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Reverse Diabetes Now

Reverse Diabetes Now is created by Matt Traverso a well-known medical researcher and diabetes expert. In fact, the author has spent years researching and studying to create this revolutionary treatment for diabetes. This diabetes healing program provides users with natural remedies for diabetes that are proven totally safe to apply. In fact, the author has research thousands of websites; read dozens of magazines, books, diet plans, and brochures out there to find out how to reverse diabetes for good. This treatment offers the tools that are proven effective by many people in many areas all over the world. Treating a chronic disease like diabetes requires patience, dedication, and attention towards each and every loose end so you can get the real results successfully. Therefore, you must follow the instructions given by Matt Traverso in this program. Author has also promised to pay back each and every penny you pay to try this treatment method in case it does not work for you. Read more here...

Reverse Diabetes Now Overview

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Oxidative Stress and Antioxidants The Antioxidant Network aLipoic Acid and Diabetes

In this introductory chapter, oxidative stress in diabetes and implications of antioxidant treatment are considered. It is thought that free radicals may play a major role in aging and disease. Free radicals arise from radiation, environmental chemicals, cigarette smoke, and various other environmental sources. In addition, all through our life, we have a fire burning inside of us our own body metabolism, which generates free radicals. Finally, many environmental substances (as well as drugs and alcohol) are metabolized in our body, generating free radicals through cytochrome P450-mediated oxidations. Many free radicals can be cytotoxic.

What is diabetes insipidus

Diabetes insipidus (DI) is caused by a deficiency of ADH synthesis, impaired release of ADH from the neurohypophysis (neurogenic DI), or renal resistance to ADH (nephrogenic DI). The result is excretion of large volumes of dilute urine, which, if untreated, leads to dehydration, hypernatremia, and serum hyperosmolality. The usual test for DI is cautious fluid

Correlation of Hypoadiponectinemia With Insulin Resistance

Low plasma adiponectin concentrations are observed in several forms of diabetes with insulin resistance, including type 2 diabetes (66), gestational diabetes (67), and diabetes associated with lipodystrophy (68). Hyperinsulinemic-euglycemic studies show that plasma levels of adiponectin are positively associated with insulin-stimulated glucose disposal (69), but inversely related with basal and insulin-stimulated hepatic glucose production (70), suggesting a potential role of adiponectin as an endogenous insulin sensitizer in humans. Multivariate analysis demonstrates that hypoadiponectine-mia is more closely associated with the degree of insulin resistance and hyperinsuline-mia than with the degree of glucose intolerance and adiposity (71). Case-controlled studies show that subjects with low concentrations of adiponectin are more likely to develop type 2 diabetes than those with high concentrations (72,73). The causative role of hypoadiponectinemia in the development of insulin...

Enhancers Of Insulin Release 21 Glucokinase activators

Glucokinase (GK) or hexokinase IV is one of the four hexokinases that phosphorylate glucose and plays a key role in whole-body glucose homeostasis through its action in (3-cells and hepato-cytes. The rationale for GK activators was derived from the study of GK mutations as manifested in maturity onset of diabetes of the h3C02S young Type II (MODY II) in humans and 1 persistent hyperinsulinemic hypoglycemia of infancy (PHHI) phenotypes associated with gene manipulation studies in mice. Recently, a potent GK activator RO0281675,1, which increased the enzymatic activity of recombinant human GK in a dose-dependent and stereospecific manner, was identified 1 . At a concentration of 3 mM, 1 increased the Vmax of GK by a factor of about 1.5 and decreased the substrate concentration at 0.5 Vmax ( S 05) for glucose from 8.6 to 2.0 mM. In numerous in vivo studies GK activators were shown to cause glucose-dependent insulin release in the pancreas, and also to increase glucose utilization in the...

Vitamin E In Diabetes

About one-half of the total plasma vitamin E is a constituent of circulating LDL. Interindividual variations in plasma vitamin E are closely related to those in LDL (24,25). The concentration of vitamin E per LDL particle is rather low (i.e., in the order of 5-9 molecules compared with 2200 molecules of cholesterol and 170 molecules of triglycerides) (26). Nevertheless, the level of vitamin E in LDL is an independent factor that influences susceptibility of LDL to oxidation. The lagtime of in vitro LDL oxidation was found to be related to the level of vitamin E in LDL when diabetic patients were supplemented with vitamin E (27,28). For persons with usual nutritional habits, the corresponding relationship was observed in two studies (29,30) but not in others (3,31,32). There are several publications on vitamin E concentrations in the plasma of diabetic patients. The assumption that the oxidative stress in diabetes is due to deficient vitamin E in plasma could not be confirmed. In most...

Vitamin A In Diabetes

The level of vitamin A in diabetes has found much attention in recent literature. Vitamin A deficiency may cause blindness. Poorly controlled diabetes mellitus is attributed to a decreased availability of retinol carrier protein and subsequently to depressed vitamin A levels in blood. The impaired vitamin A status may not be improved by vitamin A supplementation but by insulin administration (51). In persons with well-controlled NIDDM without insulin deficiency, the metabolism of vitamin A appears not to be impaired. Interestingly, persons with impaired glucose tolerance show increased (2.5 (imol L) vitamin A versus persons with normal glucose tolerance (2.1 a,mol L) (46). Most studies demonstrated lowered levels in IDDM, the difference being significant in six studies. Significantly lowered levels in NIDDM were found in two studies (Table 3). The weighed mean values are similar for control subjects and NIDDM and lower for IDDM (control subjects 1.95 0.23 imol L, IDDM 1.52 0.46 nmol...

Therapeutic Use of Insulin

3 Application of 6.1.3 Treatment of Insulin-induced Hypoglycaemia 58 6.4 Insulin 6.4.3 Treatment of Insulin Allergy 63 6.5 Anti-insulin Antibody 6.5.1 Insulin Autoantibody Hypoglycaemia Syndrome 65 6.6 Insulin 6.6.1 Forms of Insulin 6.6.2 Management of Insulin Resistance 66 6.6.3 Biochemical Defects Causing Insulin Resistance 67 7 Clinical Studies of Insulin-replacement Therapy 69 7.2 Type-I Diabetes 7.2.8 Intraperitoneal Insulin Application 74 7.2.9 Insulin Analogues in Type-I Diabetics 74 7.2.10 Nasal Absorption of Insulin 74 7.3 Type-II Diabetes Insulin is used for the treatment of Type-I and for Type-II diabetes mellitus, when other therapeutic measures, i.e. appropriate diet and oral antidiabetics, are not sufficient to produce normoglycaemia. The physiological actions of insulin including recent advances in our knowledge on signal transduction have been discussed above (chapter 4). Since treatment of diabetes with insulin attempts only to supplement inadequate insulin secretion,...

Carbonyl Stress In Diabetes

The increase in lipoxidation and glycoxidation products in diabetes is the direct result of an increase in carbonyl precursors however, not all of these intermediates are derived from oxidative reactions. 3DG, for example, is formed nonoxidatively from Amadori compounds (34) or fructose-3-phos-phate (35) and is also increased in diabetes, along with increases in both pyrra-line and 3DG-arginine imidazolone (36) adducts that are derived from 3DG by nonoxidative mechanisms. MGO adducts to protein, including CEL and MOLD, are also increased in diabetes (37,38). Like 3DG, MGO is formed by anaerobic mechanisms, either enzymatically as an intermediate in amino acid catabolism or by (3-elimination reactions of triose phosphates (39,40). However, MGO may also be produced during the oxidative chemistry of both lipids and carbohydrates, so that its precise origin in vivo is unknown. In any case, the increase in 3DG, and possibly MGO, and their adducts to proteins suggests that limitations in...

Adipocyte Dysfunction And Insulin Resistance

Adipose tissue plays a key role in directing whole-body glucose disposal, although it accounts for only about 10 of insulin-stimulated glucose disposal. There is now substantial evidence that factors that regulate adipocyte function can ultimately lead to insulin sensitization in muscle. Along these lines, the discovery of the peroxisome proliferator-activated receptors (PPARs) in the early 1990s has revolutionized Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue recruits macrophages for reasons that are not entirely clear. However, the local inflammatory milieu is thought to (a) increase adipocyte lipolysis as cytokines downregulate insulin signaling and (b) change the secretion of adipokines such as leptin and adiponectin. Photomicrograph courtesy of Barbara Kozak, PhD Figure 4.6 CD68+ macrophages in human white adipose tissue. A hypertrophic adipocyte is surrounded by macrophages. Adipose tissue...

Application of Insulins

The particular insulin employed, such as human or animal, the type of formulation, the route of administration, and the frequency of administration must be chosen to suit the needs of the individual patient. The dose must also be determined for each patient, and, although a precise dose range cannot be given, a total dose in excess of about 80 units daily would be unusual and may indicate the presence of a form of insulin resistance (Martindale, 1989). The short-acting insulins are usually injected between 30 and 45 min before meals. The intermediate-acting insulins should be given once a day before breakfast or twice a day, the long-lasting insulins are given three times on the first day as a loading dose and then as one or two injections per day, the dosage being adapted as required to maintain near normoglycaemic blood glucose levels (Kahn and Schechter, 1990).

Clinical Studies of Insulinreplacement Therapy

Clinical studies concerned with recent advances in the understanding of insulin effects predominantly applied knowledge on the physiology of insulin regulation as a prerequisite for achieving near normoglycaemic status in diabetic patients. There is now compelling evidence that a relationship exists between good metabolic control and development of late diabetic complications (DCC Trial, 1993). Other major points of interest in clinical trials are hyperinsulinaemia and insulin resistance as a common denominator of the metabolic syndrome, hyperinsulinaemia as an independent predictor of coronary heart disease, and the efficacy of new insulin analogues.

Typeii Diabetes Mellitus

In IDDM, insulin is needed, by definition, to preserve life. It is generally agreed that near-normoglycaemia can be achieved only by MDI of short- and intermediate-acting insulin. There is less consensus with regard to non-insulin-dependent (Type-II) diabetic patients about when to use what medication, and particularly at what point insulin therapy is appropriate. The natural history in obese Type-II diabetes patients usually starts with both impaired B-cell function and insulin resistance and or basal hyperinsulinaemia resulting in elevated fasting blood glucose levels. Reaven (1988) suggested that insulin resistance might be a common denominator for obesity, Type-II diabetes hypertension and hyperlipidaemia (metabolic syndrome) and should be treated rigorously to avoid coronary heart disease, the most common cause of morbidity and mortality in Type-II diabetes mellitus. However, it still remains to be proven that effective blood glucose control will reduce the mortality of the...

Oxidative Stress And Antioxidant Treatment Effects On Neurovascular Function In Experimental Diabetes

Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups ( 14-17) nondiabetic control (O) 8-week streptozotocin-diabetic ( ) a-tocopherol (1 g kg day) treated from diabetes induction ( ). (From Ref. 39.) Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups ( 14-17) nondiabetic control (O) 8-week streptozotocin-diabetic ( ) a-tocopherol (1 g kg day) treated from diabetes induction ( ). (From Ref. 39.) In rats, the diabetes-induced decrease in sciatic nutritive blood flow was accompanied by a reduction in mean endoneurial oxygen tension, which was prevented by probucol treatment (49). In nondiabetic rats, prooxidant treatment with the antimalarial drug primaquine mimicked the reductions in blood flow, endoneurial oxygen tension, and NCV...

Initiation of Insulin Secretion

Initiators of insulin secretion switch on the secretory machinery. Thereafter modulators derived from nutrient metabolism, hormones peptides and neurotransmitters determine how fast or slow the machine will run. It is now well accepted that initiation of insulin release in response to glucose and other nutrients is caused by depolarization of the B-cell as a first step followed by subsequent Ca2+ influx.

Modulation of Insulin Secretion via Adenylate Cyclase and Phospholipase C PLC

As discussed in section 3, insulin secretion is initiated through depolarization and subsequent opening of L-type Ca2+ channels. It has also been suggested that here insulin secretion and Ca2+ uptake may be modulated by nutrient metabolism, especially glucose, probably by changing islet nicotinamide nucleotide thiol redox status. Other possibilities for modulation of insulin release come from factors affecting the adenylate cyclase and PLC systems through activation of protein kinases and release of Ca+ from intracellular stores. The modulating agents include hormones from the entero-insular axis, neurotransmitters and neuropeptides from pancreatic nerves and last but not least intraislet hormones (see also section 2). Similar to other tissues, insulin-producing cells possess an adenylate cyclase-cAMP system including stimulatory and inhibitory G-proteins and phosphodiesterases. It is generally agreed that the role of cAMP in insulin secretion is not an initiating one, but, by...

Oxidative Stress In Patients With Diabetes Mellitus

Several studies have shown that increased production of reactive oxygen species and antioxidant depletion occurs in patients with diabetes mellitus (1 -11). Oxidative stress may lead to endothelial cell damage and vascular dysfunction through various mechanisms (12-32). Lately, considerable effort has been devoted to gain insights into the role of oxidative stress in the development and progression of late micro-and macrovascular complications in diabetes (17,23,27,28,31-34). Although hyperglycemia is an acknowledged pathogenic factor in diabetic complications, it is not known through which mechanism an excess of glucose results in tissue damage. Accumulating data support the hypothesis that oxidative stress might play an important role in the pathogenesis of late diabetic complications. Several pathways are leading to oxidative stress associated with acute or chronic hyperglycemia, such as the polyol pathway, prostanoid synthesis, glucose autoxidation, and protein glycation by...

Epidemiology of Diabetes

Diabetes is a growing health problem throughout the world more than 170 million people are estimated to have diabetes worldwide, the majority of whom have type 2 diabetes (DM-2). Largely unknown early in the 20th century, DM-2 is now the fifth leading cause of death in the USA. Conservative estimates suggest that by 2025 the diabetic population will more than double to over 366 million 1 . From a global perspective, Asia is expected to be the region most heavily impacted by diabetes, with an anticipated 2- to 3-fold increase in prevalence. Factors contributing to the rise in diabetes prevalence are the declining mortality from communicable diseases and infant and maternal mortality in less developed countries, aging and urbanization of the population, and, most importantly, the striking increase in obesity. The parallel rise in the prevalence of obesity and DM-2 has been appropriately labeled 'diabe-sity' 2 . The complications of diabetes, which include limb amputations, blindness,...

Modulation Of Insulin Secretion By Hormones Neuropeptides And Neurotransmitters

Although glucose is the most important initiator of insulin secretion, its effect is modified by a variety of factors, e.g. hormones peptides derived from the entero-insular axis and released into the blood during food intake, neurotransmitters released from nerves related to islet tissues (cholinergic, adrenergic, peptidergic), catecholamines reaching the islet via blood, and intrainsular hormones (glucagon, somatostatin). Cholinergic mechanisms are responsible for the early insulin response to a meal in the so-called cephalic phase which is independent of nutrient absorption (Ahr n et al., 1986). The pancreas is also innervated by peptidergic neurons, many of which contain gut peptides that function as neurotransmitters. Cholecystokinin (CCK)-, vasoactive intestinal peptide (VIP)- and gastrin-releasing peptide (GRP)-containing neurones have all been implicated in the peptidergic stimulation of insulin release, and galanin in its suppression (Dockray, 1987). In quantitative terms...

Concept of Initiation and Modulation of Insulin Secretion

A hypothetical scheme for the machinery of insulin release assuming coupling of initiation and modulation to the process of granule movement-exocytosis is given in Fig. 20. Fig. 20. Hypothetical model of how insulin secretion is regulated. The most important event is the depolarization of the B-cell which causes Ca+ influx along L-type Ca2+ channels and subsequent increase in cytosolic Ca+. Depolarization is produced by nutrient (glucose) metabolism via an increase in B-cell ATP and or ATP ADP ratio which closes KAXP channels. Also, sulphonylureas, at a distinct location, close KATP channels. The increase in Ca + j activates CaCaMK. Ca uptake appears to be modulated by nutrient metabolism (redox state of NAD(P)H and GSH). Insulin release in response to depolarization is also modulated by factors affecting PLC and adenylate cyclase. Here, production of IP3 leads to release of stored Ca2+ from the endoplasmic reticiulum. DAG activates PKC whereas cAMP activates PKA. CaMK, PKC and PKA...

Enhancers Of Insulin Release

Sulfonylureas - Sulfonylureas (SU) remain a front line treatment for Type 2 diabetes (11). SUs stimulate insulin release from pancreatic p-cells by a mechanism that involves blocking ATP-sensitive potassium (K+) (KATP) channels. Recently, a-endosulfine, an 18-kD protein, which displaces the binding of sulfonylureas to p-cell membranes, inhibits cloned KATP channels, and stimulates insulin secretion, has been proposed as an endogenous ligand for the SU receptor (12). Common side effects of SU therapy include hypoglycemia, as their action may occur at times when insulin is not required, and weight gain (11). Prolonged treatment with SU's also exacerbates p-cell exhaustion through over-stimulation of insulin production SU therapy is not effective when insulin receptor levels decline too far. Newer agents have attempted to address these liabilities. Repaglinide 3 and nateglinide 4 are recently introduced short acting non-sulfonylureas secretagogues which are taken prior to meals to...

Ischemiareperfusion In Diabetes Mellitus

Microvascular dysfunction has been studied extensively in animal models. One of the most widely used models is streptozotocin-induced diabetes in the rat. In this model, rats are treated with a single toxic dose of streptozotocin, which destroys the islets of Langerhans (27). The effect of hyperglycemia on the microvasculature is then evaluated after 4-12 weeks (21,28-37). Gly-cemic control by insulin treatment can prevent the microvascular dysfunction. In diabetic humans, metabolic status is not stable, and episodes of normogly-cemia are followed by phases of hyper- and hypoglycemia. Thus, blood sugar levels vary considerably, and in consequence to the pathophysiological changes presented above, the status of oxidative stress changes and blood flow will go up and down. Therefore, it is reasonable to assume that under realistic conditions, a diabetic patient undergoes episodes of ischemia and reperfusion during the time until manifestation of microangiopathy. The time intervals of the...

Vascular Effects of Insulin

Insulin is a slow vasodilator of peripheral resistance arteries in skeletal muscle 13 . This action of insulin is slow and requires prolonged exposure to supraphysiological doses. In normal subjects, infusion of a high physiological dose of insulin (1 mU kg min) increases peripheral blood flow slowly on average by 20 (range 10-90 ) within approximately 2 h in normal subjects 13-15 . Factors which contribute to interindividual variation in blood flow responses to insulin include limb muscularity 14 , the number of capillaries surrounding muscle fibers 16 and possibly endothelial function 17 . Regarding the mechanism responsible for insulin-induced vasodilatation of resistance vessels in vivo, stimulation of endothelial NO synthesis by insulin seems to be involved. Both Scherrer et al. 18 and Steinberg et al. 19 demonstrated that the insulin-induced increase in blood flow can be abolished by inhibiting NO-dependent vasodilatation with L-NMMA, but not by other vasoconstrictors such as...

Key Points Diabetes Mellitusy

The goal for insulin management during surgery is to maintain glucose between 120 and 200 mg dl. 3. Intraoperative glucose control in all but the shortest cases is best achieved by using a glucose-insulin intravenous infusion or a pump. 4. Patients with diabetes have a high incidence of coronary artery disease with an atypical or silent presentation. Maintaining perfusion pressure, controlling heart rate, continuous ECG observation, and a high index of suspicion during periods of refractory hypotension are key considerations. 5. The inability to touch the palmar aspects of index fingers when palms touch (the prayer sign) can indicate a difficult oral intubation in patients with diabetes. 1. Burant CF, editor Medical management of type 2 diabetes, ed 5, Alexandria, American Diabetes Association, 2004, pp 52-59. 2. Davidson MB, editor Standards of medical care in diabetes. Diabetes Care 28(Suppl) S4-S36, 2005. 3. Ferrari LR New insulin analogues and Insulin delivery devices for the...

Typei Diabetes Mellitus

IDDM patients are not suitable candidates for sulphonylurea therapy. In insulin deficiency, these drugs (e.g. glyburide) produced no changes in 24 h glucose level, glucosuria, HbAt or basal hepatic glucose production (Simon-son et al., 1987). However, in patients who were C-peptide secretors, glibenclamide was found to induce a fall in daily blood glucose and improve HbA markedly. There was no change in any of the measurements, however, in C-peptide non-secretors and no evidence was seen for any extrapancreatic effects of glibenclamide (Burke et al., 1984). In 1988, Kabachi and Birkenholz, noted that sulphonylureas enhanced the effect of endogenous insulin. In a double-blind clinical trial with tolazamide and insulin for 3 months, fasting plasma glucose and HbA markedly improved compared with placebo administration. In general, however, the enhancement of insulin sensitivity by sulphonylureas in IDDM patients is only minor and clinically without importance (Stocks et al., 1988) a...

Role of leptin resistance in obesity and insulin resistance

In addition to its function as a direct regulator of adiposity, leptin is also an insulin-sensitizing hormone (17,18). Thus, the reduced responsiveness to leptin that accompanies obesity and may play a role in causing obesity also plays a role in causing insulin resistance in the brain. Insulin receptors in the hypothalamus play an important role in glucose homeostasis (18). Primate studies have shown that direct delivery of insulin to the brain reduces feeding (18) rodent studies have shown that intracerebroventricular administration of insulin not only reduces food intake, but also suppresses hepatic glucose output (19,20). There is growing evidence that the link between leptin resistance and insulin resistance is suppressor of cytokine signaling (SOCS)3, a molecule that impairs signaling of both leptin and insulin (21), and one that is suppressed by leptin (22). Mice with reduced neuronal expression of SOCS have enhanced sensitivity to leptin and insulin and are protected against...

Role of tnfa in linking obesity to insulin resistance

TNF-a was first shown by Hotamisligil et al. to be overexpressed in adipose tissue from several strains of obese rodents (24). Weisberg et al. have shown that macrophages are the main source of TNF-a in adipose tissue (14). TNF-a expression is higher in visceral fat (VF) of rodents than in subcutaneous (sc) fat (25). In addition, TNF-a has been shown to impair insulin signaling in cultured cells by three separate molecular mechanisms. TNF-a activates serine threonine kinases that phosphorylate and impair the function of key elements in the insulin signaling pathway (26). First, TNF-a mediates a serine phosphorylation of IRS-1 (27). This alteration impairs insulin signaling by making IRS-1 resistant to subsequent insulin-stimulated tyrosine phosphorylation. Second, TNF-a phosphorylates and activates a protein tyrosine phosphatase that normally terminates insulin action, thus playing a role in the self-limiting nature of insulin signaling (28). Third, TNF-a phosphorylates and...

Role of adiponectin in insulin resistance

Adiponectin is an insulin-sensitizing hormone produced exclusively by adipocytes (35). There is a strong and positive correlation between serum adiponectin and insulin responsiveness. In a group of normal and obese subjects, Weyer et al. studied the relationship between serum adiponectin and the glucose disposal rate, measured during hyperinsulinemic euglycemic glucose clamp studies (36). Serum adiponectin varied over a fivefold range, correlated positively with glucose disposal, and accounted for approx 35 of the variance in insulin responsiveness. Adiponectin increases oxidation of free fatty acids and reduces postprandial elevation of nonesterified fatty acids (NEFAs) in mice (37). Adiponectin circulates at concentrations in the low g mL range, whereas most cytokines produced by adipose tissue are in the pg mL range (35). In rodents, adiponectin expression is considerably higher in VF than in sc fat (38), and adiponectin secretion by VF has an inverse relationship with VF mass...

Role of resistin in insulin resistance

Resistin is a recently discovered polypeptide that is secreted by mouse adipocytes and has been implicated in the development of insulin resistance. Resistin was first described in 2001, when a search for genes that are induced during adipocyte differentiation but downregulated in mature adipocytes during exposure to thiazolidinediones led to the discovery of a protein the investigators named resistin, for resistance to insulin (43). Administration of resistin in normal mice impairs glucose tolerance and insulin action. Furthermore, immunoneutralization of resistin improved blood glucose and insulin action in animal models of obesity-induced insulin resistance. In rodents, administration of thiazolidinedione drugs reverses insulin resistance. These drugs also reduce gene and protein expression of resistin in some studies (44) but not in others (45). These initial data suggested that resistin, at least in part, may explain how adiposity leads to insulin resistance and may also explain...

Other possible mediators of insulin resistance

Visfatin is a recently discovered adipokine that is produced by adipocytes (68), and is expressed in visceral fat at much higher levels than in subcutaneous fat (69). Serum visfatin increases with VF, but not sc fat, in humans and mice. Visfatin has been shown to have insulin-sensitizing properties when administered to insulin-resistant mice. Mice that are heterozygous for a targeted mutation in the visfatin gene display a small impairment in glucose tolerance, whereas homozygous mice die in utero. Visfatin binds to the insulin receptor and activates downstream signaling, but does not compete for binding with insulin. Visfatin has the ability to stimulate glucose transport in cultured muscle and adipose cells and to inhibit glucose output in cultured hepatocytes. Apart from cytokines, the most important candidate for linking obesity to insulin resistance is circulating nonesterified (or free) fatty acids. Reaven et al. reported that type 2 diabetes is associated with elevations in...

Insulin Sensitizing Drugs

In the past decade, several studies reported th+at insulin sensitization may be effective in improving several abnormalities of PCOS. In particular, metformin has been proposed as the first-line therapy for both reproductive and metabolic abnormalities in these women. Insulin sensitizers also lower serum testosterone, and a few controlled studies assessed the efficacy of these drugs on hirsutism. These studies, carried out with either metformin or troglitazone, showed limited effect of this approach on established hirsutism (26,27), suggesting that the treatment of hirsutism should not be a primary indication for using insulin sensitizers. However, it can be hypothesized that these drugs might be helpful in hirsute women with PCOS for the maintenance of the clinical improvement obtained with antiandrogen treatment.

Foot Care Tips for People with Diabetes

People with diabetes are prone to developing severe infections that are slow to heal. The feet are especially susceptible to infection, even from something as common as an ingrown toenail. Nerve damage produced by diabetes can cause numbness in the feet that reduces the person's ability to feel pain from an injury or infection. An infection can become so serious that it results in the need for amputation. Controlling your blood glucose level with diet, exercise, and your daily insulin intake can go a long way toward preventing foot problems. The following tips also can help you take better care of your feet A high level of blood glucose also can damage the small blood vessels and nerves in and around the penis. Therefore diabetes can interfere with both the nerve impulses and the blood flow necessary to produce and maintain an erection. About 60 percent of men with diabetes experience erectile dysfunction (see page 146). Diabetes can cause infection of the gums and the bones that hold...

Diabetes Prevention in the NOD Mouse

There are literally over 100 therapies known to prevent diabetes in the NOD mouse (1). Some agents used in the mouse model have included immunosuppressive drugs such as azathioprine, corticosteroids, cyclophosphamide, cyclosporin, and methotrexate. These agents generally have nonspecific immune activities that do not target specific autoreactive T lymphocytes. Furthermore, they do not appear to be effective over the long term, with disease recurrence once the drug is withdrawn. Finally, antigen-specific therapy is under study in type 1 diabetes and other autoimmune diseases for which the autoantigens have been identified. Potential autoantigens include insulin B-chain and insulin B 9-23 peptide, GAD, and heat shock protein (p277 peptide of HSP60). Autoantigen peptide vaccination is perhaps the most specific type of immunotherapy in both humans and the mouse, but has properties of a double-edged sword although such therapy may prevent diabetes, there is also potential to accelerate or...

Oxidative Stress and Pancreatic pCell Destruction in Insulin Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease (1,2). Recent reports suggest that reactive oxygen species (ROS) participate in the development of IDDM (3,4). Thioredoxin (TRX) is a small (12 kDa) reduction oxidation (redox) protein (5,6) and has protective effects on cells against oxidative stress by scavenging ROS (5-7), by repairing DNA and proteins damaged by ROS (5-8), and by blocking apoptosis induced by ROS (6,9). Nonobese diabetic (NOD) mice are well known as an excellent animal model for human IDDM (10-12). To elucidate the roles of oxidative stress in autoimmune diabetes, we generated NOD transgenic mice overex-pressing TRX exclusively in pancreatic 3-cells. Spontaneous diabetes was prevented or delayed in the NOD transgenic mice. The results indicate that ROS in pancreatic P-cells may play an essential role in the development of IDDM.

Peptide Induction Model of Type 1 Diabetes Experimental Autoimmune Diabetes

Diabetes or insulitis can be induced in animals. For example, high doses of streptozotocin can rapidly induce diabetes in several strains of mice (16), and low doses can create a more chronic form of diabetes (17). Administration of polyinosinic polycytidylic acid (poly-IC), which has been used as a viral RNA mimic to stimulate the innate immune system, can induce insulitis and diabetes in RT1u rat strains (18) similar to that seen with the Kilham rat virus (19). We found that immunization with insulin peptide B 9-23 induces IAA expression in normal mice with MHC H-2d and H-2g7 but not H-2b (15) and, if combined with poly-IC, induces insulitis. With the introduction of the B7.1 islet transgene to this model, B 9-23 peptide can induce diabetes (4). In this section, this disease induction model in mice with insulin peptide B 9-23 is described.

Insulin Sensitizing Agents

Insulin resistance with compensatory hyperinsulinemia is a prominent feature of PCOS diagnosed in both lean and obese patients (see Chapter 24). The exact mechanisms for abnormalities of insulin action in the syndrome have yet to be elucidated (65). However, hyperinsulinemia has been show to increase ovarian androgen biosynthesis (66) and decrease hepatic synthesis of SHBG (67), leading to increased bioavailability of free androgens. The increase in local ovarian androgen production mediated by hyperinsulinemia can also result in premature follicular atresia and anovulation (68). The strong association between PCOS and insulin resistance and the role of hyperinsulinemia in hyperandrogenism and disrupted folliculogenesis provide the rationale for the use of insulin sensitizers in the treatment of the syndrome. It seems logical that the therapeutic interventions directed at increasing insulin sensitivity, thereby decreasing hyperinsulinemia, would ameliorate the hyperandrogenism and...

Preventive Effects Of Trx Overexpression Against Autoimmune Diabetes In Vivo

To directly assess the roles of oxidative stress in (3-cell destruction in autoimmune diabetes, we generated NOD transgenic mice overexpressing TRX exclusively in p-cells. The incidence of diabetes in NOD transgenic mice was b. Insulin contents of pancreas remarkably reduced compared with their negative littermates. Although the incidence of diabetes was reduced, the severity of insulitis before overt diabetes was not significantly different between NOD transgenic mice and their negative littermates. To study the protective effects of TRX against ROS-generating agents, we produced (NOD X C57BL 6J (B6)) F1 transgenic mice and injected the ROS-generating agent STZ into them (Fig. 3). The elevation of blood glucose levels in (NOD X B6) F1 transgenic mice was reduced and the reduction of insulin contents was suppressed compared with their negative littermates. These results suggest that ROS play pivotal roles in (3-cell destruction, in autoimmune diabetes and in STZ-induced diabetes.

National Institute Of Diabetes And Digestive And Kidney Diseases T1draid Program

Purpose T1D-RAID is a cooperative program of the NIDDK and NCI that is designed to facilitate translation to the clinic of novel, scientifically meritorious, therapeutic interventions for the treatment of Type-1 diabetes. The goal of T1D-RAID is to support the pre-clinical tasks needed for the clinical proof of principle to determine if a new molecule merits Application Logistics NIDDK receives requests twice per year (April 1 and November 1). Requests consist of a written description of the Request, a technology transfer form, and, if required, a letter of commitment. Once a project has been approved, NIDDK staff interact directly with the investigator. NCI contractors perform the T1D-RAID tasks under the direction of NIDDK and NCI staff. There is also a related program for agents that require additional pre-clinical testing prior to entering T1D-RAID, called Type 1 Diabetes Pre-Clinical Testing Program (T1D-PTP). Information can be found at the NIDDK Research Resources website above.

Insulin Resistance A Key Factor In Type 2 Diabetes

Insulin is the predominant hormone responsible for the maintenance of glucose homeostasis through its regulation of metabolic activit s in muscle, liver, and adipose tissue. Insulin causes an increase in glucose uptake into peripheral tissues, specifically muscle and fat cells conversely, in the liver, the hormone decreases gluconeogenesis, thereby reducing hepatic glucose output. Insulin is also responsible for the promotion of protein synthesis. These effects result from both rapid and long-term metabolic actions of the hormone (1). One hundred million people worldwide suffer from type 2 diabetes (2), yet despite intense research, the primary lesion(s) responsible for type 2 diabetes remains unknown. The genetic susceptibility of this disease fails to follow simple Mendelian inheritance but is of a polygenic nature with superimposed environmental influences (3). An aggregation of small genetic effects rather than the effect of one single gene, gene-to-gene, and gene-to-environment...

Factors That May Trigger Insulin Resistance

It has been suggested that circulating and metabolic factors could play an important role in the etiology of insulin resistance. This is supported by the observation that insulin resistance of in vitro muscle preparations can be reversed by incubation in solutions of normal insulin and glucose levels (40). Circulating factors, such as tumor necrosis factor-a (TNF-a) and free fatty acids (FFA), and intracellular metabolites, such as glucosamine, can induce an insulin-resistant state in vitro and may contribute to the development of insulin resistance in vivo. The level of expression of adipose tissue TNF-a, a multifunctional cytokine, rises as a consequence of obesity. It is also closely correlated with circulating insulin levels, which serve as an index of insulin resistance, (41) and is expressed in increased levels in skeletal muscle of individuals with insulin resistance (42). Mice homozygous for a targeted null mutation in the TNF-a gene were significantly less insulin resistant...

Origin of Oxidative Stress in Type 2 Diabetes

Suspected causative agents of the increased level of oxidative stress associated with type 2 diabetes are hyperglycemia, hyperinsulinemia, and an alteration of serum antioxidant activity (Fig. 3). Figure 3 How oxidative stress may arise in diabetes. The characteristic high levels of glucose and insulin observed in type 2 diabetes may contribute to oxidative stress through the production of free radicals, protein oxidation, and by depletion of intracellular reductants and antioxidants. This increased level of oxidative stress may be attributed to the increased levels of glucose oxidation, glycation, increased activity of the polyol pathway, sympathetic nervous system overdrive, and elevated nonesteriiied free fatty acid (NEFA) concentrations resulting from high levels of glucose and insulin.

Backgroundsummary 21 Insulin Resistance and PCOS

The role of insulin resistance in the pathogenesis of PCOS has been extensively reviewed in Chapter 24. Briefly, insulin resistance is an intrinsic and virtually universal feature of PCOS. Insulin resistance exists in PCOS independent of obesity, as evidenced by the presence of insulin resistance even in lean women with PCOS (1). In addition, about 50-80 of women with PCOS are obese. Hence, in PCOS obesity further induces an added burden of insulin resistance and hyperinsulinemia in addition to the component of insulin resistance that is intrinsic to the disorder (2).

Effect of Hyperinsulinemia on Hyperandrogenism in PCOS

Several lines of evidence suggest that the compensatory hyperinsulinemia associated with insulin resistance is critical to the pathogenesis of hyperandrogenism in PCOS. In in vitro cultures of isolated human ovarian thecal cells, ovarian testosterone biosynthesis stimulated by insulin was fourfold greater in cells from women with PCOS than those of normal women, and in a dose-response study insulin stimulated thecal androgen production at physiological concentrations (3). This stimulation of testosterone production was almost fully prevented by antibody blockade of the insulin receptors. This suggests that insulin stimulates ovarian thecal testosterone biosynthesis via activation of its homologous receptor. Insulin also decreases circulating levels of sex hormone-binding globulin (SHBG), the primary circulating binding protein for testosterone (4). Because of testosterone's high-affinity binding to SHBG, lower SHBG levels translate to increased levels of free and bioavailable...

Can Oxidative Stress Cause Insulin Resistance

The question of precedence between hyperinsulinemia and oxidative stress into the subsequent development of diabetes remains unanswered (64). The studies mentioned above suggest that at least the secondary hyperinsulinemia could plausibly precede or cause increased free radical production and the resulting oxidative stress. Further studies are necessary to address whether oxidative stress, as a result of hyperinsulinemia-mediated increased free radical production, could precede insulin resistance and lead to the onset of diabetes. To date there is no evidence that primary insulin resistance is linked to oxidative effects. The following sections analyze two emerging lines of study in this direction. 1. Oxidative Stress, Antioxidants, and Insulin Resistance In Vivo There is little evidence for a role of antioxidant therapy in the prevention of insulin resistance and type 2 diabetes. Serum of individuals with type 2 diabe tes have a lower vitamin E level and a higher GSH GSSG ratio...

Effect of Hyperinsulinemia on Anovulation in PCOS

Numerous studies have demonstrated that hyperinsulinemia contributes to the chronic anovulation of PCOS. In the largest long-term study, 305 women with PCOS were randomized to the insulin sensitizer troglitazone (150, 300, or 600 mg daily) or placebo for 44 weeks (10). Women receiving troglitazone at doses of 300 and 600 mg daily had a significantly higher ovulation rate (0.42 and 0.58) than those receiving placebo (0.32 p < 0.05 and 0.0001, respectively). This increase in ovulation rate was dose dependent, suggesting that the improvement in ovulatory function was at least in part accounted for by the improvement in insulin sensitivity.

Type 2 Diabetes Mellitus

Several prospective studies in numerous countries have demonstrated an elevated risk of diabetes mellitus as weight increases (75-77). The development of type 2 diabetes is associated with weight gain after age 18 yr in both men and women such that the relative risk of diabetes increases by approx 25 for each additional unit of BMI over 22 (109). Moreover, cross-sectional and longitudinal studies show that abdominal obesity is a major risk factor for type 2 diabetes (74,82,91). There is strong evidence that weight loss reduces blood glucose levels and hemoglobin A1c levels in patients with type 2 diabetes. Moreover, in three European cohorts (> 17,000 men) followed for more than 20 yr, nondiabetic men with higher blood glucose had a significantly higher risk of cardiovascular and CHD death (110). In addition, it has been demonstrated in the Framingham Offspring Cohort that metabolic factors associated with obesity (overall and central), including hypertension, low levels of HDL...

D aLipoic Acid Stimulation of Glucose Uptake via Components of the Insulin Signaling Pathway

A-Lipoic acid has been shown in vitro to stimulate glucose utilization in isolated rat diaphragms (115), to enhance insulin-stimulated glucose metabolism in insulin-resistant skeletal muscle of obese Zucker rats (116), and to stimulate glucose transport activity in skeletal muscle isolated from both lean and obese Zucker rats (117). In streptozotocin-diabetic rats, chronic a-lipoic acid treatment reduced blood glucose concentrations by enhancement of muscle GLUT4 content and increased muscle glucose utilization (118). In addition, acute and repeated parenteral administration of a-lipoic acid improved insulin-stimulated glucose disposal in individuals with type 2 diabetes (110,119), strengthening its therapeutic value as an antidiabetic agent. Estrada et al. (120) established the ability of a-lipoic acid to stimulate glucose uptake into the insulin-responsive L6 skeletal muscle cells and 3T3-L1 adipocytes in culture. The naturally occurring (R)+ isoform of lipoic acid was shown to have...

Effect of Insulin Sensitizers on Hirsutism

Current data on the effect of insulin sensitizers on hirsutism are conflicting. In an open-label study of 39 women with PCOS, metformin 500 mg three times daily significantly decreased Ferriman-Gallwey hirsutism scores at the end of the 12-week study period (32). However, in a more rigorous randomized, placebo-controlled, 44-week trial, metformin at the same dose did not significantly reduce clinical hirsutism scores (17). In another randomized controlled 12-month study, metformin 500 mg three times daily was compared to Dianette (ethinyl estradiol 35 ig and cyproterone acetate 2 mg) in 52 women (33). Both groups demonstrated significant reductions in the Ferriman-Galwey scores, with a significantly greater reduction in the metformin arm (p < 0.01). In addition, in patient self-assessment, women taking metformin scored their hirsutism as having improved significantly more than the contraceptive group (p 0.01). In the long-term, placebo-controlled study using troglitazone, a...

Comparative Efficacy of Different Insulin Sensitizing Agents

Few studies have directly compared the utility of the various insulin-sensitizing drugs in women with PCOS. Ortega-Gonzalez et al. studied 52 obese (BMI > 28 kg m2), insulin-resistant women with PCOS who had not been previously treated and randomized them to either pioglitazone 30 mg day or metformin 850 mg three times daily for 6 months (35). Both metformin and pioglitazone significantly improved AUC-insulin and fasting glucose-to-insulin ratio despite a significant increase in weight (from BMI of 32.2 1.0 kg m2 at baseline to 34.0 1.2 kg m2 at 6 months) in the pioglitazone group. At 6 months, fasting AUC-insulin was significantly lower in the women treated with pioglitazone compared with those treated with metformin. However, women in the metformin group also had a higher AUC-insulin at baseline, and hence whether there was a true difference in the reduction of AUC-insulin between pioglitazone and metformin is unknown. Ovulation rates were not evaluated in this study. Baillargeon...

Insulin Sensitizers and Pregnancy Outcomes

Although ovulatory dysfunction is an important etiological feature of the infertility of PCOS, ovulation is only one aspect of fertility. In addition to ovulatory problems, women with PCOS suffer a high rate of early pregnancy loss (EPL) during the first trimester (30-50 in PCOS vs 10-15 in normal women) (38-42). It is possible that insulin resistance may contribute to EPL by adversely affecting the endometrial environment and or endometrial function. The effect of metformin on endometrial function has been studied using surrogate markers, such as circulating levels of glycodelin and insulin-like growth factor binding protein-1(IGFBP-1) (43). Glycodelin is secreted by endometrial glands (44,45) to lessen the endometrial immune response against the developing embryo (46,47). Decreased endometrial secretion of glycodelin has been associated with EPL (48,49). IGFBP-1 modulates adhesion processes at the feto maternal interface (50,51) and hence may be important in the peri-implantation...

Aldose Reductase Inhibitors as New Antidiabetic Drugs

8.4 Effect on Diabetic Increased aldose reductase activity is observed in tissues which are affected by complications of diabetes mellitus. The possible participation of the polyol pathway in the pathogenesis of these complications led to detailed evaluation of the role of this system both to improve the understanding of diabetes mellitus and to open up new therapeutic possibilities in the prevention of complications. The underlying therapeutic idea is to prevent lesions caused by high glucose concentrations. This seems to be possible for those tissues with insulin-independent glucose uptake and high activity of the polyol pathways (for a detailed review on aldose reductase see Sarges, 1989).

Chronic Therapy in PCOS with Insulin Sensitizers

Both metformin and the thiazolidinediones have been shown to reduce blood pressure and inflammatory markers. Obese women on metformin also tend to lose weight while on metformin in a dose-dependent manner (63). Although the insulin sensitizers' effects on cardiovascular risk factors are favorable, currently there are no prospective randomized outcome trials examining the use of insulin sensitizers in the prevention of diabetes or cardiovascular events in women with PCOS. 2.3.2.1. Insulin Sensitizers in Preventing Type 2 Diabetes Mellitus Although not specifically conducted in women with PCOS, there are several outcome studies indicating that interventions to improve insulin sensitivity may decrease the incidence of diabetes in individuals at high risk. The Diabetes Prevention Project was a prospective study sponsored by the National Institutes of Health (64). The study included 3234 patients at high risk of diabetes (history of gestational diabetes or presence of impaired glucose...

Iiinsulin Resistance In Diabetes

Insulin resistance is defined as a reduced ability of insu, n to activate specific insulin-dependent biological processes in cells of target organs. In poorly controlled type 1 diabetes, insulin resistance is thought to be a secondary effect of the dyslipidemic state (elevated free fatty acids) and the prolonged hyperglycemic state. In type 2 diabetes, insulin resistance of skeletal muscle glucose disposal is generally considered to be a primary factor in the etiology of this disease. In this latter state, the skeletal muscle insulin resistance is often accompanied by a variety of other metabolic abnormalities, including obesity, dyslipidemia, hypertension, and atherosclerosis (17-19), a condition referred to variously as syndrome X (18,19) or the insulin resistance syndrome (17). The link among these disorders has been attributed to hyperinsulinemia, a consequence of the insulin resistance (17). Indeed, the increased cardiovascular mortality associated with this condition has been...

Diabetes and Oxidant Stress

Abstract Diabetes is associated with chronic micro- and macrovascular complications. Oxidative stress has been defined as 'a shift in the pro-oxidant - antioxidant balance in the pro-oxidant direction'. Oxidant stress may initiate and exacerbate vascular (endothelial) damage through excess production of reactive oxygen species, depletion of nitric oxide, and damage to lipids, proteins, and DNA. Experimental results and theoretical constructs suggest oxidative stress is increased in diabetes, at least in some tissues, though not all studies are supportive. Potential markers of oxidation and glycoxidation are discussed. Pharmacological suppression of intracellular oxidative stress has prevented adverse biochemical and functional changes in cultured cells and animal models, and in some cases surrogate end-points of vascular damage in humans. Definitive clinical studies are awaited. Keywords diabetes complications atherosclerosis oxidative stress glycoxidation DCCT Diabetes Control and...

Definition and Prevalence of Diabetes

Diabetes mellitus, a condition characterized by hyperglycemia, is a chronic disorder of carbohydrate, lipid, and protein metabolism due to the absolute or relative lack of insulin. In 1997, there were an estimated 124 million people with diabetes worldwide, and 221 million affected people are predicted by 2010.1 While oxidative stress has also been implicated in the pathogenesis of diabetes,2 this chapter will focus on the relationship between oxidative stress and atherosclerosis in diabetes, with an emphasis on the clinical perspective. The basic mechanisms of oxidative stress are reviewed elsewhere.3-5 The presentation, diagnosis, and classification of diabetes have been reviewed elsewhere.6 Approximately 90 of cases have Type 2 diabetes, and the prevalence of both Type 1 and Type 2 diabetes is increasing,1 including a disturbing increase in Type 2 diabetes in children, usually associated with adiposity and a relatively poor prognosis with respect to the subsequent development of...

Chronic Complications of Diabetes and Risk Factors

The chronic complications of diabetes are predominantly vascular, and are usually categorized as macrovascular or microvascular.915 Diabetes is associated with at least a two-fold increased risk of macrovascular disease (coronary artery, cerebrovascular, and peripheral vascular disease), and is the cause of death in 70-80 of people with diabetes.9-13 The microvascular complications of diabetes are nephropathy, retinopathy, and (peripheral and autonomic) neuropathy.1415 Diabetes accounts for over a third of all patients with end stage renal disease (ESRD), and diabetic retinopathy is the most common cause of adult-onset blindness in the Western world.91415 Subjects with microvascular complications are particularly prone to accelerated atherosclerosis and premature death.1617 Both men and women with diabetes are at heightened risk of atherosclerosis, with loss of female cardioprotection in diabetes, even prior to the menopause.11 Atheroma develops earlier, progresses at a faster rate...

Oxidative Stress And Insulin Sensitivityclinical Observations

Paolisso et al. (25) demonstrated close correlations between the presence of (K and insulin sensitivity in an elderly nondiabetic population. Epidemiological studies found a close correlation between low levels of antioxidants, such as vitamin E or vitamin C, and a high risk of developing frank type 2 diabetes (26,27). Several groups report a higher prevalence of radical oxygen species in prediabetic individuals who had an impaired oral glucose tolerance test (17-19). An increase in plasma thiobarbituric acid reactive substance (TBARS) was found in healthy subjects when free fatty acids (FFA) were experimentally kept elevated by an infusion of intralipid and heparin (28) under these experimental conditions, insulin sensitivity was markedly reduced (28). It could thus be speculated that the elevation of FFA seen in patients with type 2 diabetes or with insulin resistance (29) could be a source for such an augmented oxidative stress.

Role Of Impaired Insulin Action In The Pathogenesis Of Type 2 Diabetes Mellitus

In type 2 diabetes mellitus, plasma glucose levels are elevated as a result of an impairment of several metabolic pathways (29-31) (Table 1). Skeletal muscle is the principal organ for postprandial glucose uptake (29,30). In the pathogenesis of diabetes mellitus type 2, reduced insulin-stimulated glucose disposal (insulin resistance) plays a key role (21,29). When clearance of plasma glucose is impaired, blood glucose after a meal will remain slightly elevated Table 1 Metabolic Alterations in Type 2 Diabetes Diminished insulin-mediated peripheral glucose disposal and metabolism (insulin resistance) Impaired insulin secretion (reduced first-phase response, prolonged second phase) Decreased insulin-mediated inhibition of lipolysis Increased gluconeogenesis and will thus induce hyperinsulinemia to overcome resistance (Fig. 1). Hyper-insulinemia, however, will evoke an alteration of the insulin-signaling cascade, which will further augment insulin resistance, thus leading to a vicious...

Exenatide Antidiabetic [3741

Exenatide is the first drug in a new class of anti-diabetics known as the incretin mimetics, and it is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, or both, but have not achieved adequate glycemic control. Exenatide is a functional analog of the human incretin Glucagon-Like Peptide-1 (GLP-1). GLP-1 is naturally released from cells in the GI tract in response to food intake and acts on its receptor on p-cells to potentiate glucose-stimulated insulin secretion. Exenatide is a long-acting agonist at the GLP-1 receptor. It is a synthetic version of a 39-amino acid peptide found in the salivary secretions of the Gila monster lizard. It has 53 amino acid homology with GLP-1, but unlike GLP-1, exenatide is less susceptible to degradation by neutral endopeptidase, has a longer half-life, binds with greater affinity to GLP-1 receptor, and is a more potent insulinotrope. In addition to stimulating...

Is Oxidative Stress per se Increased in Diabetes and Vascular Damage

There are many theoretical reasons why oxidative stress should be increased in diabetes, including hyperglycemia hyperglycemia-related glucose autoxidation, increased glucose flux through the polyol pathway, and activation of reduced forms of NADPH oxidase, therefore Brownlee's unifying hypothesis33,34 is appealing. There are several excellent review articles.3,39,40,45,47,49,75-77 However there are other areas of research, such as with vitamin E, in which the theory, biochemistry, cell culture and animal model data, and even human surrogate end-point data has been positive, yet human trials with hard clinical end-points of the successful interventions have not proven beneficial.78 While biochemical studies, cell culture, and animal models contribute valuable knowledge regarding mechanisms of damage, and facilitate development and preclinical testing of interventions, they may not adequately reflect the whole human condition - that most relevant to clinical practice. Yet as evidenced...

Pramlintide Antidiabetic [6568

Pramlintide is an injectable human amylin analog that has been launched for the treatment of both type 1 and type 2 diabetes, in conjunction with insulin. While it is also a 37-amino acid peptide, it differs from its parent predecessor by the substitution of Ala-25, Ser-28, and Ser-29 with prolines. Not only do these modifications improve the solubility of the peptide, they also eliminate the aggregation observed with amylin, resulting in a stable synthetic analog with retention of biological activity that is suitable for pharmaceutical use. As an indication of potency, pramlintide inhibits the binding of radioiodinated rat amylin to rat nucleus accumbens membranes with a Ki value of 23 pM. Its mechanism of action mimics amylin as a neurohormone that is co-secreted with insulin from the pancreatic p cells in response to meals, it is involved in glucose homeostasis. Both peptides lower postprandial glucose levels by inhibiting glucagon and by restraining the vagus-mediated rate of...

Homocysteine NO and Insulin Sensitivity

Homocysteine levels were found to be significantly higher in patients with coronary artery disease and in those with diabetes mellitus (50-54). Elevated homocysteine levels induce oxidative stress and reduce NO availability (55) this can contribute to endothelial dysfunction. It seems possible that hyperho-mocysteinemia could also alter insulin sensitivity by this mechanism. Therefore, it remains to be clarified whether there are any interactions between elevated homocysteine levels and the development of insulin resistance in nondiabetic subjects. The interesting observation of an augmented oxidative stress, insulin resistance, and elevated homocysteine levels in smokers (14,23,24,50) suggests some interactions. However, this still remains to be evaluated.

Mitiglinide Antidiabetic [6367

Mitiglinide is a non-sulfonylurea hypoglycemic agent that has been developed and launched in Japan for the treatment of type-2 diabetes. Similar to the sulfonylurea insulinotropic drugs, mitiglinide adopts a U-shaped configuration in which the base of the U contains an amide linkage, and each branch of the U incorporates a hydrophobic side chain. This similarity in conformation suggests that mitiglinide also binds to the sulfonylurea receptor to cause the direct closing of ATP-sensitive potassium channels in pancreatic p-cells the result is stimulation of insulin secretion. In contrast to typical sulfonylurea agents that frequently cause hypoglycemia due to slowly reversed insulinotropic activity, mitiglinide's short duration of action should be advantageous in preventing this adverse effect. It also enjoys a rapid onset of insulin release. Mitiglinide can be prepared by several closely related methods, which involve either classical resolution of racemic intermediates, or...

Malaria And Insulin Dependent Diabetes Mellitus An Ecological Study

There is scientific merit in studying the association between insulin dependent diabetes mellitus and malaria, since they are both associated with the human leukocyte antigen system. The human leukocyte antigen system is involved in controlling immunological responses, and the association between this system and insulin dependent diabetes mellitus has long been established.12 Malaria is the most important natural selective factor on human populations that has been discovered to date.13 In areas of high endemicity, malaria operates the genetic selection responsible for the influence on the susceptibility to autoimmune diseases.14 In Sardinia, malaria is known to have selected for some serious hereditary diseases such as 3-thalassaemia, Cool-ey's disease and favism the latter is caused by a deficiency of glucose-6-phospate dehydrogenase enzyme.10 Sardinia is therefore particularly suitable for investigating the association between insulin dependent diabetes mellitus and malaria. The...

Enhancers Of Insulin Action

Non-thiazolidinediones (non-TZDs) - There are now a variety of potent non-TZD PPARy ligands which exhibit antidiabetic activity in vivo, including GW-1929 26 (61,62), GI-262570 27 (63), GW-409544 (64), JTT-501 28 (65),and YM-440 (66). GW-1929 is approximately 100-fold more potent in rats than troglitazone in glucose lowering based on serum drug levels (67). The (S)-enantiomer of SB-219994 29 is considerably more potent and efficacious than its antipode (68). The phenylacetic acid derivative 30 (69) reduces hyperglycemia by 65 at 30 mg kg day in Zucker rats. The arylsulfonylamide 31 was obtained from high-throughput screening (70) and the quinoxaline L-764406 32 has been reported to be a PPARy partial agonist (71). fta Adrenergic Receptor (SaARs) Agonists - Agonists of P3ARS increase the release of energy stores as heat in brown adipose tissue, increase lipolysis in white adipose tissue, suppress food consumption, suppress leptin gene expression and serum leptin levels. Uncoupling...

Measurement Of Insulin Resistance And Clinical Assessment

Glucose Clamp Techniques

Clinically, a number of techniques have been developed to detect the presence of insulin resistance and assessments vary in complexity and precision (Figure 2.2)2-6. However, from a clinical perspective, the most practical way of assessing insulin resistance is the measurement of plasma insulin levels. (Insulin is produced in pancreatic p-cells and is released into the bloodstream in response to stimulation that occurs after a meal ingestion (Figures 2.3 and 2.4)7. As type 2 diabetes is characterized by an antecedent phase of insulin resistance that requires a compensatory increase in insulin secretion to maintain euglycemia, an elevated insulin level in the fasting state is indicative of insulin resistance.) It is suggested that this be performed in the overnight fasting condition, since in the postprandial state glucose levels are changing rapidly, and variable levels of glucose confound the simultaneous measurement of insulin. The homeostasis model assessment (HOMA)4,5 of insulin...

Choice of Insulin Sensitizing Agent in PCOS

Currently, the commercially available insulin-sensitizing agents include metformin and the thiazolidinediones (rosiglitazone and pioglitazone). Most of the clinical studies in women with PCOS have been conducted with metformin. In addition, for several decades metformin has been used worldwide to treat diabetes, and thus its side effect profile has been well described. Adverse effects of metformin include gastrointestinal distress, such as diarrhea and nausea. More serious toxicity includes a documented, but rare, risk of lactic acidosis. Nearly all reports of lactic acidosis occurred in patients with renal insufficiency (plasma creatinine > 1.4 in women), hepatic dysfunction, heart failure, or other pulmonary and circulatory dysfunctions that can by themselves lead to hypoxia and lactic aci-dosis (70,71). Careful attention to these contraindications will prevent most occurrences of lactic acidosis. As discussed in a previous section, metformin is classified by FDA as Pregnancy...

Leptin in type 1 autoimmune diabetes

Leptin is involved in other autoimmune conditions (17). Leptin accelerates autoimmune diabetes in female NOD LtJ mice (18). Fluctuations in serum leptin levels have also been observed in a study performed by our group in an animal model of CD4+ T-cell-mediated autoimmune disease, such as T1D. Nonobese diabetic (NOD LtJ) female mice, spontaneously prone to the development of -cell autoimmunity, have higher serum leptin levels, as compared with NOD LtJ males and nonsusceptible strains of mice, and show a serum leptin surge preceding the appearance of hyperglycemia (19). Furthermore, leptin administration early in life significantly anticipated the onset of diabetes and increased mortality and inflammatory infiltrates in beta-islets this phenomenon correlated with increased secretion of IFN-y in leptin-treated NOD mice (20). More recently, it has been found that a natural leptin receptor mutant of the NOD LtJ strain of mice (named NOD LtJ-db5J) displays reduced susceptibility to T1D...

Impaired Glucose Tolerance Impaired Fasting Glucose Insulin Resistance And Diabetes

Impaired glucose tolerance, impaired fasting glucose, insulin resistance, and diabetes mellitus represent a spectrum of disorders that is associated with an elevated risk of cardiovascular complications. Impaired glucose tolerance, impaired fasting glucose, and insulin resistance are also risk factors for the development of overt diabetes. Importantly, the NCEP ATP III considers diabetes to be a coronary heart disease risk equivalent, conferring the same risk for coronary events as would be observed in a patient with known coronary artery disease33. While diabetes has been a well-established cardiovascular risk factor, impaired glucose tolerance, impaired fasting glucose, and insulin resistance are emerging risk factors that are also associated with the metabolic syndrome as well as the development of overt diabetes. In general, impaired glucose tolerance is determined with an oral glucose tolerance test, impaired fasting glucose is detected by serum glucose after a fast, and insulin...

Recent Advances in Therapeutic Approaches to Type 2 Diabetes

Introduction - Diabetes mellitus is the only non-infectious disease designated as an epidemic by the World Health Organization (1). The prevalence of all types of diabetes is estimated to be 2.3 of the world's population, with the number of diabetics increasing by 4-5 per annum. It is projected that as many as 40-45 of persons aged 65 or older have either Type 2 diabetes or its precursor state, impaired glucose tolerance (IGT). In the US -10 of the diabetic population suffer from Type 1 diabetes, an autoimmune disease characterized by the loss of pancreatic P-ceil function and an absolute deficiency of insulin. The remainder of the diabetic population suffers from Type 2 diabetes or IGT, which, although related to the body's inability to properly respond to insulin, have a more complex etiology (2). Diabetes can be treated by a combination of lifestyle change, dietary change and medication. However, the metabolic disorder underlying diabetes also affects protein and lipid metabolism,...

Adiponectin as Insulin Sensitizing Hormone

The role of adiponectin as an important regulator of insulin sensitivity was first reported by Fruebis and colleagues in 2001 (16). The authors found that injection of a COOH-terminal globular adiponectin into mice acutely decreased postprandial blood glucose levels and enhance lipid clearance via increasing fatty acid -oxidation in skeletal muscles. This observation was subsequently confirmed and extended by several pharmacological studies using different forms of recombinant adiponectin. Yamauchi's group demonstrated that chronic infusion of full-length or globular adiponectin produced from E. coli significantly ameliorated insulin resistance and improved lipid profiles in both lipoatrophic diabetic mice and diet-induced obese mice (17). On the other hand, Berg's group showed that intraperitoneal injection of full-length adiponectin expressed in mammalian cells triggered a significant and transient decrease in basal blood glucose levels by inhibiting the rates of endogenous glucose...

The Link Between Oxidative Stress and Vascular Damage in Diabetes

We currently lack good measures of oxidative stress and oxidative damage in human Type 1 and Type 2 diabetes specific studies to make a definitive decision as to whether oxidative stress is increased in diabetes per se, or in relationship to its vascular complications. Once an appropriate measure, or more likely panel of Fig. 7.1 Schema of risk factors and mechanisms for accelerated atherosclerosis in diabetes Fig. 7.1 Schema of risk factors and mechanisms for accelerated atherosclerosis in diabetes measures, are validated and standardized, a reference range in healthy non-diabetic subjects over a wide age range must be determined. Oxidative stress and damage damage-related levels can then be compared in well well-characterized Type 1 and Type 2 diabetic subjects with and without micro- and macrovascular complications, over a range of glycemic control, and with known lifestyle (e.g., smoking) and medications (which may have antioxidant activity). Based on current knowledge, oxidative...

Molecular Basis of Insulin Action and Insulin Resistance in Peripheral Tissues

To understand the molecular basis of insulin resistance (whether primary or secondary) in muscle and fat cells, it is imperative to gain knowledge of the normal mechanisms of insulin action. In these tissues, insulin stimulates glucose uptake by rapidly mobilizing preexisting glucose transporters (primarily the GLUT4 isoform) from an intracellular storage organelle (or vesicle) to the plasma membrane (5,6). This is achieved by a series of signals elicited from the receptor, which are detected in an unknown fashion by the intracellular organelle. The latter is then free to find and interact with docking sites on the plasma membrane (7) that will ultimately enable fusion of the two membranes to provide functional glucose transporters. Detailed knowledge has emerged on the signals emanating from the receptor that are essential for GLUT4 translocation and the nature of the proteins engaged in vesicle docking and fusion with the plasma membrane. The signaling events involved in the...

Glucose Insulin and Potential Mechanisms of Vascular Stiffening

Among patients with diabetes 15 or the metabolic syndrome, arterial stiffening is observed across all age groups. In children with severe obesity, arterial wall stiffness and endothelial dysfunction are accompanied by low plasma apolipoprotein A-I levels, insulin resistance, and android fat distribution, changes that may be the main risk factors for the early events leading to atheroma formation 16 . The positive correlation between insulin resistance and central arterial stiffness and the close relationship between the extent of metabolic changes and the degree of arterial stiffness suggest that insulin resistance is a primary underlying factor. In animal models of insulin-resistant diabetes, chronic hyperglycemia and hyperinsulinemia increase local angio-tensin II production and expression of vascular Ang II type I receptors via stimulation of TGF- 1, upregulate plasminogen activator inhibitor-1, and downregulate matrix metalloprotease activity, all of which play a critical role in...

Role of il6 in insulin resistance

IL-6 is a pleiotropic circulating cytokine that has important roles in inflammation, host defense, and response to tissue injury (53). It is one of several proinflammatory cytokines with a proposed role in the development of insulin resistance. IL-6 is secreted by many cell types, including immune cells, fibroblasts, endothelial cells, skeletal muscle, and nonadipocyte cells in adipose tissue, and circulates as a variably glycosylated 22- to 27-kDa protein (2). IL-6 is released from contracting skeletal muscle, causing the serum concentration to increase as much as 100-fold (54). IL-6 increases hepatic glucose production when administered to human subjects, and there is evidence to suggest that the release of IL-6 from exercising muscle mediates the early phase on exercise-induced hepatic glucose output. The fact that IL-6 opposes insulin action in the liver has led to speculation that its oversecretion may play a role in insulin resistance. In the liver, IL-6 causes release of NEFAs...

Insulin

Reactions to insulin include local or systemic reactions and insulin resistance. Although human recombinant DNA insulin appears to be less antigenic than bovine-type insulin, it can cause allergic reactions. Local reactions are the most common and are generally encountered during the first 1-4 wk of therapy. They are usually IgE-mediated and consist of mild erythema, swelling, burning, and pruritus at the injection site. These local reactions usually disappear in 3-4 wk with continued administration of insulin. Dividing the insulin dose into two or more sites or switching to a different preparation is generally helpful. If not, antihistamines may be given until the reaction disappears. Local reactions may precede anaphylactic reactions. Therefore, epinephrine should be available to these patients. Systemic reactions include urticaria, angioedema, bronchospasm, and hypotension. Most of these reactions occur upon re-starting of insulin after an interruption in therapy. In treatment of...

Insulins

Insulin - Therapy of insulin dependent diabetes mellitus (IDDM or Type I diabetes) attempts to replace insulin in a manner that mimics the physiologic pattern of release seen in the non-diabetic (7,8). In addition, insulin is used in the treatment of non-insulin dependent diabetes mellitus (NIDDM or Type II diabetes) when oral therapy alone fails (9). While management of the acute symptoms of IDDM is generally achievable, the long-term complications of diabetes, including retinopathy, nephropathy, and neuropathy are not currently well-treated. However, there are clinical data suggesting that strict metabolic control in IDDM can improve long-term prognosis (10-12). Confirmation in longer term, large prospective studies of the effect of primary intervention with intensive insulin therapy has been shown to be feasible (13,14). Risk of symptomatic and severe hypoglycemic episodes associated with intensive insulin therapy is greater, however, than that seen with conventional treatment. New...

Diabetes

Type 2 diabetes affects around 8 of adults in the United States and is substantially related to obesity (48). In a 10-yr follow-up study, men and women with a BMI > 35.0 had a relative increased risk of developing diabetes of 23- and 17-fold respectively, compared with a control group with a BMI between 18.5 and 24.9 (49). Independent of BMI, the relative risk of developing diabetes mellitus increases with weight gain, as shown in the Nurses' Health Study (50). Moreover, in that study, women who voluntarily lost more than 5.0 kg reduced their risk of diabetes by 50 . In a review of 440 obese patients (mean weight of 183 kg) who underwent BPD with duodenal switch, all of the 36 patients with type 2 diabetes discontinued their medication over a 7-yr follow-up period. It should be kept in mind, however, that the operative mortality for this particular weight loss surgery is between 0.5 and 2 (14). Weber et al. reported on 103 consecutive patients with laparoscopic gastric bypass who...

Diabetes mellitus

Diabetes mellitus is a glucose metabolism disorder caused by a relative or absolute lack of insulin. Insulin deficiency results in hyperglycemia. Two principal forms of diabetes mellitus are recognized type I diabetes and type II diabetes. Type I diabetes is an autoimmune disease that destroys the insulin-producing cells in the pancreas, whereas type II diabetes is caused by a complex biochemical disturbance of insulin receptors. Patients suffering from type I diabetes depend on exogenous insulin intake. This disease is fatal if untreated. After several years of diabetes, numerous complications such as accelerated arteriosclerosis or diabetic retinopathy are common. A characteristic feature of this disease is the presence of auto-antibodies directed toward p cells in the islets of Langerhans.1

Insulin Resistance

Insulin release (P-cell Dysfunction) Figure 2 Schematic diagram of the glucose transporter translocation hypothesis. Insulin-responsive tissues, specifically adipose tissue and skeletal muscle, contain intracellular stores of glucose transporter proteins (GLUT). The binding of insulin and the subsequent increase in tyrosine kinase activity of the insulin receptor initiates a signaling cascade, which results in the tyrosine phosphorylation of insulin receptor substrates (IRS 1 -n), their binding to the enzyme phosphatidylinositol 3-kinase (PI 3-kinase), and the resultant activation of PI 3-kinase to produce phosphorylated phosphoinositides. This signaling cascade leads to the mobilization and insertion of stored glucose transporters into the plasma membrane, allowing for increased glucose influx into the cell in response to insulin. insulin signals, defects in detecting transducing the signal, a reduction in the total amount of glucose transporters, and or inability of the transporters...

Type 1 Diabetes

The most widely used animal model of type 1 diabetes is the streptozotocin-induced diabetic rat. Streptozotocin is a compound that causes hypersecretion of insulin from the pancreatic P-cells, resulting in their eventual dysfunction and leading to a hypoinsulinemic state (23). The streptozotocin-diabetic rat is characterized by marked postprandial hyperglycemia and by an elevation in free fatty acids without ketoacidosis (23). Skeletal muscle from the streptozotocin-diabetic rat is markedly insulin resistant for stimulation of glucose transport (24,25) and expresses a significantly reduced protein expression of the GLUT4 glucose transporter isoform (24,25).

Type 2 Diabetes

Although numerous rodent models of type 2 diabetes exist, the focus here is on the obese Zucker (fa fa) rat. The obese Zucker rat is an animal model of severe skeletal muscle insulin resistance also characterized by marked hyper-insulinemia (26), glucose intolerance (27,28), dyslipidemia (26), moderate hypertension (29), and central adiposity (30). It is therefore an excellent model with which to study the underlying pathophysiology and potential interventions in the insulin-resistance syndrome. Studies have identified at least one cellular locus for the insulin resistance of glucose transport in this animal model. Insulin-stimulated GLUT4 protein translocation (8,31) and glucose transport activity (8,32,33) are substantially impaired in isolated skeletal muscle from these obese animals. Anai et al. (34) have very recently shown that in skeletal muscle from obese Zucker rats, there are significant defects in crucial aspects of the insulin signaling cascade. Compared with age-matched...

Implications of leptin signal transduction

Leptin increases insulin sensitivity in peripheral tissues via a CNS mechanism (80-82). Our studies and others have demonstrated a profound trophic action of leptin in the brains of adult Lep b ob mice (83,84). Leptin deficiency is associated with deficits in brain weight and neuronal and glial proteins, some of which are restored by leptin treatment (83,84). Analogous to the mouse studies, treatment of leptin-deficient humans with recombinant methionyl human leptin not only decreases body weight, but also increases the volume of the anterior cingulate gyrus, inferior parietal lobule, and the cerebellum, within 6 mo (85). These brain volume increases were maintained over 18 mo, demonstrating that leptin can have sustained effects on the human brain (85). Bouret et al. (86) reported that projections from the Arc to PVN were disrupted in Lep b ob mice. Leptin treatment reversed this defect in neonatal Lepob ob but not adults, indicating that leptin plays a neurotrophic role during a...

Leptin action in peripheral tissues

Nonetheless, numerous studies have demonstrated leptin signaling in blood cells, pancreatic P-cells, pituitary, kidney, hepatocytes, muscle, and adipocytes (18,91-100). Apart from immune cells, most of these tissues lack functional LEPRb or at best express very low levels, suggesting that short-form leptin receptors may mediate leptin signaling (91-100). Ex vivo studies of isolated T-lymphocytes from mice and humans indicate that leptin promotes cellular survival and enhances immunity, especially during starvation (91). Leptin inhibits insulin secretion from isolated pancreatic islets, although the opposite effect has been reported (92,93). Furthermore, leptin induces LH and follicle-stimulating hormone (FSH) release from pituitary explants and sympathetic nerve activity to the kidneys (94,97). mice, supporting a role for LEPRb in adipocyte leptin action (95). The latter is consistent with the presence of LEPR on human and rodent adipocytes (96). Leptin has no direct effect on glucose...

Oligomerization of Adiponectin and Its Regulation

A growing body of evidence suggests that different oligomers of adiponectin possess distinct biological activities. Earlier studies from Tsao's group showed that the trimeric adiponectin, but not the hexameric and HMW forms, could activate AMP-activated protein kinase (AMPK) in skeletal muscle (10). On the other hand, the HMW oligomeric complex of adiponectin has been the major bioactive form responsible for inhibition of hepatic glucose production (13), and for protection of endothelial cells from apoptosis (14). It has recently been proposed that the oligomeric complex distribution, but not the absolute amount of total adiponectin, determines insulin sensitivity (15). In both human and rodents, the ratio of HMW to total adiponectin in females is much higher than in males (9,11). This gender difference is primarily attributed to the selective inhibition of testosterone on secretion of the HMW species from adipocytes (9). In addition, acute treatments with insulin and glucose...

Pleiotropic biological functions of adiponectin

Over the past several years, the functions of adiponectin have been extensively studied in numerous animal models and in vitro systems. It is now appreciated that adiponectin is a multifunctional protein that regulates insulin sensitivity, energy homeo-stasis, vascular reactivity, inflammation, cell proliferation, and tissue remodeling. Thus

Bernard Testa Urs A Meyer

ANTIDIABETIC AGENTS RECENT ADVANCES IN THEIR MOLECULAR AND CLINICAL PHARMACOLOGY This book tries to give an overview on present knowledge about pharmacological and clinical aspects of antidiabetic drugs. In this connection it was found to be important to include chapters on the regulation of glucose homoeostasis and pathophysiology of Type-I and Type-II diabetes mellitus. Since diabetes mellitus is a disease of inadequate insulin secretion and inadequate action of insulin, especially in Type-II diabetes mellitus, special emphasis has been put on the molecular basis of insulin secretion and insulin actions. Several experts have contributed different topics. The clinical part was written by H. Laube, and insulin action by H. U. Haring, M. Kellerer and L. Mosthaf. The secretory machinery and mechanisms of sulphonylurea actions were contributed by H. P. T. Ammon. The author of pharmacodynamics of other antidiabetic drugs, side effects and drug interactions is E. J. Verspohl and finally M....

Antiatherogenic Actions

In addition to its insulin-sensitizing effect, adiponectin possesses direct antiatherogenic properties (30,31). Both adenovirus-mediated overexpression of full-length adiponectin (32) and transgenic overexpression of globular adiponectin (20) have been shown to inhibit atherosclerotic lesion formation in the aortic sinus of apoE-deficient mice. On the other hand, disruption of the adiponectin gene results in impaired vaso-reactivity (33) and increased neointimal thickening in response to external vascular cuff injury (23,34).

Adiponectin Receptor 1 and Adiponectin Receptor

In humans, both adipoR1 and adipoR2 are highly expressed in skeletal muscle, with the expression ratio of adipoR1 to adipoR2 approx 6 1 (57,58). A significant correlation between the expression levels of these two receptors and insulin sensitivity was reported in nondiabetic Mexican Americans with or without a family history of type 2 diabetes (57). In addition, the expression of adiponectin receptors were found to be decreased in obese subjects and type 2 diabetic patients (59,60). Notably, two more recent studies have found that the effect of globular adiponectin to stimulate fatty acid oxidation and glucose uptake in skeletal muscles was blunted in obese subjects (58,61). However, whether adiponectin resistance observed in obese subjects is caused by the defects of adipoRl and adipoR2 remains to be clarified.

Adiponectin Deficiency and Cardiovascular Diseases

Adiponectin is inversely correlated with a panel of traditional cardiovascular risk factors, including blood pressure, heart rate, and total and low-density lipoprotein (LDL) cholesterol and triglyceride levels, and is positively related to high-density lipoprotein (HDL) cholesterol levels (80,81). Hypoadiponectinemia has been shown to be an independent risk factor for endothelial dysfunction and hypertension, regardless of insulin resistance (82,83). In addition, the association of hypoadiponectinemia with coronary heart disease (84), ischemic cerebrovascular disease (85), and coronary artery calcification (86) was also reported to be independent of classical cardiovascular risk factors, such as diabetes, dyslipidemia, and hypertension. A recent report by Kumada et al. showed that the prevalence of coronary artery disease in male subjects with hypoadiponectinemia (< 4 pg mL) was 2.05-fold higher than those with adiponectin concentrations of more than 7.0 pg mL, after adjustment for...

Classification and evolution of increased cardiometabolic risk states

It has been accurately observed that certain risk factors in humans appear to 'cluster' with clinical states such as obesity and type 2 diabetes. Specifically, this risk factor clustering, and the association with insulin resistance, led investigators to propose the existence of a unique pathophysiological condition1. Many names have been provided to describe this clinical state including 'metabolic syndrome', 'syndrome X', and 'insulin resistance syndrome'1. The particular names that refer to this risk factor clustering describe the human condition characterized by the presence of co-existing traditional risk factors for cardiovascular disease (CVD), such as hypertension, dyslipidemia, glucose intolerance, obesity, and insulin resistance, in addition to non-traditional CVD risk factors, such as inflammatory processes and abnormalities of the blood coagulation system2-6. Table 1.1 lists conditions and components associated with the clustering of risk factors. As seen, the components...

Plasma Adiponectin Levels and Chronic Liver Diseases

Many recent studies have demonstrated a close association of hypoadiponectinemia with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) (89-92). Plasma levels of adiponectin are inversely correlated with hepatic fat contents, the grade of hepatic necroinflammation, and measures of liver injury, such as serum alanine aminotransferase and y-glutamyltranspeptodase (43,93-95). Importantly, this association remains significant even after adjustment for sex, age, BMI, and insulin resistance. In a multiple logistic regression analysis model, low adiponectin level was found to be the only independent predictor of NAFLD in men (96).

Adiponectin as a potential therapeutic target

As discussed above, promising results obtained from numerous animal experiments and human epidemiological studies support the role of adiponectin as a potential drug target for developing novel therapeutics against a panel of obesity-related chronic diseases. However, adiponectin is an abundant plasma protein (5-30 p.g mL). The production of recombinant adiponectin is also challenging because of the complex tertiary and quaternary structure of the protein and the distinct activities of the different isoforms. Direct supplementation of recombinant adiponectin in human subjects would be extremely expensive. An alternative approach is to use pharmacological or dietary intervention to increase the suppressed endogenous adiponectin production in obesity, or to enhance adiponectin actions in its target tissues. In this respect, it is interesting to note that the PPARy agonists thiazolidinediones (TZDs), such as rosiglitazone and pioglita-zone, which increase adiponectin production in both...

Tumor Necrosis Factora

TNF-a was originally identified as a macrophage product implicated in the metabolic disturbances of chronic inflammation and malignancy. Later on, its biological actions were shown to further extend to anorexia, weight loss, and insulin resistance (7). Elevated adipose tissue expression of TNF-a mRNA has been reported in different rodent models of obesity as well as in clinical studies involving obese patients (23). TNF-a mRNA expression is positively correlated with body adiposity as well as with hyperinsulinemia, showing positive associations with fasting insulin and triglyceride concentrations. TNF-a inhibits the expression of the transcription factor CCAAT enhancer binding protein-a (CEBPa) and the nuclear receptor peroxisome proliferator-activated receptor (PPAR)y2 (8,12,14). Furthermore, TNF-a stimulates the nuclear factor- kB transcription factor (NFkB), which orchestrates a series of inflammatory events, including expression of adhesion molecules on the surface of both...

Plasminogen Activator Inhibitor1

Although PAI-1 is primarily derived from platelets and the endothelium, it has been demonstrated that most of the elevated concentrations of this regulatory protein of the coagulation cascade in inflammatory and obese states is attributable to an upregulated expression by adipose tissue itself (12,58). Therefore, WAT represents a quantitatively relevant source of PAI-1 production, with consequently increased circulating concentrations present in obesity. Stromal cells have been shown to be the main PAI-1 producing cells in human fat, with a fivefold higher expression in the visceral than in the subcutaneous depots, which is in agreement with the strong relationship observed between circulating PAI-1 concentrations and visceral fat accumulation (59). However, whether adipose tissue itself directly contributes to circulating PAI-1, or whether it exerts an indirect effect via adipokines, such as TNF-a , IL-1 , and TGF- , to stimulate PAI-1 production by other cells has not been clearly...

Induction Of Aox Enzymes

Relevance to Diabetes Both steady-state levels of 80HdG in blood monocytes (46) and urinary excretion of 80HdG (47) have been reported as elevated in diabetic patients. Gas chromatography mass spectrometry has recently shown elevated levels of a wide range of base oxidation products in DNA from white blood cells of diabetic patients. The pattern of base damage was diagnostic of increased OH formation in vivo (48). Lipid peroxidation is important in vivo for several reasons, in particular because it contributes to the development of atherosclerosis (49-51), a process known to be accelerated in diabetic patients (6). Lipid peroxides and other end products of the peroxidation process may be toxic to vascular endothelium in diabetics (6,52). Many assays are available to measure lipid peroxidation, but the simpler ones, such as the TBA test and diene conjugation, are notoriously unreliable when applied to human tissues and body fluids (reviewed in Ref. 53), although the TBA test can be...

Molecular links underlying the adiposityinflammationimmunity cluster

The body of knowledge of the pathophysiological effects of adipokines on vaso-activity and inflammation has been gathered from different types of studies, including epidemiological observations, animal model experiments, in vitro approaches, and microarray application. The consistent interrelationship between several adipokines with known effects on inflammation, atherosclerosis, and insulin resistance provides support for the crucial role of adipose tissue in the regulation of obesity-linked CV derangements. Although the existence of inflammatory events is well-known to exert a The molecular mechanisms linking the adiposity-inflammation-immunity cluster are complex and their understanding is in continous evolution. The triad of obesity-insulin resistance-CVD is interwoven in a setting of inflammation, endothelial dysfunction, and atherosclerosis. Obesity is characterized by a low-grade systemic inflammation and a hypercoagulable state contributing to atherosclerosis. Endothelial...

Mechanisms of leptin action in immune cells

The possible activation of STAT-3 by human leptin in mononuclear cells has also been studied at different time-points in peripheral blood mononuclear cells (57) by antiphosphotyrosine immunoblotting of anti-STAT-3 immunoprecipitates. The effect of leptin promoting STAT-3 tyrosine phosphorylation is maximal at 10 min, and the effect is dose-dependent, reaching maximal effect at 10 nM leptin. Leptin stimulation of mononuclear cells not only activates and phosphorylates STAT-3 but also promotes the tyrosine phosphorylation of the RNA binding protein Sam68, which has been previously found to be recruited upon TCR, and insulin receptor activation (59,60) associates with STAT-3 in the same signaling complex (57). Tyrosine phosphorylation of Sam68 by the Src family kinase p59fyn has been shown previously to regulate negatively its association with RNA (61). In mononuclear cells we have found that leptin not only promotes the tyrosine phosphorylation of Sam68 (57), but also inhibits the RNA...

Leptin and pathophysiology of the immune system

Recent data also suggest the possible role of leptin in the pathophysiology of some autoimmune diseases. This has already been demonstrated in some animal models, such as the experimental autoimmune encephalomyelitis, antigen-induced arthritis, models of type 1 diabetes, autoimmune colitis, and experimental hepatitis, as well as some clinical studies (15,17,72-74). However, this is the subject of other chapters in this book, and we are not reviewing the possible role of leptin in the pathophysiology of immune diseases.

Plasma Vitamin E Status In Healthy And Diabetic Subjects

Data are conflicting on the a-tocopherol status in diabetic subjects. Some studies report no changes, others a decrease, and still others an increase (23-25). One problem with the previous studies was a failure to standardize a-tocopherol for lipid concentration, which would produce misleading results in hyper-lipidemic patients. We have found that absolute plasma a-tocopherol levels in diabetic subjects were slightly, but significantly, lower than those of the control subjects (Table 1). Plasma a-tocopherol levels between the two groups differed markedly when a-tocopherol levels were expressed per unit of cholesterol. No difference was found in absolute plasma or cholesterol-standardized a-tocopherol in the diabetic patients with and without complications (Table 2). These findings have recently been confirmed by Borcea et al. (22). Further studies are needed to address the question whether the low plasma oc-tocoph-erol in the diabetic patients is related to increased oxidative stress...

Relationship Between Rooh And Glycemic Control

INFLUENCE OF INSULIN THERAPY ON PLASMA ROOHs Little information is available on the effect of glycemic control on plasma markers of oxidative stress. Berg et al. (26) compared the effect of continuous intensified insulin treatment (CUT) and conventional insulin treatment (CIT) on plasma lipid peroxides as measured by the FOX assay. Plasma ROOHs in patients receiving CIIT fell by 31 as compared with baseline over a period of 24 months. HbAlc fell by 15 during the same period (Fig. 4). By contrast, no difference was seen in patients receiving CIT over the same period. Faure et al. (27) also examined the effect of CIIT on plasma lipid peroxides using the TBA assay. They too reported a marked reduction in TBARs after CIIT as compared with the baseline level (2.42 0.25 vs. 3.03 0.27 (imol L n 16) over a period of 7 years (27). These observations provide further support for the hypothesis of a beneficial effect of insulin therapy on lipid peroxidation brought about by decreasing...

Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

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