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Kachin Diabetes Solution

John Goodridge is the author of this product.Kachin Diabetes Solution is a medically proven regime inspired by the traditions and lifestyle of the ancient people of Myanmar. It is comprehensively about a regime based on and inspired by the ancient ethnic group; the Kachin It is focused on making your mental, physical, and emotional health and a life free from diabetes.This secret will reveal to you a faster simple and effective way to keep your blood sugar in the safe zone. What's more fascinating is that you can treat your diabetes in just a month or less!The product is presented to you in the format of an e-book.This product is for anyone who wishes to destroy their type II diabetes and live a healthy life. Continue reading...

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Potential Pitfalls Of Stem Cellbased Therapies For Diabetes In Humans

Both embryonic and adult stem cells represent an underdeveloped resource for the treatment and potential cure for a host of diseases, including type I diabetes. As efforts are made to develop transplantable tissue from each stem cell Embryonic stem cells have been shown to differentiate into various cell types, both in vitro and in vivo, including pancreatic islet lineages (39,49,98). However, functional islet tissue has not been derived from human ES cells to date, and whether ES cell-derived islet tissue will exhibit mature glucose-stimulated insulin secretion or immature function akin to fetal islets remains to be determined. Because theoretically there is no limit to the number of undifferentiated ES cells that can be grown in vitro, the amount of tissue for therapy generated from these cells is also potentially unlimited.

Methods to Quantify EE and Physical Fitness in Type 2 Diabetes Mellitus

Levels of voluntary physical activity can be assessed using questionnaires. A series of validated questionnaires has been reviewed by Kirska and Caspersen 39 . The Diabetes Prevention Program 9 and our study 12 used the Modifiable Activity Questionnaire 39 . Energy expenditure was calculated as the product of the duration (hours x week) of the different activities weighted by an estimate of metabolic equivalent (MET) of each activity. The major limitations of calculating EE through questionnaires are (1) it is not possible to rule out that some patients might over report their amount of physical activity (2) not all patients are willing to compile a diary (3) to convert the questionnaires filled by patients into METs is time consuming. The recent availability of wearable body monitoring devices might overcome these drawbacks and offers a direct measurement of free-living activity more feasible and accurate than previous methods. One such device, the SenseWear ArmBand (BodyMedia,...

The Insulin Connection

Until recently, carbohydrates were ignored as a health issue. They are at least as important, and probably more so, than fats in determining weight and cardiovascular fitness. The key to carbohydrates' influence is insulin. Insulin is a hormone secreted by the pancreas in response to a carbohydrate-heavy meal. It is impossible to live without it, but it is possible to live much better without too much insulin. Insulin has many actions, but some of the most important affect body fat, cholesterol levels, and cardiovascular health. Insulin The bottom line is that insulin, certainly in excessive amounts, causes the body to produce and store fat as well as produce inordinate amounts of cholesterol. Insulin is now recognized as an important factor in the development of cardiovascular disease. It is known to act directly on the walls of arteries to produce atheroma atherosclerotic plaques that can narrow the blood vessels, limit blood flow and oxygen delivery, and result in strokes and heart...

Therapy for Diabetes Mellitus

Diabetes mellitus is a metabolic syndrome with a diversity of etiologies, clinical presentations, and outcomes. It is characterized by insulinopenia, fasting or postprandial hyperglycemia, and insulin resistance. Type 1 diabetes mellitus, referred to as juvenile or insulin-dependent diabetes mellitus is typically characterized by insulinopenia, hyperglycemia, and secondary insulin resistance (14). Type 2 diabetes mellitus, referred to as adult onset or non-insulin-dependent diabetes mellitus, is characterized by hyperglycemia and varying degrees of primary insulin resistance with elevated plasma insulin concentrations, but a decreased insulin response to challenge by a secretagogue (15). Diabetes mellitus need not be overt and grossly hyperglycemic to induce detrimental metabolic changes. A growing body of evidence suggests that there are detrimental consequences to normal physical challenges such as aging, which may be inherently linked to alterations in body composition. Such...

Es Cells And Diabetes

Islet transplantation as a procedure to induce insulin independence is still a long way from benefiting the population of more than 1 million type 1 diabetic patients in the United States. In addition to the problems involved with immune suppression, a remaining, significant obstacle is the scarcity of human organs for transplantation. For the last 5 years the number of donated pancreases (approximately 6000 per year) has changed little, and of those, only 50 could be expected to produce islet yields suitable for clinical purposes. Also, most transplant recipients require two or more organs to obtain a sufficient islet mass for insulin independence. Alternative sources of p cells are necessary for endocrine replacement if diabetes is to be a target for cell-based insulin therapies. Potential endocrine replacements from human tissue include adult p cells expanded with growth factors and extracellular matrix components (38,39), putative endocrine precursors from adult pancreases such as...

The Insulinlike Growth Factor 1 Igfi A Key Modulator Of Neurogenesis And Cognitive Functions

Activity of insulin-like proteins was discovered in 1957. The precise action of insulin-like growth factor I (IGF-I) remained poorly understood until the production in the 1980s of recombinant human IGF-I. This trophic factor has been well characterized as a factor mediating growth hormone action (Jones & Clemmons, 1995 Isaksson, Ohlsson, Nils-son, Isgaard, & Lindahl, 1991). IGF-I is found in high levels in the blood and is believed to originate mainly from the liver (Pankov, 1999). The detection of the IGF-I gene using molecular techniques showed its presence in several organs, including the brain (Rotwein, Burgess, Milbrandt, & Krause, 1988). Substantial evidence supports the importance of IGF-I and insulin in normal development and maintenance of adequate neuronal functions throughout the entire lifespan. The structure of IGF-I is quite similar to insulin (Isaksson et al., 1991). Interestingly, researchers have suggested that the level of insulin in the brain is quite low and that,...

IGFI and Insulin Receptor Levels in Cognition

No significant differences are found in IGF-I or insulin receptor levels in any subfields of the hippocampus of young versus aged rats (Dor , Kar, Rowe, & Quirion, 1997). Furthermore, deficits in cognitive performance do not relate to alterations in the levels of these receptors in aged impaired (AI) compared to aged unimpaired (AU) rats. It thus appears that IGF-I and insulin receptor binding sites are not markedly altered during the normal aging process in rats, and cognitive deficits observed in the Morris water maze are not mirrored by changes in these markers. Accordingly, spatial learning deficits observed in the AI group are not due to alteration in IGFs and or insulin receptor sites. However, these data do not rule out the potential of altered IGFs or insulin postreceptor signaling efficacy between AU and AI groups (discussed later). These results can also be related to those obtained in the human brain. No significant differences in the levels of IGF-I binding sites were...

Insulin Secreting Cells

Type 1 diabetes occurs secondary to the autoimmune-mediated destruction of insulin-producing p-cells in pancreatic islets. In contrast, insulin resistance is important in the development of type 2 diabetes, although p-cell dysfunction characterized by an inability to secrete adequate amounts of insulin to overcome insulin resistance also contributes to the pathogenesis of type 2 diabetes. Thus the development of insulin-secreting cells would provide an effective therapy for type 1 and, possibly, type 2 diabetes. The molecular mechanisms of pancreatic development provide insight into the transcription factors needed to initiate the hierarchical cascade of gene expression that results in differentiation along an islet cell lineage. This knowledge will facilitate developing strategies to generate insulin-secreting cells from stem cells. The molecular and cellular mechanisms important for pancreatic development have been the subject of several recent reviews (14,18-20). A brief overview...

Bone marrowderived cells may form extrapancreatic insulinexpressing cells

A recent study produced the surprising result that insulin gene expression is upregulated in multiple extrapancreatic tissues in conditions of hypergly-caemia, and bone marrow appears to be the major source of these proinsulin-expressing cells, thus highlighting the potential of extra-pancreatic cell sources in the treatment of diabetes. Following bone marrow transplantation and STZ-induced hyperglycaemia in mice, proinsulin and insulinpositive cells were present in the liver, adipose tissue, spleen, bone marrow and thymus, and many of these cells produced glucagon, somatostatin and C-peptide.66

Selection of Insulin Producing Cells From Spontaneously Differentiating ES Cell Cultures

It has been shown previously that genetic selection against heterologous cell types generated during the course of spontaneous ES cell differentiation can result in enrichment for the cell types of interest. For example, this approach has been used to obtain purified cardiomyocyte- and neural-like cells from mouse ES cell cultures (21,22). Soria and coworkers used a similar strategy to select insulin-producing cells from spontaneously differentiating mouse ES cells (43). They introduced into the ES cells a plasmid conferring resistance to two antibiotics. The first antibiotic-resistance gene was under control of a constitutive promoter, and the second gene was under control of an insulin promoter. During the first stage of the culture the undifferentiated ES cells were selected for resistance to the first antibiotic. This allowed generation of a stable cell line in which every cell carried the plasmid. After this step, the ES cells were transferred into differentiation medium...

Liver Directed Cell Therapy for Type 1 Diabetes Mellitus

It is reasonable to conclude that liver-directed cell therapy has prospects for type 1 diabetes mellitus. Besides the developmental relationships between liver and pancreas, additional evidence indicates that hepatocyte-like cells can emerge in the pancreas. Such evidence includes studies in hamsters or rats treated with carcinogens or peroxisome proliferators (96,97), dietary copper depletion and repletion in rats (20,98), transgenic mice expressing keratinocyte growth factor under insulin promoter (99), and transplantation of murine pancreatic oval cells in FAH mice (21). On the other hand, some liver tumors display typical pancreatic markers (e.g., amylase and lipase) (100). Pancreatic genes are expressed in sorted fetal mouse liver cells, including the P-cell transcription factor, Pdx-1, as well as amylase and lipase (27). Moreover, expression of transgenes, such as Pdx-1 or neuroD-P cellulin in liver cells induces insulin expression in rodent and human cells (101-104). This...

A NOD Mice as an Animal Model of Autoimmune Diabetes

The NOD mouse is an animal model of insulin-dependent diabetes mellitus with striking similarities to human type I diabetes (42,43). Similarly to the human disease, the induction of diabetes in these mice is under polygenic control and involves at least three autosomal recessive genes located outside of chromosome 17 location of the major histocompatibility complex (MHC) and MHC-linked gene(s) responsible for the generation and activation of autoreactive T cells inherited in dominant fashion 44-46 ). Although genetic predisposition appears to be an important prerequisite in the development of type I diabetes, it seems that certain environmental factors (viral or bacterial infections, chemicals, diet) are mainly responsible for inducing the initial lesions and or precipitating the disease. Of primary significance in the pathogenesis of type I diabetes is the progressive infiltration of islet cells of the pancreas by mononuclear cells (insulitis). The infiltration of islets encompasses...

Expression of Hsp 60 in Islet Cells of Prediabetic and Diabetic NOD Mice

The redistribution of hsp 60 in P cells of prediabetic NOD mice appeared to be consequence of insulitis. Progression of insulitis from nondestructive, peri-islet to destructive, intraislet insulitis was associated with a gradual reduction of hsp 60 antibody binding to secretory granules and increased binding to the cytosol (65). In view of the strong immunogenicity of hsp 60 proteins, the emerging question was whether altered distribution of hsp 60 would change the antigenicity of p cells and evoke autoimmune responses in diabetes-prone mice.

Diabetes and Metabolic Syndrome

Survivors of HSCT may be at risk for insulin resistance, impaired glucose tolerance and type II diabetes 45 . Risk factors relevant to the development of these problems include obesity, family history of diabetes, inactivity, diet, use of growth hormone and race. In one study of 748 patients evaluated for type II diabetes, 34 had developed this condition at a median follow-up of 11 years. The prevalence of type II diabetes was 9 among the survivors of leukemia, with CML patients at highest risk 15 . The prevalence was age-related, with 12 occurring among leukemia survivors 20-39 years old and 43 occurring among survivors 40-49 years 15 . The prevalence of diabetes type I, although less common, was three times higher than in the general population. Most patients evaluated were not obese and experienced a relatively early onset of type II diabetes. Racial minorities were more likely to develop diabetes TBI was not a risk factor in this analysis. Hyperinsulinemia and hypertriglyceridemia...

Structure and Action of Insulin

The primary role of insulin is to control the absorption of glucose from the bloodstream into cells where glucose is utilized as an energy source or converted into glycogen for storage. Insulin functions to regulate the level of glucose in blood. Carbohydrates, such as starch, taken in the diet are digested into glucose, which is transferred to the blood stream. The high level of blood glucose stimulates the pancreatic p cells to release insulin directly into blood stream. Insulin binds to insulin receptors on the surface of a cell, generating signals for movements of glucose transporters to the cell membrane. The glucose transporters aggregate into helical structures creating channels for entrance of glucose molecules into the cells. Insulin is produced in pancreatic cells as prepro-insulin which contains 4 segments (1) an N-terminal signal sequence of 16 amino acids, (2) a B chain of 30 amino acids, (3) a C peptide of 33 amino acids, and (4) an A chain of 21 amino acids. In a later...

Autologous Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

Loss of islet p cells occurs over a time span of 3-5 years and is initially balanced by regeneration however, persistent autoimmunity eventually exhausts or overwhelms the regenerative capacity of pancreatic stem cells (27). Clinical symptoms manifest when the number of islet p cells falls below the threshold necessary to maintain glycemic control, but before complete ablation of islet p cells. Patients with residual islet p cells have better metabolic control, are less likely to experience acute hypoglycemic or ketotic episodes, and are less likely to develop chronic complications (28). Therapeutic intervention designed to control autoimmunity in patients with recent onset type 1 diabetes may preserve remaining islets and thus improve disease management. Autologous HSCT has the potential to restore self tolerance to islet p cells, and thus preserve remaining pancreatic islets. The rationale for autologous HSCT is based on the observations that (1) development of type 1 diabetes in...

Pancreas And Islet Transplant For Autoimmune Type 1 Diabetes Mellitus

In contrast to HSCT for rheumatic autoimmune diseases, HSCT for patients with type 1 diabetes cannot provide relief from clinical symptoms of chronic disease. Frequently, clinical presentation of type 1 diabetes is subsequent to autoimmune-mediated damage to islet p cells therefore, damaged or destroyed endocrine tissue must be regenerated or replaced in order to alleviate clinical manifestations of disease. Conversely, islet or pancreas transplant may lead to recurrent autoimmune-mediated destruction of donor tissue, and thus HSCT may be necessary to cure autoimmunity before endocrine tissue replacement. Pancreatic transplantation has been used to correct insulin deficiency in patients with type 1 diabetes, and is performed most often in conjunction with renal transplantation in patients with diabetic nephropathy (55). Solid-organ transplantation for type 1 diabetes is limited to patients with life-threatening disease however, because of the risks associated with invasive surgical...

Basis for Sports Nutrition Interest 1 Insulinomimetic Actions

The insulin-like actions of vanadium have been well reviewed.203,208 According to these reviews, the anti-diabetic effect of vanadium was first reported more than 100 years ago, but its potential as an orally active insulin-mimetic agent was stimulated by reports beginning in 1985. Since then, studies with animal models of type 1 diabetes showed that chronic treatment with vanadium salts lowered plasma glucose concentration, increased peripheral glucose utilization and normalized hepatic glucose output, but had no effect on plasma insulin concentration. One of the reviews203 noted that the vanadium supplementation had no or minor effects on plasma glucose and insulin concentrations in normal control animals. Treatment of human patients with type 1 diabetes reduced insulin requirements. Several organic vanadium compounds have been developed and, in addition to inorganic vanadium compounds, have been examined as potential therapeutic agents for type 2 diabetes. The vanadium compounds...

Regulation of Drosophila imaginal disc growth by the insulinIGF signalling pathway

Leevers I would like to give a brief summary of what is known about the role of signalling by the insulin insulin-like growth factor (IGF) pathway during the growth of Drosophila imaginal discs, and then contrast this with what we have heard in the previous papers in this book. There is a pathway in Drosophila that is highly homologous to the insulin IGF signalling pathway in mammals (Fig. 1 Leevers ). A number of different labs have studied various genes on this pathway (Edgar 1999, Leevers 1999, Lehner 1999). The pathway is activated by an insulin IGF receptor homologue, Inr, which autophosphorylates and phosphorylates an insulin receptor substrate protein, Chico (Chen et al 1996, Bohni et al 1999). This results in the activation of a class IA phos-phatidylinositol-3-kinase (PI3K) made up of a catalytic subunit (Dp110) and adaptor subunit (p60) (Leevers et al 1996, Weinkove et al 1999). In addition, at least two downstream components have been identified and studied they are the...

Possible interaction of IDGFs with the insulin pathway

Like other growth factors, the IDGFs presumably activate a signal transduction pathway that ultimately controls transcription and replication. One possibility is that they interact in some way with the insulin receptor (InsR) pathway, which has been shown by several genetic studies to be involved in controlling imaginal disc growth in vivo (Weinkove & Leevers 2000). Neither insulin nor the IDGFs are effective alone, but the combination of these factors is effective in stimulating growth of imaginal disc cells in vitro. Although the Drosophila equivalent of insulin has not yet been reported, an insulin-like molecule has been detected in larvae using antibodies against mammalian insulin (Seecof & Dewhurst 1974, Meneses & De Los Angeles Ortiz 1975). Mammalian insulin is one of the requirements for the culture of imaginal disc cell lines in vitro (Cullen & Milner 1991) and it promotes growth of Drosophila cell primary cultures (Echalier 1997). An insulin-like hormone (prothoracicotropic...

Case Study Insulin Production Systems

Type I diabetes mellitus is a disorder affecting over 80 million people worldwide. At present exogenous insulin delivery via injection or pumps equipped with glucose sensors cannot provide the minute-to-minute normoglycemia needed to prevent the complication associated with this autoimmune disorder. The sensor pump technology also lacks durability, with device function often limited to only hours. The exacting requirement placed on insulin dosage and timing of administration in diabetic patients, as well as the many years of safe and reliable treatments expected from the insulin delivery technology, have pointed to the advantages of implantable systems in which insulin would be synthesized as needed and made available to the organism on demand. Four alternatives have been considered and have undergone clinical evaluation whole organ transplantation, human islet and xenogeneic islet transplantation, immunoisolation of normal or tumoral insulin-secreting tissue, and transplantation of...

Insulin Glucagon and Diabetes Mellitus

The pancreas, in addition to its digestive functions, secretes two important hormones, insulin and glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism. Although the pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide, their functions are not as well established. The main purpose of this chapter is to discuss the physiologic roles of insulin and glucagon and the pathophysiology of diseases, especially diabetes mellitus, caused by abnormal secretion or activity of these hormones. Physiologic Anatomy of the Pancreas. The pancreas is composed of two major types of tissues, as shown in Figure 78-1 (1) the acini, which secrete digestive juices into the duodenum, and (2) the islets of Langerhans, which secrete insulin and glucagon directly into the blood. The digestive secretions of the pancreas are discussed in Chapter 64. The beta cells, constituting about 60 per cent of all the cells of the islets, lie mainly in...

Insulin and Synthetic Hypoglycemic Agents

Drugs used for lowering the glucose level in the blood are called hypoglycemic agents. Likewise, substances that raise the level of glucose in the blood are called hyperglycemic agents. Changes in the level of glucose in the blood can be caused by various reasons, the primary cause being diabetes mellitus. Diabetes mellitus is a metabolic disease associated with a high level of blood sugar and as a rule, disturbance of carbohydrate, lipid, and protein metabolism. The most common biochemical condition in diabetes mellitus is ketoacidosis. Insulin and other hypoglycemic agents are used to treat diabetes mellitus. Depending on the condition of the organism, diabetes is classified into two types. Insulindependant (type I), in which there is suppression of endogenous insulin production by the organism itself, and insulin-independent (type II), which results either because of insufficient insulin production, or because of a breakdown of insulin receptors, which is usually a result of other...

Therapeutic Utility Of Spirulina In Diabetes Mellitus

Noncommunicable diseases are increasing to alarming proportions and gaining their hold over the developing countries. One of the noncommunicable diseases that has gained importance is diabetes mellitus because of its rising prevalence. Worldwide, the number of cases of diabetes is currently estimated to be around 150 million. This number is predicted to double by 2025, with the greatest number of cases being expected in China and India.3 The rising prevalence of diabetes and its associated complications place a high burden on the health care systems. The major therapeutic goal in diabetic patients therefore, is to optimize blood glucose control in order to improve the well-being of the patients and reduce the risk of diabetes-induced complications. The recent years have witnessed a renewed interest in identifying probiotics, antioxidants, neutraceuticals, and designer foods that can be used as alternative therapies for sustaining and managing health. This prompted us to assess the...

Skeletal Muscle Metabolic Alterations Associated with Insulin Resistant States

In type 2 diabetes patients treated with steady-state plasma concentrations of insulin, muscle glycogen synthesis was 50 lower than in normal individuals and accounted for almost the entire insulin-stimulated glucose uptake in both normal and diabetic subjects 17 . These studies demonstrate that under hyperglycemic, hyperinsulinemic conditions, muscle glycogen synthesis is the major pathway for glucose utilization in both normal and diabetic subjects and that impairment in muscle glycogen synthesis may have a key role in causing insulin resistance in patients with type 2 diabetes. Intracellular glucose-6-phosphate is an intermediary metabolite between glucose transport phosphorylation and glycogen synthesis, hence the intracellular concentration of glucose-6-phosphate will be determined by the relative activities of these two steps. In patients with type 2 diabetes, the decreased activity of glycogen synthase should lead to increased glucoses-phosphate concentrations compared with...

Low Blood Sugar or Thyrotoxicosis

Low blood sugar, also known as hypoglycemia, triggers the very same adrenaline rush reaction that can occur in a panic attack. Low blood sugar can be measured, and a reading below 50 mg dl (or in Canada, 3.5 mmol L) is considered too low. But many people assume they suffer from low blood sugar even when their blood sugar levels are normal because they feel shaky and irritable when hungry, which is relieved by food. In fact, the common feature to panic attacks and true hypoglycemic attacks is a rapid activation of the adrenergic system (adrenaline release), the same system enhanced by thyrotoxicosis. In this way, thyrotoxicosis can be confused for both panic attacks and hypoglycemia. Treatment of these adrenergic symptoms by beta-blockers can relieve most of these symptoms, and correction of the underlying thyrotoxicosis relieves the rest of them.

Gestational Thyroid Disease Thyroid Disease During Pregnancy

With two rare exceptions, discussed further on, the causes of thyroid disease during pregnancy are the same as in the general population. The most common thyroid diseases in pregnancy mirror the most common thyroid diseases in the general population. As in the general population, Hashimoto's disease (see Chapter 5) is the most common thyroid disease in pregnancy, followed by Graves' disease (see Chapter 6). In both cases, the risk spikes during the first three months of pregnancy, and then spikes again in the first six months after delivery. Many women will first develop Hashimoto's or Graves' disease within a year of their pregnancies. After delivery, up to 20 percent of all women (particularly those with thyroid antibodies or insulin-dependent diabetes) will develop postpartum thyroiditis, which usually resolves on its own but 25 percent of the time can leave women permanently hypothyroid.

Elevated Blood Glucose Concentration and Adrenal Diabetes

Both the increased rate of gluconeogenesis and the moderate reduction in the rate of glucose utilization by the cells cause the blood glucose concentrations to rise. The rise in blood glucose in turn stimulates secretion of insulin. The increased plasma levels of insulin, however, are not as effective in maintaining plasma glucose as they are under normal conditions. For reasons that are not entirely clear, high levels of glucocorticoid reduce the sensitivity of many tissues, especially skeletal muscle and adipose tissue, to the stimulatory effects of insulin on glucose uptake and utilization. One possible explanation is that high levels of fatty acids, caused by the effect of glucocor-ticoids to mobilize lipids from fat depots, may impair insulin's actions on the tissues. In this way, excess secretion of glucocorticoids may produce disturbances of carbohydrate metabolism very similar to those found in patients with excess levels of growth hormone. The increase in blood glucose...

Cloning Human Insulin Gene

Before the advent of biotechnology, the insulin used for the treatment of type I (insulin-dependent) diabetes mellitus was obtained from extracting the hormone from porcine or bovine pancreatic tissues. In the early eighties, human insulin produced by recombinant technology entered the pharmaceutical market. In one of the approaches (Geoddel et al. 1979. Proc. Natl. Acad. Sci. USA 76, 106-110), the sequences for the A and B chains were synthesized chemically and inserted separately downstream of the P-galactosidase structural gene controlled by the X lac promoter. The construction was such that the insulin chains would be made as fusion proteins joined by a methionine to the end of the p-galactosidase protein (see Section 9.1.1). The expression vector also contained an AmpR marker. Transformants were screened by plating on a culture medium containing X-gal and ampicillin. Insulin A chain and B chain transformants were grown to harvest the cells in large quantity. The cells were lysed...

Insulin andor IGFI Resistance with Aging

In general, aging is associated with insulin resistance. Is it possible that neurons also become resistant (or somewhat diabetic) and that their uptake of glucose is not as efficient to satisfy energy demand In the periphery, previous studies showed age-related alterations in tyrosine kinase activity (Ruiz et al., 1992). Moreover, despite normal levels of insulin receptors in 20-month-old Wistar rats, it was shown that receptor autophosphorylation was reduced by 25 , in addition to decreased IRS-1 levels. Moreover, insulin-stimulated IRS-1 association with phosphatidyl-inositol 3-kinase (PI3-kinase) was decreased by 70 in the liver and 98 in muscles of 20- versus 2-month-old rats, with no change in PI3-kinase level the phosphorylation of IRS-2 followed a similar pattern (Carvalho et al., 1996). Interestingly, insulin could not induce sodium potassium-ATPase activation and plasma membrane hyperpolarization of certain cell types in aged Wistar rats (Frolkis, 1995). It was also...

Physical Activity and HRQL in Diabetes

The levels of physical activity of patients with various chronic diseases, including diabetes, hypertension, congestive heart failure, recent myocardial infarction, depressive symptoms, or current depressive disorder, are associated with subsequent functioning and well-being 37 . Greater levels of exercise were also associated with better functioning for patients with chronic conditions over a 2-year period. Physical activity has become an essential component of prevention and treatment of type 2 diabetes, and very recent recommendations of the American Diabetes Association classified as level of evidence A the benefits achieved by 30 min physical activity per day in subjects with impaired glucose tolerance or diabetes 38 . In both type 1 and type 2 diabetes mellitus, HRQL is remarkably impaired when tested with generic and disease-specific questionnaires 39 , with type 1 diabetes having the greater negative effect 40 . In a large US sample of adults with diabetes, the respondents...

Mitochondrial Dysfunction Might Underlie Type 2 Diabetes

Increased deposition of lipids in muscle and liver is a marker of insulin resistance 10 , but whether this is causal in the development of insulin resistance is less clear. More recently, it has been hypothesized that impaired mitochondrial function leads to the accumulation of lipid metabolites and alters insulin signaling 4,11,16,42 . Recent experiments have shown that insulin resistance in the elderly could be attributed to intramyocellular lipid content, which in turn is linked to a reduction in mitochondrial oxidative-phosphorylation activity 3 . The reduction in mitochondrial function and lipid accumulation in muscle can probably be ascribed to an age-related reduction in mitochondrial content caused by accumulated mutations in mtDNA, which are known to occur with aging 43 . Furthermore, recent studies have shown that a reduction in mitochondrial activity is associated with an increase in intramyocellular lipid content in young, lean, insulin-resistant offspring of parents with...

Allogeneic Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

In contrast to autologous HSCT, allogeneic HSCT may cure autoimmunity, and consequently preserve remaining pancreatic islets in patients with recent-onset type 1 diabetes. The rationale for allogeneic HSCT for patients with recent-onset type 1 diabetes is based on the following observations (1) allogeneic HSCT will halt autoimmune-mediated destruction of islet p cells (2) preservation of intact islet p cells is beneficial to the patient even in the absence of full metabolic control (3) because hyperglycemia is more easily managed in patients with functional islet p cells, chronic complications are less likely to develop and (4) there is a low probability of disease relapse or recurrence after allogeneic HSCT. Allogeneic HSCT is difficult to justify in recently diagnosed patients, however, because chronic effects of hyperglycemia are unlikely to manifest before complete loss of islet p cells. In patients likely to receive maximum therapeutic benefit from allogeneic HSCT, therefore,...

Taurine Fluxes In Insulin Dependent Diabetes Mellitus And Rehydration In Streptozotocin Treated Rats

Abstract The effect of streptozotocin induced diabetes mellitus and rehydration on brain taurine and brain water content was studied in 4 groups of rats. Two groups of rats with diabetes mellitus were used. In one group, taurine and brain water content were determined following induction of diabetes for one week. In the second group, diabetes was induced for one week but before sacrifice, 15 of body weight of normal saline was introduced into the peritoneum, half at time 0, half 30 minutes later with sacrifice 60 minutes after the first infusion. In two groups of animals (controls), the brain taurine and water content were estimated in normal conditions and after hydration, in exactly the same way as diabetic rats. Brain taurine content was greater in diabetic rats than nondabetic rats and there was no decrease in brain taurine content within the first hour following rehydration of the diabetic rats. Brain water content was greater in rehydrated diabetic rats than in non-rehydrated...

Immune Responses to Mycobacterial Hsp 60 in Diabetes

The potential role of the heat shock protein hsp 60 in the development of diabetes in NOD mice was first postulated by Elias et al. (6,7). This hypothesis was based on the detection of T-cell and antibody responses against a 62-kDa molecule cross reactive with a mycobacterial 65-kDa heat shock protein. These hsp 65 cross-reactive T-cell and antibody responses developed coincidently with the progression of insulitis and were followed by induction of anti-insulin antibodies and anti-idiotypic antibodies (6). An isolated diabetogenic T-cell clone was able to transfer disease to naive mice. The importance of the hsp 60 cross-reactive immunity in the pathogenesis of NOD mice diabetes was supported further by the finding that administration of hsp 60 antigen or synthetic peptide epitope to young NOD mice protected them against diabetes (7). These results provided strong evidence that one of the antigens in diabetes is related to hsp 60. The concept of hsp 60 as an antigenic target in type I...

Autoimmune Type 1 Diabetes Mellitus

Of the endocrine autoimmune diseases, autoimmune type 1 diabetes mellitus (hereafter referred to as type 1 diabetes) is the most extensively studied because of both disease prevalence and severity. In 2002, approximately 13 million people in the United States (6.3 of the population) suffered from diabetes, and approximately 5-10 of these cases were diagnosed as type 1 diabetes (15). Furthermore, in the year 2000, diabetes was the sixth leading cause of death listed on death certificates in the United States (15). Thus, despite supportive therapy, diabetes mellitus causes significant morbidity and mortality. Type 1 diabetes is characterized by insulin deficiency secondary to progressive T-cell-mediated destruction of insulin-producing pancreatic p cells within the islets of Langerhans. Clinical therapy is supportive blood glucose is controlled by insulin injections, diet, and exercise. Nevertheless, homeostatic maintenance of blood glucose through shifting physiologic conditions is...

Diabetes Insipidus

Diabetes insipidus may be caused by histiocytosis, germinomas, surgical trauma or CNS-involved leukemia. Patients with diabetes insipidus usually present with obvious symptoms of excessive thirst and urination with nocturia or enuresis. However, diabetes insipidus may not be recognized until affected patients have dehydration during an intercurrent illness. The urine remains clear in color throughout the day. In patients with CNS-involved leukemia, severe hypernatremic dehydration can occur if the CNS lesion also affects the centers for thirst regulation.


There is an increased incidence of type 1 diabetes mellitus (formerly known as juvenile diabetes or insulin-dependent diabetes) in families where Graves' disease or Hashimoto's thyroiditis has been diagnosed. Antibodies and lymphocytes attacking the special cells in the pancreas responsible for making insulin cause this autoimmune type of diabetes. If you do happen to have both conditions, an overactive thyroid will often make the diabetes worse and more difficult to control with insulin. Once your thyroid condition is treated, though, you will find it easier to regain control over the diabetes. On the other hand, there are not usually any problems of glucose control directly related to hypothyroidism. If true hypoglycemia is documented by low blood sugar levels (often this is inappropriately diagnosed see Chapter 4) in people with hypothyroidism, it is important to see if the pituitary gland is abnormal, causing both hypothyroidism and loss of adrenal function (causing the low blood...

Insulin Resistance

In recent years, essential hypertension, in conjunction with several other physiological parameters (glucose intolerance, upper-body obesity, elevated triglycerides), has been shown to be related to insulin resistance. The combination of these variables has been called the insulin resistance syndrome or Syndrome X (Reaven, 1988). Insulin resistance is commonly cited as a causal agent for Type II diabetes. In contrast to Type I diabetes, which is characterized by the body's lack of insulin production, normal or even enhanced amounts of insulin are typically available in Type II diabetes the insulin receptors, however, are insensitive to insulin. It is generally thought that insulin resistance represents an adaptive bodily response to prevent additional weight gain that accompanies unhealthy lifestyles and dietary practices. Under conditions of extreme insulin resistance, an overabundance of sugars and lipids remains in the bloodstream rather than being absorbed into body tissue....

Gestational Diabetes

A type of diabetes present only during pregnancy was noted in 1882. However, it was not until the 1940s that the term gestational diabetes appeared in medical literature. This form of the disease is difficult to distinguish from type II diabetes because a woman could have diabetes before pregnancy but not have it diagnosed until pregnancy. Babies born to diabetic mothers usually are large but may have immature organ systems, in which case they may not survive. In general, cities in the United States report a higher prevalence of gestational diabetes than do European cities. The highest reported rate of gestational diabetes occurs among the Pima Indians of Arizona, who also have the highest prevalence of type II diabetes of any known population.

Diabetes mellitus

Type 1 diabetes Type 1 diabetes (T1D) accounts for up to 10 of all diabetes, and is usually diagnosed in children and adolescents, although demographics are changing, predominantly due to the emergence of Type 2 diabetes (T2D) in adolescents, most likely as a consequence of the recent epidemic of obesity in this generation.2 T1D is characterised by abnormally high blood glucose levels following autoimmune f cell destruction, and can lead to serious long-term complications including blindness, kidney failure, stroke, heart and vascular diseases.3 T1D is currently incurable, and is most commonly treated by lifelong daily insulin injections, although if inappropriately managed, this carries an increased risk of hypoglycaemia, and the restoration of normoglycaemia does not always alleviate the aforementioned secondary complications, and patients often have a reduced life expectancy.4 Type 2 diabetes T2D is the most common form of diabetes, characterised by insulin resistance and impaired...


Insulin secretion is increased in OSA and while this is partly due to the central obesity which is common in this condition, the levels are raised even when this is taken into account. This may be because of increased sympathetic stimulation of the beta cells in the pancreas. Insulin resistance develops independently of the body mass index 15 and leads to an increase in low-density lipoproteins (LDL) and a fall in high-density lipoproteins (HDL). This combination taken with hypertension comprises the metabolic syndrome to which OSA appears to be a contributory factor 16 .

Tropical Diabetes

A type of diabetes found primarily in many tropical areas of the world has characteristics of both type I and type II. The clinical profile involves the following (1) a different genetic pattern of diabetes than in temperate regions (2) a low prevalence rate of type I DM (3) a younger age of onset of type II (4) a sex ratio with male predominance in India and Africa, but female predominance in the West Indies (5) an association of low calorie and protein intake with underweight diabetic individuals in Old World areas but overweight individuals in the Western Hemisphere (6) the predominance of diabetes in urban areas, with the exception of rural populations in the West Indies and (7) intermittent need for insulin therapy. Information is relatively sparse on the genetics of diabetes in tropical countries. Recent studies have shown great population variability in increased susceptibility to diabetes. Genetic studies of Indian populations suggest a stronger familial factor among them...

High Blood Sugar

Thyrotoxicosis, as we discussed in Chapter 4, can increase your need for insulin if you have type 1 diabetes or in some cases of type 2 diabetes. If you have type 2 diabetes (as one in four adults over forty-five do), you are already at a much greater risk of heart attack or stroke because of blood vessel complications. It is critical that you have your diabetes medications or insulin and your blood-sugar targets reassessed by your doctor, since they can be thrown off by the symptoms of Graves' disease and thyrotoxico-sis. If you have diabetic eye disease, it's important to assess whether new eye symptoms are a result of developing thyroid disease or a worsening of preexisting diabetes eye disease (also worsened by smoking).

Risk factor diabetes

Thomas Willis Diabetes

The urine of diabetics is wonderfully sweet as if imbued with honey or sugar. Thomas Willis (1621-1675), physician to King Charles II, England Diabetes is a risk factor for coronary heart disease and stroke, and is the most common cause of amputation that is not the result of an accident. Insulin is a hormone produced by the pancreas and used by the body to regulate glucose (sugar). Diabetes occurs when the body does not produce enough insulin, or cannot use it properly, leading to too much sugar in the blood. Symptoms include thirst, excessive urination, tiredness, and unexplained weight loss. There are two main types of diabetes. Type 1 diabetes, in which the pancreas stops making insulin, accounts for 10 to 15 of cases. The majority of people with diabetes have type 2 disease, in which insulin is produced in smaller amounts than needed, or is not properly effective. This form is preventable, because it is related to physical inactivity, excess calorie intake and obesity. People...

The Role of Insulin

The history of insulin is fascinating and has been told especially well by Michael Bliss in The Discovery of Insulin.18 cells producing insulin. They constitute 60-80 of the cells in the islets, i.e. 6-800 cells islet There is a delicate and profuse capillary network and nerve connections in the islet, somewhat resembling the renal glomerulus. The capillaries of the islets anastomose with the main pancreatic vasculature which may facilitate signaling between endocrine and exocrine pancreatic cells. The interaction of cytokines between the individual cell types may be important attributes that would be lost to separated islets or surrogate cells. The pancreas contains one million islets and therefore 6-8 x 108 cells. The endocrine secretions of the islets enter the portal blood and the first organ they reach is the liver. Insulin is partially metabolized by the liver, which converts glucose to glycogen. In the 1920s, the connection between removal of the pancreas and diabetes was...

Glucocorticoid Secretion Under Stressful Conditions

Generally, the stress response, with the resultant elevation of glucocorticoid levels, is meant to last only for a limited duration. The time-limited nature of this process renders its accompanying catabolic and immunosuppressive effects beneficial, with no adverse consequences. Chronic activation of the stress system, however, is detrimental. For example, prolonged exposure to elevated glucocorticoid levels results in suppression of anabolic processes, muscle atrophy, reduced sensitivity to insulin and a risk for diabetes, hypertension, hyperlipidemia, arterial disease, peptic ulcers, amenorrhea, impotence, immunosuppression, and the impairment of growth and tissue repair (Munck et al., 1984). In addition, elevated glucocorticoid levels are associated with psychopathology, neuronal damage, and impaired cognitive function (McEwen, 1994 Tsigos & Chrousos, 1994). An efficient endocrine response to stress is one that is rapidly mobilized in the presence of a threat and ef

Death by Brain Criteria

The ability to transplant organs successfully led to the need of criteria for brain death, and national and international definitions have been developed. Many now argue that current criteria are restrictive and should be expanded to include patients who have no reasonable chance of regaining consciousness. y If this change is to be made, a substantial shift in societal thinking about life and death may need to precede it. However, in North America, death by brain criteria is still considered to be irreversible loss of brain function, including that of the brain stem. The single exception to this rule appears to be in the area of osmolar control, and diabetes insipidus is not required for this diagnosis.

Physicochemical Properties Of Drugs

Movement into or through the cerebral endothelium of molecules of the size of peptides and proteins (e.g., insulin, transferrin, lipoproteins) may depend on receptor-mediated endocytosis. Alternatively, cationization of albumin may stimulate a nonspecific endocytosis. Significant flux into brain of drugs linked to monoclonal antibodies against the transferrin receptor or the insulin receptor also takes place. This topic is also reviewed in this volume (28).

The Most Difficult Puzzles Ever Devised

Charles Best, one of the pioneers in the search for a cure for diabetes, once explained what it is about medical research that intrigued him so. It's not just the gratification of knowing one is helping people, he confided, although that probably is a more heroic and selfless motivation. Those feelings may enter in, but truly, what I find best is the feeling of going toe to toe with nature, of trying to solve the most difficult puzzles ever devised. The answers are there somewhere, those keys that will solve the puzzle and make the patient well. But how will those keys be found has resulted in the saving of untold millions of lives. The isolation of the enzyme insulin has reversed what was once a death sentence for anyone with diabetes. There have been great strides in combating conditions for which there is not yet a cure, too. Medicines can help AIDS patients live longer, diagnostic tools such as mammography and ultrasounds can help doctors find tumors while they are treatable, and...

Nutrients Growth And The Development Of Programmed Metabolic Function

Abstract For each individual, the genetic endowment at conception sets the limits on the capacity or metabolic function. The extent to which this capacity is achieved or constrained is determined by the environmental experience. The consequences of these experiences tend to be cumulative throughout life and express themselves phenotypically as achieved growth and body composition, hormonal status and the metabolic capacity for one or other function. At any time later in life the response to an environmental challenge, such as stress, infection or excess body weight is determined by an interaction amongst these factors. When the metabolic capacity to cope is exceeded, the limitation in function is exposed and expresses itself as overt disease. During early life and development the embryo, fetus and infant are relatively plastic in terms of metabolic function. The effect of any adverse environmental exposure is likely to be more marked than at later ages and the influence is more likely...

Prospects For Gene Therapy

The extensive background of knowledge on mouse embryo-derived stem cells provides an experimental model for human ES cell research and a means of testing ideas on the biological basis of therapeutic interventions involving stem cells. Given the extensive database of genomic and developmental information and the long history of mutagenesis and ES cell experimentation, the mouse is the ideal model organism for this purpose. The differentiation pathways leading to many specific cell types have been elucidated for stem cells in vitro and are supported by studies on developmental potential as assayed through contribution in vivo (reviewed by Odorico et al., 2001). Even highly organized structures such as insulin-expressing cells with the three-dimensional structure of pancreatic islets have been differentiated from ES cells, demonstrating their potential for the assembly of functional organs (Lumelsky et al., 2001). The feasibility of using ES cells to effect cures through tissue...

Thinking Is Usually Self Aware

Actions are characteristically, even by definition, self-aware. That is, when performing an action we are generally aware of and can describe what it is we are doing. One indication that our concept of thinking is a basically actional concept is that this automatic self-awareness feature also applies to thinking. We generally know, and can say, both that we are thinking and what we are thinking. This cannot be said of the natural processes going on in our bodies. Such inner goings-on as digestion, circulation and oxidation of the blood, insulin secretion by the pancreas, and conception are not usu-ally and certainly not characteristically or by definition subject to awareness by the host person. Some internal processes are sometimes accessible to awareness however, few are characteristically so, and none necessarily. In the normal course of events, we are never aware of the neurophysiolog-ical goings-on in our own brains and yet we usually are aware of our thinking.

Affective Disorder Syndromes

The differential diagnosis of depression includes primary psychiatric syndromes other than major depression such as behaviors associated with schizophrenia, generalized anxiety disorder, and obsessive-compulsive neuroses. Medical and neurological disorders either associated with or mimicking depression include malignancy, infections, medications (steroids, reserpine, levodopa, benzodiazepines, propranolol, anticholinesterases), endocrinological dysfunction (Cushing's disease, hypothyroidism, apathetic hyperthyroidism, diabetes), pernicious anemia, and electrolyte and nutritional disorders (inappropriate secretion of antidiuretic hormone, hyponatremia, hypokalemia, hypercalcemia). Depression is also associated with multiple sclerosis, Parkinson's disease, head trauma, stroke (particularly of the left frontal lobe), and Huntington's disease. Interictal changes in temporal lobe epilepsy may mimic depression, particularly with right-sided epileptic foci. Patients with diencephalic and...

Fetal Origins Of Adult Disease

Until recently it was generally considered that the chronic non-communicable diseases of adulthood, heart disease, hypertension, diabetes and cancer, were caused by a genetic predisposition acting with lifestyle factors such as smoking, diet and activity. Over the last decade it has become clear that other factors may play a substantial role, and in particular programming of the metabolic capacity during early life may be especially important. The first evidence for this proposition came form a series of epidemiological studies carried out by Barker and his colleagues which suggested that growth during early life potentially represents a major risk factor for the later development of ischaemic heart diseases4 13 The proposition is that early nutritional exposure programmes future metabolic competence and behaviour by imprinting a change upon genomic expression. The first evidence came from ecological studies which showed that geographical differences in death from ischaemic heart...

Differentiation Of Es Cells Into Pancreatic Lineages

Isolated islet and whole-organ pancreas transplants are accepted therapies for some patients with type I diabetes. Fewer than 100 islet cell transplants and approximately 1400 pancreas transplants are performed annually in the United States, and cadaver donor shortages severely limit more widespread application. The generation of glucose-responsive, insulin-secreting p cells from a renewable human source would thus be an ideal alternative to organs procured through donation. Unfortunately, current technology does not allow precise directed differentiation of ES cells, whether from mouse or human, into islet lineages. Several approaches have been taken toward the generation of cells of pancreatic lineage from mouse and human ES cells. protocol including EB formation for 5-7 days followed by plating and further differentiation in the presence of FBS. In these differentiated cultures, foci of pancreatic lineage cells emerge, including cells that stain positively for PDX1 (pancreatic...

Host Risk Factors For Severity Of Illness

Host factors related to underlying diseases and enhanced oxidative stress also appear to determine severity of rickettsioses. Patients with diabetes mellitus have an increased risk of a fatal outcome with Mediterranean spotted fever. Anecdotal descriptions suggest that alcohol abuse and cardiovascular disease may be risk factors for severity of rickettsial illness.

Therapeutic Application Of Es Cell Technology By Cell Transplantation

Transplantation of ES cell-derived cell populations into normal and disease model animals has demonstrated the potential for these cells in disease control. ES-derived neurons and neural precursors (Brustle et al., 1999 McDonald et al., 1999 Arnhold et al., 2000 Kawasaki et al., 2000 Liu et al., 2000 Bjorkland et al., 2002), cardiomyocytes (Klug et al., 1996), mast cells (Tsai et al., 2000), and insulin-secreting cells (Soria et al., 2000) have been transplanted successfully into appropriate recipient sites and shown to survive integrate and, to some measurable extent, function within host tissue (Brustle et al., 1999 McDonald et al., 1999 Liu et al., 2000 Tsai et al., 2000 Bjorkland et al., 2002). For example, differentiating mouse ES cells and ES cell-derived neural precursors have been implanted to the brains of rats, into both ventricles and sites of solid tissue, and found to survive and incorporate into the recipient brain migrate away from the site of injection and...

Clinical Evaluation of Isolated ROA1 Family

Four out of the five sibs of the ROA1 family (Figure 4.3) were affected with an isolated, early-onset but slowly progressive optic neuropathy. Between 2 and 6 years of age, all patients complained of a visual impairment that could not be corrected by glasses. At age 10, fundus examination, fluorescein angiography, visual field testing, colour vision analysis and electrophysiological recordings of individual V2, led to the diagnosis of optic atrophy without retinal degeneration. The three younger sibs displayed the same phenotype (Figures 4.1 and 4.2). In all affected sibs, the progression of the disease was very slow (visual acuity ranging from 1 10 to 2 10 for distant vision at 36 age of patients 45 years old). Moderate photophobia and dyschromatopsia with red-green confusion was noted. None of the four patients had nystagmus. Both parents (IV1 and IV2), and V1 underwent complete ophthalmologic exploration and no symptom of optic neuropathy was noted. A normal ocular pressure was...

Genome IntegrityDNA Damage Response in Postmitotic Aging

Because of the close correlation between telomere length regulation and cell cycle checkpoint control, it is intriguing to ask whether the role of telomere length maintenance is also linked to the aging of nondividing cells and possibly organismal aging. In the mouse, it is clear that mitotic cell proliferation supercedes longevity regulation in telomerase knockout mice (Hemann et al. 2001) however, it is not clear how telomere length regulation impacts the aging of nondividing cells. Two reports indicate that there is no impact of somatic aging upon telomere length regulation. In one, knocking out the telomerase catalytic subunit did not alter the life span of worms, although germ line maintenance and survival was greatly altered (Meier et al. 2006). In the second study, wild isolates of C. elegans with different telomere lengths had no difference in longevity or stress resistance. Furthermore, clonal isolates of the widely used laboratory strain N2 showed stable variance in telomere...

Primary Cultures of Rat Hepatocytes

Hepatocytes from Sprague-Dawley rats were isolated aseptically by collagenase perfusion as described by Berry et al.7. The initial viability of isolated hepatocytes was more than 85 as determined by 0.2 (w v) Trypan blue exclusion. The freshly isolated hepatocytes were resuspended in Williams E (WE) medium to give a final cell concentration of 7.5 x 105 cells per ml. The basal WE medium contained 1 g ml insulin, 50 ng ml EGF, 50 nM dexamethasone, 3 nM Na2SeO3, 100 units ml penicillin G, 100 g ml streptomycin sulfate, 0.25 g ml amphotericin B. Five ml of the diluted cell suspension (0.18 ml per cm2) were plated on each 60 mm diameter collagen-coated dish14. Cells were allowed to attach in basal medium over for a 4-h period. At 4 h, the basal medium was replaced with either fresh basal medium or the designated treatment medium. Cells were cultured with either standard WE with or without 2 mM methionine plus 0.05 mM bathocuproine disulfonate (BCS) for a total culture time of 48 h.

Pancreasderived Stem Cells

(91), and the adult pancreas has regenerative capacity after partial pancreatectomy (92) and inflammation (93) at least in rodents, there has long been speculation as to the existence of a progenitor cell within the pancreas (recently reviewed in refs. 75 and 94). In concert with these in vivo findings, several groups have demonstrated that culture of pancreatic ductal tissue can result in growth of islet-like tissues from both mice (95) and humans (96,97). In each case, an expansion of p cell-like tissue was observed, as demonstrated by expression of pdxl and insulin, as well as insulin secretion in response to glucose. Ramiya and colleagues showed that their in vitro generated islets could reverse insulin-dependent diabetes in an NOD mouse model (95). Most evidence suggests ductal or acinar tissue as the source of putative islet stem cells unfortunately, however, the characterization and isolation of an islet stem cell has been hindered by the absence of specific cell surface...

Cariogenicity Potential Of Stevioside

In addition to their use in calorie control and for diabetics, alternative sweeteners offer another benefit in maintaining good dental health by reducing the intake of sucrose (Grenby 1997). Pure stevioside and rebaudioside A were tested for cariogenicity in an albino rat model at the College of Dentistry, University of Illinois at Chicago. In this study, 60 Sprague-Dawley rats were colonized with Streptococcus sobrinus and divided into groups fed basal diet 2,000 supplemented with either 0.5 stevioside, 0.5 rebaudioside A, 30 sucrose, or with no test compound at all. All four groups were sacrificed after five weeks of feeding, and viable S. sobrinus counts enumerated and caries evaluated according to Keyes' technique. It was concluded that stevioside and rebaudioside were not cariogenic under the conditions of the study (Das et al. 1992). In a more recent in vitro study, the eight sweet constituents of S. rebaudiana (stevioside, rebaudiosides A E, dulcoside A, steviolbioside) and two...

Injury of the Hypothalamic Pituitary Axis in Patients with Cancer

Diabetes insipidus Fasting insulin and glucose Oral glucose tolerance test with insulin levels Diet and exercise Ritalin or Dexedrine Metformin (monitor for hypoglycemia) Octreotide GH, growth hormone CRT, cranial radiation therapy TBI, total body irradiation HPA, hypothalamic-pituitary axis IGF-1, insulinlike growth factor 1 IGFBP3, IGF binding protein 3 GHRH,growth hormone-releasing hormone GnRH, gonadotropin-releasing hormone LH, luteinizing hormone FSH, follicle-stimulating hormone T4, thyroxine TSH, thyroid-stimulating hormone TRH, thyrotropin-releasing hormone ACTH, adrenocorticotrophin

Es Cell Differentiation

As with their murine counterparts (Evans and Kaufman, 1981), human ES cells are pluripotent, immortal, continually proliferating cell lines with the capability to form all three of the embryonic germ layers (Thomson et al., 1998). Differentiation into many useful human cell types has been demonstrated, by either spontaneous or directed differentiation, including insulin-producing cells (Assady et al., 2001), nerve cells (Reubinoff et al., 2001 Zhang et al., 2001), and hematopoietic cells (Kaufman et al., 2001).

Associated Neurological Findings

Decreased position, vibratory, temperature, and pain appreciation occurs in several neuropathies associated with hyposmia. These include diabetes, the neuropathy of renal and hepatic failures, and a large variety of toxic neuropathies. In patients with pernicious anemia, the large myelinated central fibers carrying position and vibration senses are preferentially affected. In the context of hepatitis, the acquired immune deficiency syndrome (AIDS), and other virus-related illnesses, hyposmia can occur along with an ascending polyneuropathy of the Guillain-Barre type. In seizure patients with uncal or temporal lobe foci that induce dysosmic auras, altered sensations in a hemibody distribution can occur as part of the seizure or as a postictal transient sequela.

Directed Differentiation

Factor (TGF) Fetal bovine serum Insulin hormone insulin, are known to influence tissues derived from the mesoderm, such as muscle and cartilage. In some cases, the growth factors producing a certain kind of cell are unknown. This occurs when stem cells differentiate in vivo or when they are cultured in the presence of fetal bovine serum (blood serum obtained from a fetal cow), which contains many yet-to-be-identified growth factors.

Device Geometry Considerations

Microencapsulation refers to the formation of a spherical gel around each group of islets, cell cluster or tissue fragment. Microcapsules based on natural or synthetic polymers have been used for the encapsulation of both mammalian and microbial cells as well as various bioactive substances such as enzymes, proteins and drugs.55 A review of alternative semipermeable microcapsules prepared from oppositely charged water soluble polyelectrolyte pairs has been presented in recent papers.56,57 The main advantage of this approach is that cells, or bioactive agents, are isolated from the body by a microporous semipermeable membrane and the encapsulated material is thus protected against the attack of the immune system. In the case of microencapsulated pancreas islets, a suspension of microcapsules is typically introduced in the peritoneal cavity to deliver insulin to the portal circulation.

Regulating differentiation via hEBs

Recently it was demonstrated that, using a protocol consisting of several steps, insulin-producing cells can be generated from hESCs.13 The procedure included the following phases culturing and plating of hEBs in medium supplementation of medium with N2, B27, and bFGF reduction of glucose concentration in the medium, withdrawal of bFGF addition of nicotinamide and, finally, dissociation of the cells and re-growing them in suspension. This process resulted in the formation of clusters which exhibited higher insulin secretion and had longer durability than cells grown as monolayers. In addition to insulin, most cells also co-expressed glucagon or somatostatin, indicating similarity to immature pancreatic cells.73

Hypothalamic Obesity

Part of the therapy for hypothalamic obesity involves early identification and initiation of preventive measures, including caloric and dietary control and maintenance of regular exercise. In addition to maintaining these lifestyle choices, several drug therapies have been used pragmatically or in research efforts. These include Dexedrine, Ritalin, metformin, and octreotide. Dexedrine and Ritalin are taken orally and act as stimulants with the side effect of appetite suppression (in this situation, beneficial). Metformin is taken orally twice a day and acts as a sensitizer to insulin effects and may serve to probe the etiology of

Reactive Oxygen Species and Exercise

Aerobic exercise is intrinsically linked to increased oxygen consumption. During exercise the body as a whole uses 10-fold more oxygen than at rest, while in muscle tissue oxygen consumption may increase by 50 to 100-fold 40 .Various studies have demonstrated a connection between this increase in oxygen consumption during exercise and the formation of reactive oxygen species (ROS). In addition it has been shown that macromolecular structures within the cell can be damaged by elevated ROS. In fact, oxidative stress contributes to the accumulation of somatic mutations and oxidative damage to mtDNA. This has been apparent in mitochondrial diseases 41 , tumorgenesis 42 , aging 43 , degenerative diseases 44,45 , and diabetes 46 . However, skeletal muscle not only has the ability to produce ROS, but also has an elaborate system to regulate these reactive molecules and prevent their damaging effects. The cellular antioxidant defense system includes the mitochondrial and cytosolic forms of...

Organization Of Foetal Echocardiography

Maternal diabetes is associated with a statistical risk of cardiac malformation of about 1 in 50. Good diabetes control in early pregnancy probably diminishes this risk. In the hands of the specialist foetal echocardiogra-pher, it is possible to visualize the cardiac connections in almost every patient. The ideal gestational age for specialist evaluation is between 14 and 20 weeks, depending on the experience of the examiner. Some minor defects, such as small ventricular septal defects and mild valve stenosis, are overlooked in the foetus and some lesions, such as cardiac tumours, develop in the latter half of pregnancy and therefore may not be detected if only one early scan is performed. Secundum atrial septal defects and, of course, persistence of the ductus arteriosus are not possible to predict prenatally. With the exception of coarctation of the aorta, which is a notoriously difficult diagnosis to make or exclude prenatally, false positive diagnosis of CHD by the specialist is...

Chronic Radiation Effects

Radiation retinopathy (Fig. 6.5) is a well-documented consequence of radiation treatment. It is characterized by specific examination findings, including mi-croaneurysms, hard exudates, cotton-wool spots, optic disc swelling, vascular occlusion, hemorrhages and neovascularization. These changes are clinically indistinguishable from retinal changes due to diabetes. Radiation retinopathy can develop as soon as 3 weeks, and as late as 15 years, following RT, although, typically, it occurs between 1 and 3 years. Although as little as 15 Gy of external beam radiation has led to signs of retinopathy, 30-60 Gy are usually required. In the authors' experience, fewer than 5 of children treated with external beam radiation for retinoblastoma develop radiation retinopathy. 50 Gy is regarded as the threshold for the development of retinopathy following radioactive plaque exposure. Either a history of diabetes mellitus or concurrent treatment with chemotherapy is believed to increase...

Medical and Nursing Management

Retinal hemorrhages and cotton wool spots as part of radiation retinopathy will resolve without treatment however, they are clear indications of retinal damage and are cause for ophthalmologic referral. Retinal edema manifests as blurred vision when it affects the macula. It is diagnosed by careful slit lamp biomicroscopy with the aid of fluorescein angiography. Current treatment options include laser photocoagulation and corticosteroids. Neovascularization (both iris and retinal) is a manifestation of chronic retinal ischemia and is also treated with laser photocoagulation. Because diabetes mellitus and hypertension can mimic and or potentiate radiation retinopathy, strict control of blood sugar and blood pressure should be emphasized.

Potential For Cellbased Therapies

Animal models suggest that umbilical cord blood cells may be useful in treatment of amyotrophic lateral sclerosis by slowing motor neuron degeneration when injected intravenously (84). Ende and coworkers found that intravenous injection of umbilical cord blood cells could extend the survival of several mouse knockout models of human disease, including amyotrophic lateral sclerosis (85), Alzheimer's (85), Huntington's (86), Parkinson's (87), and type 1 diabetes (88). Human umbilical cord blood cells also improve the mobility of rats with spinal cord injuries when injected intravenously. Cord blood cells were observed in the areas of injury of spinal cord but not others and never seen in the control, uninjured animals (89). Similarly, umbilical cord blood cells were able to improve function in a stroke model in the rat when injected intravenously. The human umbilical cord blood cells differentiated into cells that expressed glial or neuronal markers (90). This suggests that umbilical...

Nutrition for a Healthy Heart

Insulin A hormone produced in the pancreas that promotes the use of glucose by the cells and protein formation. Glucose is a simple sugar derived from digested starches, more complex sugars, and other foods. Insulin is also responsible for the formation and storage of fats (lipids). any appreciable amount, only a few hundred grams as glycogen in the liver and muscles. Most consumed carbohydrates (sugars) are converted under the influence of insulin into fat and are stored throughout the body, often in aesthetically undesirable places. In fact, sugar is directly responsible for most cholesterol. Only 40 percent of ingested cholesterol is absorbed from the gastrointestinal tract. Most cholesterol is actually manufactured by the liver under the influence of insulin. The higher the insulin level, the more cholesterol is manufactured. What makes insulin levels rise Sugar

Tolerance of Nicotinic Acid

Large doses of nicotinic acid have been used to bring about changes in cholesterol levels for more than 50 years,32 despite annoying side effects. Flushing, a reddening of the skin with the sensation of heat or itching, is the most common side effect. This flushing response mainly affects the upper body and face, occurring 1 to 2 h after ingestion, and the symptoms usually disappear after repeated nicotinic acid administration. Reduced oral glucose tolerance has also been commonly reported in the past with ingestion of nicotinic acid, but recent evidence demonstrates that niacin can be used safely and effectively in diabetics who have good glucose control.33,34 Although the use of pharmacologic doses of niacin have been associated with adverse side effects like flushing, liver dysfunction and gastrointestinal stress, newer formulations of niacin (extended-release) demonstrate minimal side effects with comparable effectiveness.35

Making Better Choices

Because insulin secretion is a direct result of eating carbohydrates, should everyone stop or slash their carbohydrate intake Of course not The body is primarily fueled by carbohydrates diets too restrictive in all carbohydrates are unhealthy. However, people should learn to make better carbohydrate choices. This involves avoiding carbohydrates that are highly insulin producing or high-glycemic. Certain carbohydrates, such as white potatoes, white rice, white bread, corn, and beets, should be avoided or used sparingly. Foods containing more than five grams of added sugar are generally unhealthy. Check the labels of foods for unnecessarily added refined sugar these foods even though they may be low in fat will result In a high insulin response, causing the body to convert and store this sugar as fat.

Regulation of ER Function

Enhancement of the N-terminal AF-1 function. MAPK is activated by tyrosine kinase cell membrane receptors, that in turn are stimulated by growth factors such as insulin, IGF-1, EGF and TNF-a. Furthermore, phosphorylation at ER residue 118 also enhances the interaction of this receptor with the p68 RNA helicase, resulting in increased AF-1 but not AF-2 activity.

General Characteristics

Because of its acute onset and obvious symptoms, type I diabetes is readily identified and, therefore, permits a more accurate picture of worldwide prevalence. Type II DM is a chronic disease with generalized symptoms therefore, many cases are not diagnosed. However, rates of type II do appear to be increasing in developing nations. Generally, investigators have been cautious in interpreting an actual increase in the incidence of insulin-dependent DM. Prevalence rates continue to rise because of increased longevity of individuals with type I diabetes. Incidence rates for type II diabetes vary extensively by age and sex for different populations. In general, the incidence increases with age for both males and females until the sixth or seventh decade of life. Diabetes is among the top 10 causes of death in developed countries. In Western countries, DM ranks seventh as a cause of death. Data since the early twentieth century document a decrease in early diabetes mortality because of...

Far Distal Peripheral Lesions

Isolated lesions of either the glossopharyngeal or vagus nerves are unusual. As noted earlier, glossopharyngeal nerve abnormalities may be clinically undetectable unless adjacent structures are also involved. Perhaps the most common vagus nerve lesion is that involving the recurrent laryngeal nerve, resulting in ipsilateral vocal cord paresis and hoarseness of voice. The left nerve has a longer course, with its looped recurrence in the chest rather than in the neck, as on the right. The nerve passes around the aorta before returning rostrally to the larynx. The left recurrent laryngeal nerve may be compromised by an expanding aortic arch aneurysm or other intrathoracic processes, such as enlargement of the left atrium of the heart, pulmonary neoplasm, or mediastinal adenopathy. Both right and left superior or recurrent laryngeal nerves may be injured during the course of neck surgery such as thyroidectomy. Vocal cord paralysis has been described with vagal neuropathy attributed to...

Mucous Membrane Candidiasis

The clinical picture is an oozing, red, sharply bordered skin infection surrounding an inflamed vagina that contains a buttermilk-like discharge. This type of candidal infection is frequently seen in pregnant women, diabetics, and those who have been on antibiotics systemically.

The Metabolic Syndrome

In 1979, Kannel and McGee 4 discovered increased incidence of cardiovascular disease in patients with diabetes. Almost a decade later, Reaven 5 described the metabolic syndrome as consisting of three or more of the fol- lowing criteria central obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance or glucose intolerance, prothrombotic state, and proin-flammatory state. According to the International Diabetes Foundation (http www.idf.org) the new consensus worldwide definition of the metabolic syndrome, for persons to be defined as having the metabolic syndrome they must be centrally obese and have any two of the following four factors raised triglyceride level, reduced HDL cholesterol, raised blood pressure, raised fasting plasma glucose, or previously diagnosed type 2 diabetes. The metabolic syndrome is now present in at least 25 of the US population, according to updated statistics from the American Heart Association (http www.americanheart.org). The metabolic...

Preoperative Evaluation

As with all patients, a thorough medical history to assess the risk of anesthesia, a propensity for bleeding, and the use of both prescribed anticoagulants as well as herbal supplements which may influence clotting ability is necessary 47 . It is important to establish a social history with emphasis on tobacco use and exposure as well as environmental exposures that may contribute to nasal irritation. A complete review of systems with attention to endocrine disorders such as diabetes, immunologic disorders such as HIV and y-globulin deficiencies, as well as systemic disorders such as Wegener's granulomatosis provides significant diagnostic information.

Polymorphism Of The Hsp 702 Gene As A Susceptibility Marker In

A role in the development of autoimmunity in SLE. Indeed, several groups have reported an increase in the frequency of the Pstl 8.5-kb allele of the hsp 70-2 gene associated with a C4A deletion in type I diabetes and Graves' disease (41,42). In addition, Pociot et al. (43) have observed decreased hsp 70-2 mRNA expression in individuals who are homozygotes for the pstl 8.5-kb allele as compared with homozygotes for the pstl 9.0-kb allele.

Syndrome of Diffuse Excitation of Internuncial Pool

When the inhibitory tone in gamma motor neurons provided by the inhibitory interneuron in the internuncial pool is removed, the spontaneous excitability of the lower motor neurons is unleashed. This phenomenon of unrestrained excitation of contraction of the skeletal muscles is known as tetanus. In the most common generalized form of tetanus, all skeletal muscle, both agonists and antagonists as well as diaphragm, paravertebral, and respiratory muscles, contract uncontrollably in paroxysms of painful muscle spasms (tetanic seizures) (see T.a.ble.J.S-S ). In the absence of any inhibitory check, any environmental stimuli increase the intensity of the paroxysms, preventing coordinated respiratory movements. Tetanus may remain localized to the area of the wound (local, or cephalic, tetanus if wound is of the face or head). Tetanus is produced by impairment of function of the neurotransmitters employed by the inhibitory interneurons (i.e., GABA and glycine). Tetanus toxin blocks glycine...

Introduction Historical Perspective

Few molecules have been more closely linked to cancer than the protein tyrosine kinases. Tyrosine phosphorylation and the tyrosine kinase enzymes which create phos-photyrosine residues in their substrate proteins were discovered during studies of the oncogenic factors in tumour viruses. The identification of v-Src as the transforming factor of the Rous sarcoma virus and the recognition of its activity as a protein tyrosine kinase conceptualized the oncogene theory of tumorigenesis, creating a model which has dominated much of cancer research over the past two decades. The importance of the work on viral oncogenes in the early research on tyrosine phosphorylation is shown by an accounting of landmark events in this area (Table 1) (Hunter, 1998). The discovery of a cellular counterpart (c-Src) of the viral Src (v-Src) tyrosine kinase indicated a much broader role for these enzymes and suggested a major role for c-Src and tyrosine phosphorylation in mediating normal cell behaviours. For...

Stenosis at Stomal Site

Stomal stenosis may be minimized or avoided altogether by attention to details, performance, and management. First, the surgeon should make no larger an opening for the tracheostomy tube than is necessary. The tube should not be too large for the particular patient. Its curve should be appropriate. In order to minimize the size of the stoma and destruction of tracheal tissue, I prefer a simple linear vertical incision in the trachea (see Chapter 22, Tracheostomy, Minitracheostomy, and Closure of Persistent Stoma ). The procedure is done in an operating room with aseptic technique. Bacteria are always present in the tracheal lumen and further colonization will occur after tube placement, despite exquisite postoperative care. Staphylococcus aureus and Pseudomonas aeruginosa are the most common. However, invasive sepsis may be limited by scrupulous postoperative care. The tracheostomy tube should be well seated and fastened securely to the patient's neck. Avoidance of leverage on the...

Metabolic and endocrine effects

Both acute and chronic sleep deprivation impair glucose tolerance during wakefulness. Sleep deprivation alters glucose uptake in the cell membrane and cytoplasm. It also reduces the initial insulin response to glucose, probably because of increased sympathetic activity which regulates pancreatic beta cell function and insulin release. There may also be effects on the later increase in plasma insulin because of impaired synthesis of insulin in response to a raised blood glucose level. The lack of leptin and increase in ghrelin reduce the sensation of satiety and increase hunger and appetite, with an increase particularly for carbohydrate and fatty foods. Sleep deprivation in effect leads to an internal misperception of body fat and other energy stores, leading to increased energy intake coupled with an impaired ability to utilize the absorbed carbohydrates and fats. The insulin resistance due to sleep deprivation further increases the risk of diabetes and is associated with an...

General Conduct of an Invasive Investigation

Measures should be undertaken to ensure that the body temperature is maintained, particularly during an extended procedure, and the oesophageal or rectal temperature is monitored. Fluid balance should be maintained intravenously, and arterial blood gas and blood sugar measurements made at regular intervals. The ECG and arterial blood pressure will need to be monitored from both an anaesthetic and a cardiological viewpoint. Excessive blood loss is unlikely to be encountered during diagnostic procedures, although it may be necessary to replace losses during interventional procedures involving the use of large-diameter catheters, especially if unexpected and sudden.

Associated Medical Findings

Skeletal abnormalities like kyphoscoliosis and pes cavus, as well as diabetes and cardiac symptoms, are associated with Friedreich's ataxia. Cold intolerance, dry skin, and hair loss indicate hypothyroidism. Pulmonary and gynecological examination might show signs of bronchial or ovarian carcinoma, respectively. Cervical adenopathy might reveal Hodgkin's disease. Subacute, reversible ataxia associated with pyrexia suggests viral cerebellitis. Repeated bronchopulmonary infections suggest ataxia-telangiectasia. Examination of the cardiovascular system might disclose a structural cardiac lesion or rhythm disturbances, which indicate a possible

Alternative Tissue Sources

The optimal source of xenogeneic islets remains controversial. Islets have been isolated from primates and xenografted into immunosuppressed, diabetic rodents, with short-term reversal of diabetes.98 However, there are ethical issues surrounding the use of primates for these studies. Other promising islet sources are porcine, bovine and rabbit islets, all of which function remarkably well in diabetic rodents.99 Long-term human, bovine and porcine islet xe-nograft survival has been documented in nude mice and rats, suggesting that, in the absence of an immune response, sufficient islet-specific growth factors are present in xenogeneic recipients.100 Porcine islets are at present receiving the greatest attention since pigs produce an insulin which is structurally very similar to human insulin and pigs are, on the other hand, the only large animals slaughtered in sufficient quantities to supply the estimated demand from type I diabetics.101'102 In addition, porcine islets within...

Laser Photocoagulation Ocular Research And Therapy In Diabetic Retinopathy

Diabetic retinopathy is a severe complication of diabetes leading to some degree of vision impairment in long-term diabetes sufferers. Currently, the most successful treatment available for diabetic retinopathy is laser photocoagulation, a therapy that destroys part of the retina to save central vision. The principal aim of laser photocoagulation in the treatment of diabetic retinopathy is to effect regression of abnormal vessels, reduce oxygen tension and reverse angiogenesis in the retina. Although laser photocoagulation has been employed for more than 30 years, its underlying molecular mechanisms remain unknown. Research is now focused on identifying and understanding these factors, to ultimately develop therapies to protect against the initiation and progression of neovascularisation. Many studies have been conducted to examine the effects of laser photocoagulation on specific factors in the rat and mouse. These studies clearly demonstrated that laser photocoagulation does not...

Asymmetry is not proof of bias alternative sources of funnel plot asymmetry

Some interventions may have been implemented less thoroughly in larger trials, thus explaining the more positive results in smaller trials. This is particularly likely in trials of complex interventions in chronic diseases, such as rehabilitation after stroke or multifaceted interventions in diabetes mellitus. For example, an asymmetrical funnel plot was found in a meta-analysis of trials examining the effect of inpatient comprehensive geriatric assessment programmes on mortality.1323 An experienced consultant geriatrician was more likely to be actively involved in the smaller trials and this may explain the larger treatment effects observed in these trials.1323

General Management Goals

Acquired ataxias need to be treated according to the primary disorder. However, ataxia is often associated with progressive degenerative disease, and it is rarely possible to influence the underlying cause. Only a few forms of inherited ataxias can be treated effectively, such as episodic ataxias using acetazolamide. In most cases, no pharmacological treatment is known. The pharmacological trials using various drugs--GABA agonists (baclofen, sodium valproate), choline chloride, lecithin, physostigmine, gamma-vinyl gamma-aminobutyric acid, thyrotropin-releasing hormone, and 5-hydroxytryptophan--have been disappointing. Other drugs, like buspirone, amantadine, and a combination of sulfamethoxazole and trimethoprim, are still being investigated in clinical trials. Physical therapy is the most important treatment of disorders of coordination and ataxia. Dyssynergia might be reduced by placing additional weight on an ataxic limb to increase inertia. Genetic testing is available in an...

Islet Viability and Function

The oxygen levels to which the islet cells are exposed are important from two standpoints, viability and function. Because oxygen is consumed at a high rate by islet cells, particularly when stimulated by increased glucose concentration, steep gradients in oxygen concentration can develop. Thus, the oxygen concentration decreases from that of the local blood supply as it diffuses across the tissue, the immunoisolation membrane, and throughout the islet. Consequently, islet cells may be exposed to hypoxic, or even anoxic, conditions.60 This can lead to loss of cell viability and to a reduction in the insulin secretion capacity. Further studies should focus on finding a practically applicable method to reduce the barrier between encapsulated islets and the bloodstream in order to improve both the functional performance and the survival of encapsulated islet grafts. However, an interchange between vascularization and hence nutrient supply and retrievability will always be present.

Integrin Clustering and Cell Shape

One of the most critical events required for propagation and maintenance of signals generated following binding of integrins by ECM is clustering of the integrin receptors, often at sites known as focal adhesions or focal contacts. Without the appropriate clustering, ligand occupation of the receptor is not sufficient to induce a full biological response (Miyamoto et al., 1996). The clustering is believed to facilitate interactions between the integrin cytoplasmic tails and adaptor proteins to allow focal adhesion complexes to assemble. Not surprisingly, immunoprecipitation of these FA complexes showed that the growth factor (GF) receptors are also found within these integrin-containing complexes. For example, both PDGF-BB and insulin receptors were immunoprecipitated in complexes isolated using antibodies against avft3 integrin (Schneller et al., 1997). The colocalization of GF receptors and integrins is believed to facilitate 'crosstalk' between ECM and GF receptors and coordinate...

BCD4 T Cells as Direct Effectors of pCell Lysis

A transgenic mouse model in which allogeneic MHC class II expression is limited to p cells using a rat insulin promoter did not support this hypothesis (18). The mice expressed allogeneic class II MHC on the p cells but did not develop insulitis or IDDM. Potentially autoreactive CD4+ T cells were rendered anergic. However, this model is an incomplete test of the hypothesis, as the p cells did not express the necessary costimulator molecules (19), such as B7 (CD80) or B7-2, and MHC class II-associated invariant chain (Ii) (20) was not included in the transgenic model. Recent evidence in a triple transgenic model shows that expression of the B7 molecule on the P cells was critical in the activation of autoreactive T cells (21). The model used the rat insulin promoter to direct expression of a viral protein, lymphocytic choriomeningitis virus (LCMV) cell surface glycoprotein, and B7 to the p cells, and a transgenic T-cell receptor (TCR) which skews the T-cell repertoire exclusively to...

Current Possibilities

Euthenics, the alteration of the environment to allow aberrant individuals to develop normally and to lead a normal life, is currently being employed. Medical examples include special diets for children with a variety of inborn errors of metabolism who would, in the absence of such diets, either die or grow up mentally retarded. Such action, of course, requires very early diagnosis of these diseases, and programs are currently in effect to routinely examine newborns for such defects. Other examples include the treatment of diabetics with insulin and the provision of special devices for children with skeletal deformities. Social measures are of extreme im

Decline in Skeletal Muscle Mitochondrial Function Associated with Aging

Impaired oxidative phosphorylation by skeletal muscle mitochondria has been postulated to contribute to age-associated insulin resistance and fat accumulation within skeletal muscle 3 . This impaired mitochondrial functional capacity associated with aging has been attributed to a reduced mitochondrial content, as reflected by lower mtDNA content 50 . Many age-related declines in physiological function can be partially attributed to mitochondria dysfunction 51 . There is a significant loss in the number of muscle fibers as well as biochemical and morphological abnormalities in aging skeletal muscle 52,53 . Age-related muscle wasting, muscle weakness, and reduced aerobic capacity result in many metabolic disorders and diminished physical performance in humans 54-56 . The specific mechanisms leading to the age-related changes are currently unknown. Mitochondria are primary sites of reactive oxygen species formation that causes progressive damage to mtDNA and proteins 53,57 . Increased...

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