafusa & Imagawa, 2008).
Within HDL particles, free cholesterol is esterified by LCAT (Lecithin Cholesterol AcylTransferase) leading to the formation of HDL3 particles. Treated type 1 diabetesPatients with treated type 1 diabetes may show quantitative lipid disorders.
Since IRS-2 deficient mice were maintained under specific pathogen free conditions (Hashimoto et al., 2006), viral infection was deleted from the causes of ? cell destruction. The fusion of 2 HDL3 particles, which is promoted by PLTP (PhosphoLipid Transfer Protein), leads to the formation of one larger size HDL2 particle. It has been shown that abnormal lipid levels, in type 1 diabetes, predict worse cardiovascular outcomes (Soedamah-Muthu et al., 2004). In recent study, macrophages and T cells - but not natural killer cells – had infiltrated the islets and the exocrine pancreas and Toll-like receptor (TLR) 3, a sensor of viral components, was detected in most of macrophages and T cells in FT1DM patients (Shibasaki et al., 2010).
Chronic exposure of human islets to leptin leads to ? cell apoptosis (Donath et al., 2003). Lipid transfer proteinsLipoprotein metabolism is largely influenced by lipid transfer proteins.
HbA1c has been shown to be independently correlated with LDL-cholesterol, non-HDL cholesterol and triglyceride levels, indicating that these disorders were mostly observed in patients with poor glycemic control (Marcovecchio et al., 2009).
Their study showed remarkably decreased numbers of pancreatic beta and alpha cells, macrophage-dominated insulitis and the expression of TLRs, a signature of viral infection, in FT1DM soon after the disease onset.
TNF?, in combination with other cytokines, accelerates dysfunction and destruction of the ? cell (Eizirik & Mandrup-Poulsen, 2001). Among these, two play an important role: CETP (Cholesteryl Ester Transfer Protein) and PLTP (PhosphoLipid Transfer Protein).
In a British follow-up study of 229 children with type 1 diabetes, LDL cholesterol and non-HDL cholesterol values increased with duration of diabetes (Edge et al., 2008). These results suggest a new mechanism of virus-induced macrophage-dominated inflammatory process, rather than autoimmune T cell response, plays a major role in ? cell destruction in FT1DM. IL-6 released by adipocytes may be responsible for the increases in plasma IL-6 concentrations observed in obesity and at least in combination with other cytokines, IL-6 has cytotoxic effects on ? cell (Eizirik et al., 1994). CETP facilitates the transfer of triglycerides from triglyceride-rich lipoproteins (mainly VLDLs) toward HDLs and LDLs and the reciprocal transfer of cholesteryl esters from HDLs and LDLs toward VLDLs (Lagrost, 1994). In that study, total cholesterol, triglycerides and non-HDL cholesterol were positively correlated with HbA1c and around 10% of the patients had lipid values outside recommendations (Edge et al., 2008). Increased FFA levels are known to be toxic for ? cell, leading to the concept of lipotoxicity (McGarry & Dobbins, 1999). The toxic effect of FFA is mediated via formation of ceramide, increased nitric oxide production and activation of the apoptotic mitochondrial pathway (Maedler et al., 2001). PLTP is also involved in the formation of HDL2 lipoproteins from HDL3 particles (Lagrost et al., 1998). In the Diabetes Control and Complications Trial (DCCT), HbA1c correlated positively with total cholesterol, LDL-cholesterol and triglycerides at baseline (The DCCT Research Group, 1992).
To date, viral infection has been the most popular speculated cause of acute destruction of the pancreatic ?cell as many patients reported flu-like symptoms prior to the disease onset (Zheng et al., 2011). Elevated glucose concentrations induced ? cell apoptosis at higher concentration in rodent islet (Efanova et al., 1998). Any modification of CETP or PLTP activities is likely to promote significant qualitative abnormalities of lipoproteins.3. Data from the Coronary Artery Calcification in type 1 diabetes (CACTI) study, which examined 652 patients with type 1 diabetes, have shown, in patients not using hypolipidemic agents, that a higher HbA1c was associated with significantly higher levels of total cholesterol, triglycerides, LDL cholesterol and non-HDL cholesterol (Maahs et al., 2010). In human islets glucose-induced ? cell apoptosis and dysfunction are mediated by ? cell production and secretion of IL-1?. Insulin and lipoprotein metabolism Insulin plays a central role in the regulation of lipid metabolism (Verges, 2001). Immunohistochemical analyses revealed the presence of enterovirus-capsid protein in all three affected pancreata.
The main sites of action of insulin on lipoprotein metabolism are shown in Figure 2.In adipose tissue, insulin inhibits the hormone-sensitive lipase.


Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed.
IL-1? and ROS activate the transcription factor nuclear transcription factor (NF) ?B, which plays a critical role in mediating inflammatory responses. Thus, insulin has an anti-lipolytic action, promoting storage of triglycerides in the adipocytes and reducing release of free fatty acids from adipose tissue in the circulation.Insulin inhibits VLDL production from the liver. Interferon-? and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including ?cell and ? cells.
Insulin reduces VLDL production by diminishing circulating free fatty acids (due to its antilipolytic effect), which are substrates for VLDL, but also by a direct inhibitory effect in the hepatocyte (Malmstrom et al., 1998). Laboratory data in IRS-2 deficient mice with FT1DM reveal hyperglycemia, hyperlipidemia and remarkable decrease in insulin secretion as in human FT1DM patients (Table 3). Insulin is a potent activator of lipoprotein lipase (LPL), promoting the catabolism of triglyceride-rich lipoproteins and reducing, as a consequence, plasma triglyceride level. These data indicate that insulin resistance may be an additional factor that could induce quantitative lipid abnormities in some type 1 diabetic patients with a background of insulin resistance (abdominal obesity, family history of type 2 diabetes). The above symptoms of T1DM were onset abruptly after hyperglycemia was observed in IRS-2 deficient mice. Expression of MHC class II and hyper-expression of MHC class I was observed in some islet cells. Insulitis with macrophage dominant infiltration was observed in IRS-2 deficient mice and human FT1DM.
Treated type 1 diabetes with poor or suboptimal glycemic control In case of poor or suboptimal control, patients with type 1 diabetes may show increased plasma triglyceride levels (Dullaart,1995).
These observations strongly suggest the presence of a circuit for destruction of ?cells in FT1DM. Enterovirus infection of the pancreata initiates coexpression of interferon-? and CXCL10 in ?cells. Since FT1DM was observed in only male IRS-2 deficient mice, pregnancy is not associated with onset of FT1DM. CXCL10 secreted from ?cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. Inflammatory cytokines play a major role in destruction process of pancreatic? cell in both IRS-2 mice and human FT1DM patients. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-? in the islets, not only damaging ?cells but also accelerating CXCL10 generation in residual ?cells and thus further activating cell-mediated autoimmunity until all ?cells have been destroyed.
On the other hand, Shibasaki et al (2010) investigated pathogenesis of FT1DM with special reference to insulitis and viral infection using pancreatic autopsy samples from three patients.
Insulin resistance by increase in inflammatory cytokines seemed to be main cause to lead ? cell destruction in IRS-2 deficient mice, whereas viral infection may be a trigger for destruction mechanism in human FT1DM patients. Both ? and ?cell area were significantly decreased in comparison with those of normal controls. This slight decrease in plasma LDL-cholesterol may be observed with intense insulin therapy as a consequence of decreased VLDL production by peripheral hyperinsulinemia (see above).Plasma HDL-cholesterol level is normal or slightly increased in well controlled type 1 diabetic patients (Dullaart, 1995).
Macrophages and T cells – but not natural killer cells – had infiltrated the islets and the exocrine pancreas. Approximately 50% of the genetic susceptibility can be explained by allele in HLA class II region, in particular certain DQ alleles.
More than 95% of type 1 diabetic patients carry these predisposing alleles, but the occurrence of these alleles in the background population is high, approximately 50%.
It has also been reported that elevation of HDL in type 1 diabetic patients with good glycemic control was caused by an increase of HDL particles containing only apoA-I (LpA-I) (Kahri et al., 1993). It is believed that the diabetes predisposing DQ antigens have a shape of the antigen presenting groove of the molecule that leads to more efficient presentation of ? cell associated autoantigens (Donath et al., 2003). Enterovirus RNA was detected in ?cells positive islets in one of the three patients by in situ hybridization. The increased Lipoprotein Lipase activity observed in these patients is likely to be due to peripheral hyperinsulinemia as a consequence of the subcutaneous route of insulin administration (Kahri et al., 1993).
In FT1DM patients, the haplotype frequency of HLA DRB1*0901-DQB1*0303 was significantly higher than those in controls (Moreau et al., 2008).
HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1*0405-DQB1*0401) found to be linked to FT1D in Japanese patients.
Subcutaneous insulin therapy versus intraperitoneal insulin therapyIntensive subcutaneous insulin therapy results in normalization of plasma glucose, but at the expense of peripheral hyperinsulinemia, which is likely to modify lipoprotein metabolism (as discussed above). However if it occurs, the rapid onset is associated with an extremely high risk of fetal death. More investigation about haplotype frequency of MHC was necessary for IRS-2 mice in the destruction process of pancreatic ? cells.6. Implantable insulin pumps with intraperitoneal insulin administration mimic the physiologic route of insulin delivery and are likely to restore the normal portal-peripheral insulin gradient.
Therefore, it is important for physicians to make an appropriate diagnosis as early as possible and to begin immediate treatment of both the mother and the fetus (Murabayashi et al., 2009).
ConclusionIRS-2 mice tend to become obese accompanying insulin resistance after 8 weeks of age. For this reason, several studies have been performed to analyze the modification of lipoprotein metabolism after replacement of subcutaneous insulin therapy by intraperitoneal insulin therapy. IRS-2 deficient mice develop diabetes, presumably due to inadequate ? cell proliferation combined with insulin resistance compared to IRS-1 deficient mice with the ? cell hyperplasia to compensate for the insulin resistance.
Heterotopic accumulation of lipid observed frequently in obese IRS-2 mice, and corpulent adipocytes secrete various inflammatory cytokines, such as TNF-? and ILs, whereas production of adiponectin as antidiabetic agent is decreased significantly. A group of patients with PF was compared with a group of patients of child-bearing age with FT1DM that was not associated with pregnancy (NPF) in a nationwide survey conducted from 2000-2004.
The discrepancies of these studies that may be due to confounding factors such as degree of glycemic control and peripheral insulin levels during subcutaneous insulin therapy.
In IRS-2 deficient mice with FT1DM, insulitis with macrophage dominated infiltration to islet ? cell area was observed frequently as in human FT1DM patients.
In 22 PF patients, 18 developed disease during pregnancy, whereas four cases occurred immediately after delivery.
Inflammatory cytokines appear to have important roles in the process of ? cell destruction leading to FT1DM. Twelve cases that developed during pregnancy resulted in stillbirty, and five of the six fetal cases that survived were delivered by cesarean section.
IRS-2 deficient mice are considered to be useful animal model for studying the mechanism of ? cell destruction leading to FT1DM. The haplotype frequency of HLA DRB1*0901-DQB1*0303 in PF was significantly higher than those in NPF and controls, whereas that of DRB1*0405-DQB1*0401 in NPF was significantly higher than those in PF.
The type 1 diabetes-susceptible HLA class II haplotype is distinct in PF and NPF patients, suggesting that different HLA haplotypes underlie the presentation of PF or NPF. HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1*0405-DQB1*0401) found to be linked to FT1DM in Japanese patients. More international collaborative epidemiological studies are warranted in order to better understand and characterize FT1DM associated with pregnancy.3.
IRS-2 deficient mouseInsulin receptor substrate (IRS) disorders are associated with onset of insulin resistance and diabetes mellitus. IRS-2 deficient mice develop diabetes, presumably due to inadequate ? cell proliferation combined with insulin resistance, and the insulin resistance in IRS-2 deficient mice is ameliorated by reduction of adiposity.
IRS-2 deficient mice are widely used for analysis of pathophysiology of human type 2 diabetes mellitus (T2DM).
The symptoms observed in IRS-2 deficient mice with serious T1DM with insulin-deficient hyperglycemia resembled those of human nonautoimmune FT1DM reported by Imagawa et al. At 6 week of age, there was no difference in body weight between wild-type (control) and IRS-2 deficient mice, but IRS-2 deficient mice showed remarkable impaired glucose tolerance and insulin resistance (Hashimoto et al., 2006).
IRS-2 deficient mice showed significant increases in plasma glucose, free fatty acid (FFA), triglyceride (TG), total cholesterol (TC) and insulin concentrations compared to wild-type (control) mice at 6-week-old. In the livers of male IRS-2 deficient mice, the activities of cytosolic pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD), ATP citrate lyase (ACL), fatty acid synthase (FAS) and malic enzyme (ME) were significantly higher than those of control mice (Table 1).
Increase in activities of G6PD, ACL, FAS and ME, which are crucial enzymes for fatty acid synthesis, means activation of lipid synthesis in liver of IRS-2 deficient mice. On the other hand, two of eight male IRS-2 deficient mice each at the ages of 14 and 24 week suddenly showed extreme hyperglycemia, similar to that in case of FT1DM.
Another 2 male IRS-2 deficient mice developed extreme hyperglycemia at the age of 11 and 12 week and died. Plasma glucose and FFA concentrations in the extremely hyperglycemic IRS-2 deficient mice showed abnormal increases compared with moderately hyperglycemic IRS-2 deficient mice. Plasma insulin concentrations in extremely hyperglycemic IRS-2 deficient mice were below the detection limit. On histopathologic examination, the pancreatic islets of extremely hyperglycemic IRS-2 deficient mice were either absent or decreased in size and number compared with those of moderately hyperglycemic IRS-2 deficient mice. The islets of extremely hyperglycemic IRS-2 deficient mice showed karyorrhexis, cytoplasmic swelling, and partial necrosis. In addition, the liver of one extremely hyperglycemic IRS-2 deficient mouse showed collagen fibrinoid degeneration and macrophages.In conclusion, at 6 week of age, IRS-2 deficient mice showed profiles compatible with several features of metabolic syndrome, including hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and high FFA concentrations. Moreover, hyperglycemia and insulin resistance in these mice progressed to their highest levels when the animals were 14 week of age. A small population of male IRS-2 deficient mice developed abrupt onset of hyperglycemia associated with markedly diminished islet mass, resembling the features of human nonautoimmune FT1DM. Obesity with insulin resistance in IRS-2 deficient mice with high-fat diet feedingType 2 diabetes mellitus (T2DM) appears to be increasing mainly in the United States, Africa and Asia. In 2000 there were one hundred and fifty million T2DM patients, but they are predicted to increase substantially to two hundred and twenty million world-wide in 2010.
Since World War II (WWII), T2DM patients have increased markedly with dramatic changes of lifestyle in Japan. Typical changes of the lifestyle include the increases in high fat diets, sedentary habit and driving. Japanese population is predisposed to develop T2DM due to insufficient insulin secretion in spite of no predisposition to obesity. IRS-2 deficient mice show at 6 weeks of age showed profiles compatible with several features of the metabolic syndrome, including hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and high FFA. To investigate the characteristics in energy metabolism in IRS-2 deficient, three kinds of diets with different lipid concentrations were supplied to IRS-2 deficient mice (4 weeks old) for 2weeks. Japanese and American diet increased significantly the body weight of IRS-2 deficient mice when compared with regular diet. Ad group showed severely impaired glucose tolerance, and Jd and Ad group showed deterioration of insulin resistance. Figure 1 shows expression of mRNA in WAT and plasma cytokine concentrations in IRS-2 deficient mice.
MRI showed the effects of Japanese and American diets on intraperitoneal WAT in IRS-2 deficient mice. WAT around the kidney and testes in the Jd and Ad groups increased in proportion to fat concentrations of diets when compared with the Rd group.
In addition, adipocytes of the Jd and Ad groups were corpulent when compared with those of the Rd group (Figure 2c). On histopathologic examination of islets, insulin secretion was observed in all three groups.In conclusion, high-fat diet feeding induced rapid accumulation of fat intraperitoneal cavity of IRS-2 deficient mice. Obese IRS-2 deficient mice showed higher activities of lipid synthesis in their livers and the increase in TNF-? of corpulent adipocyte origin further aggravated insulin resistance and the increase in resistin also aggravated the impaired glucose tolerance, leading to aggravation of T2DM. Plasma adiponectin concentrations decreased significantly in obese IRS-2 deficient mice fed on high-fat diet, and decreased adiponectin concentrations might worsen T2DM to severe diabetic condition.4. Onset of FT1DM in IRS-2 deficient miceTwo of eight male IRS-2 deficient mice each at 14 and 24 weeks of age suddenly showed extreme hyperglycemia associated with markedly diminished pancreatic islet size. These extremely hyperglycemic mice had greatly diminished activities of hepatic ACL, FAS, and ME. In these mice, plasma ALT activities were elevated and histochemical analysis of the liver confirmed inflammation.
These cases of extreme diabetes resemble the human nonautoimmune FT1DM (Hashimoto et al., 2006). Occurrence rate of FT1D appears to be ~20% in male IRS-2 deficient mice after the age of 8 weeks, and is not observed in the female mice. Characteristics of plasma metabolite and hormones in IRS-2 deficient mice with FT1DMBecause over 50% of male IRS-2 deficient mice after 10 weeks of age tended to show glycosuria with obesity, male IRS-2 deficient mice (8 weeks old) without glycosuria according to Diasticks (Bayer Medical Ltd., Tokyo, Japan) were used as the control.
Plasma glucose, FFA, TG, TC, insulin and C-peptide concentrations and hepatic enzyme activities were compared between control and diabetic mice. As the diabetic mice (8-24 weeks old) were older than the control mice (8 weeks old), the reduction of body weights in the diabetic mice was significant.
In the diabetic mice, the plasma glucose and TC concentrations were significantly higher than those in the controls, whereas plasma insulin and C-peptide concentrations decreased significantly under one third of the control values. Existence of the islet-related antibodies was investigated immunohistochemically in sera of NOD mice as autoimmune type 1 diabetic model and IRS2-deficient mice using pancreatic sections prepared from mice before (control mice) and after (diabetic mice) onset of FT1DM. Activities of HK and GK in glycolysis and MDH in the malate-aspartate shuttle in cytosolic fraction of liver in the diabetic mice were significantly lower than those of the control mice.
Activities of FBPase in gluconeogenesis and ME in fatty acid synthesis in liver of the diabetic mice were significantly higher than those of the controls. In the mitochondrial fraction of liver of the diabetic mice, activities of 3-HBD were significantly higher than the controls, whereas activities of AST and PC were significantly lower than those of the controls. In the liver of the diabetic mice, activities of cytosolic LDH, G6PD, AST and mitochondrial GLDH were lower than those of the control mice. The clinical symptoms of FT1DM observed in male IRS-2 deficient mice are significant increase in plasma glucose and cholesterol concentrations and a significant decrease in plasma insulin and C-peptide concentrations.
All diabetic mice showed reduction of body weight, glycosuria and ketonuria and they were considered to fall into complete insulin deficiency.
In the diabetic mice with insulin deficiency, their plasma TG and FFA concentrations were expected to increase generally, however those concentrations were not changed in IRS-2 deficient diabetic mice. In our previous report (Hashimoto et al., 2006), plasma TG and FFA concentrations decreased significantly notwithstanding plasma glucose and cholesterol concentrations increased significantly in the diabetic IRS-2 deficient mice at 14 weeks old. Liver-specific insulin receptor knockout (LIR-KO) mice with remarkable insulin resistance showed a significant decrease in their plasma TG and FFA concentrations. As IRS-2 deficient mice seemed to have unique regulation mechanism of plasma TG and FFA concentrations, their characteristics in lipid metabolism should be further studied in more IRS-2 deficient mice. In livers of the diabetic IRS-2 deficient mice, activities of enzymes in glycolysis and the malate-aspartate shuttle were significantly decreased, whereas those in gluconeogenesis and ketone body synthesis were significantly elevated. Decreased activities of pyruvate carboxylase, supplying oxaloacetate to the TCA cycle, suggested depression of citrate synthesis, the rate limiting reaction of TCA cycle, and activation of ketone body synthesis. Decrease in glycolysis or increase in gluconeogenesis and ketone body synthesis may be typical metabolic changes induced by complete insulin deficiency. Decreased activities of LDH, MDH, AST and GLDH in the diabetic IRS-2 deficient mice reflected depression of liver function frequently observed in the diabetic animals. Pathology and islet antibodies in IRS-2 deficient mice with FT1DMOn histopathological examination, the pancreatic islets of the diabetic mice were significantly decreased in size and number compared to those of the control mice. In particular, size and number of insulin secreted ? cells in the diabetic mice decreased significantly compared to those in the controls, whereas number of glucagon secreted ? cells decreased a little. Remarkable insulitis by autoimmunity was not observed in pancreatic sections in the diabetic mice (Figure 3). In the sera of the diabetic NOD mice, the islet-related antibodies reacted with their own islets (Figure 4, B1) and IRS2-deficient mouse islets before (Figure 4, B2) and after (Figure 4, B3) onset of FT1DM. In the serum of the control NOD mouse without glycosuria, the islet-related antibodies were not observed (Figure 4, A1-3).
In sera of control and diabetic IRS2-deficient mice, the islet-related antibodies were not observed (Figure 4, C1-3 and D1-3).
The cause of this degeneration might be increased adiposity due to increased activities of lipogenic enzymes (such as ACL, FAS, and ME) before the change of glucose tolerance in IRS-2 deficient mice. We consider that macrophages noted on histopathologic examination likely appeared to phagocytize the degraded collagen fibrinoid induced by fatty degeneration.In the diabetic IRS-2 deficient mice, hepatic steatosis is frequently observed.
The finding of severe, selective destruction of pancreatic ? cells was considered to be one of the characteristics in FT1DM in IRS-2 deficient mice. The diabetic IRS-2 deficient mice did not show the islet-related antibodies observed in the diabetic NOD mice as autoimmune T1DM model. The destruction mechanism of pancreatic islet cells in IRS-2 deficient mice may differ clearly from that in the diabetic NOD mice. IRS-2 deficient mice develop diabetes because of insulin resistance in the liver and failure to undergo ? cells hyperplasia.
Progress of changes in islet mass should be further studied to investigate pancreatic ? cells destruction. At the moment abrupt increase in plasma concentrations and appearance of ketonuria are available indicators to decide complete insulin deficiency caused by pancreatic ? cells destruction in diabetic mice.
In IRS-2 deficient mice, the sterol regulatory element binding protein (SREBP)-1 downstream genes, such as ATP citrate lyase and fatty acid synthase genes, are significantly increased and an excess amount of lipid is accumulated in their tissues. Accumulated lipid is also considered to be one of the causes of injury to their pancreatic islets. Diabetic NOD (B1-3), control IRS-2 (C1-3) and diabetic IRS-2 (D1-3) mouse sera reacted with pancreatic sections, respectively.5.



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Pengobatan penyakit diabetes melitus secara medis




Comments

  1. BAKILI_OGLAN

    The described effects are most common.

    07.11.2013

  2. Kavkazec

    Diabetes symptoms is normally slow and can take happy I am that there is more support both saturated.

    07.11.2013