Instant Cure for Diabetes

Reverse Diabetes Now

Reverse Your Diabetes Today by Matt Traverso can be described as comprehensive eBook that reveals what can you do to reverse diabetes, what can you eat to reverse diabetes and what can reverse type 2 diabetes and part 1 diabetes conditions by natural means with 3 short weeks or fewer. Reverse Your Diabetes today is presented especially for those who are experiencing difficulty with their blood sugar levels. This entire e-book contains 114 informative pages, covering a lot of useful knowledge and treating plan for diabetes that people should learn and follow. The whole guidebook is divided into 12 small sections. Firstly, people will get the overview of diabetes and how you can realize if you are suffering from this terrible disease. 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...

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Antidiabetic Agents Insulins

See also Antidiabetic Agents Hyypo-glycemic Agents. See also the following individual entries Insulin injection Insulin injection concentrated Insulin lispro injection Insulin zinc suspension (Lente) Insulin zinc suspension, Extended (Ultralente) General Statement Insulin preparations with different times of onset, peak activity, and duration of action have been developed. Such products are prepared by precipitating insulin in the presence of zinc chloride to form zinc insulin crystals and or by combining insulin with a protein such as protamine. Based on these modifications, insulin products are classified as fast-acting, intermediate-acting, and long-acting. These preparations permit the provider to select the preparation best suited to the life-style of the client. RAPID-ACTING INSULIN Insulin injection (Regular Insulin, Crystalline Zinc Insulin, Unmodified Insulin) INTERMEDIATE-ACTING INSULIN 1. Isophane insulin suspension (NPH) 2. Insulin zinc suspension (Lente) LONG-ACTING...

Insulin Like Growth Factor

The insulin-like growth factor (IGF) family can also neu-ralize the Xenopus animal cap (Pera et al., 2001). The necessity for IGF signaling has also been shown using a truncated IGF receptor. In these embryos, neural induction mediated by noggin is inhibited. The authors propose that the IGF pathway may act downstream of BMP inhibition during neural induction, and that as well as a passive role for BMP inhibition, neural induction may not be a default as previously thought. Instead, it may also require an active signal, induced as a result of BMP inhibition.

Molecular models insulin

The opposite page presents models of insulin, a small protein. The biosynthesis and function of this important hormone are discussed elsewhere in this book (pp.160,388). Monomeric insulin consists of 51 amino acids, and with a molecular mass of 5.5 kDa it is only half the size of the smallest enzymes. Nevertheless, it has the typical properties of a globular protein. Large quantities of pure insulin are required for the treatment of diabetes mellitus (see p. 160). The annual requirement for insulin is over 500 kg in a country the size of Germany. Formerly, the hormone had to be obtained from the pancreas of slaughtered animals in a complicated and expensive procedure. Human insulin, which is produced by overexpression in genetically engineered bacteria, is now mainly used (see p. 262). A. Structure of insulin O There are various different structural levels in proteins, and these can be briefly discussed again here using the example of insulin. The primary structure of a protein is its...

Role of the reninangiotensin system in cardiovascular disease in diabetes

As reviewed elsewhere in this book, multiple factors, including hyperglycemia, insulin resistance, dyslipidemia, hypercoagulability, and inflammation contribute to the pathogenesis of atherosclerosis in DM. Although there is considerable evidence for a role of the RAS in vascular remodeling, inflammation, thrombosis, and atherogeneis (81-83), the role of this system in atherosclerosis in the context of the other diabetes-associated cardiovascular risk factors is not fully understood. There is a growing body of evidence from both clinical studies and experiments in diabetic rodent models suggesting that the RAS contributes to CVD in both type 1 and type 2 diabetes.

Outcomes in Diabetic Patients

Meta-analyses of ACE inhibitor trials provide compelling evidence that ACE inhibitors reduce cardiovascular events and mortality related to acute myocardial infarction (MI) and heart failure (90,91). Because diabetes is an independent risk factor for CVD (92) and the RAS and diabetes appear to interact at multiple levels, it is possible that diabetes may affect the efficacy of ACE inhibition on CVD. Several recent reports have provided retrospective analyses of data from diabetic subgroups, which participated in large ACE inhibitor trials. Although some of these trials were not designed to specifically address the effects of ACE inhibition in diabetes, comparison of the relative effects of ACE inhibition in the diabetic and nondiabetic subgroups may provide important insight into the role of the RAS in CVD in diabetes. An underlying question regarding the vascular protective effects of antihypertensive therapies is whether these effects are mediated via the reduction in BP or whether...

Description Medical Diabetes

Diabetes mellitus (DM) is a chronic disorder of carbohydrate, protein, and fat metabolism in which there is a discrepancy between the amount of insulin required by the body and the amount of insulin available. DM affects over 10 million persons in the United States, and more than 35,000 people die from it each year. DM is classified into several categories (Table 1). The beta cells of the pancreas produce insulin and a protein called C-peptide, which are stored in the secretory granules of the beta cells and are released into the bloodstream as blood glucose levels increase. Insulin transports glucose and amino acids across the membranes of many body cells, particularly muscle and fat cells. It also increases the liver storage of glycogen, the chief carbohydrate storage material, and aids in the metabolism of triglycerides, nucleic acids, and proteins. Long-term complications such as disease of the large and small blood vessels lead to cardiovascular disease (coronary artery disease,...

Effect of Angiotensin Converting Enzyme Inhibition Following Acute Myocardial Infarction on Cardiovascular Outcomes in

The GISSI-3 study examined the short-term effects of ACE inhibition when administered within 24 hours following an acute MI in a population of more than 18,000 patients, including 2790 patients who reported a history of diabetes (10). Retrospective analysis of results from this study revealed that ACE inhibitor treatment provided greater protective effects against 6-week mortality in diabetic patients compared with nondiabetics. The overall risk reduction by ACE inhibitor treatment for the diabetic group was 32 , compared with a risk reduction of 5 for nondiabetic patients. Within the diabetic group, ACE inhibitor treatment reduced mortality rates for both insulin-dependent (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) patients by 49 and 27 , respectively. Although this report indicates that the benefit of ACE inhibitor treatment in the diabetic group was greater than that for the nondiabetic group, the basis for this difference is unclear. Although the baseline...

And Insulin Sensitivity

There is growing evidence that inhibition of the RAS system by either ACE inhibition or ATI receptor antagonism can increase insulin sensitivity and glucose utilization. Studies using euglycemic hyperinsulinemic clamps have shown that ACE inhibitor treatment improves insulin sensitivity in most (136-140), but not all (141,142) individuals with hypertension, obesity, and or type 2 diabetes. Similarly, although ATI antagonism has been reported to improve muscle sympathetic nerve activity and insulin sensitivity in obese hypertensive subjects (143) and increase basal and insulin-stimulated glucose oxidation in normotensive individuals with type 1 diabetes (144), other clinical studies have not observed improvement on insulin sensitivity and glucose homeostasis following treatment with ATI receptor antagonists (139,145,146). In experimental rodent models, ACE inhibition has been shown to enhance glucose transport skeletal muscle and adipose tissue in insulin-resistant obese Zucker rats...

Renin Angiotensin System Inhibition and New Onset Diabetes

Several large clinical studies have reported that ACE inhibitor treatment is associated with a reduction in the incidence of new-onset diabetes. The MICRO-HOPE study reported that the relative risk for new diagnosis of diabetes in the ramipril ACE inhibitor-treated group was 0.66 (p < 0.001) compared with the placebo-treated controls (96). The Captopril Prevention Project trial reported that the relative risk of developing diabetes in the ACE inhibitor treated group was 0.86 (p 0.039) compared with the conventionally (diuretics, -blockers) treatment group. Recently, the LIFE trial reported that AT1 receptor antagonism using Losartan was associated with a 25 lower incidence of new-onset diabetes compared with patients treated with atenolol, which were similarly matched for initial clinical characteristics and BP control (154). Consistent with the clinical finding on the effects of RAS inhibition on the onset of diabetes, experimental studies have also indicated that ACE inhibition...

Peroxisome Proliferator Activated Receptory Key Regulator of Adipogenesis and Insulin Sensitivity

PPAR-y was first identified as a part of a transcriptional complex essential for the differentiation of adipocytes, a cell type in which PPAR-y is highly expressed and critically involved (6). Homozygous PPAR-y-deficient animals die at about day 10 in utero as a result of various abnormalities including cardiac malformations and absent white fat (7-9). PPAR-y is also involved in lipid metabolism, with target genes such as human menopausal gonadotropin coenzyme A synthetase and apolipoprotein (apo)-A-I (10,11). Chemical screening and subsequent studies led to the serendipitous discovery that thiazolidinediones (TZDs) were insulin sensitizers that lower glucose by binding to PPAR-y. Used clinically as antidiabetic agents, the TZD class includes pioglitazone (Actos) and rosiglitazone (formerly BRL49653, now Avandia) (12,13). Troglitazone (ReZulin) was withdrawn from the market because of idiosyncratic liver failure. Naturally occurring PPAR-y ligands have been proposed, although with...

Diabetes and vascular disease

Complications of macrovascular disease are responsible for 50 of the deaths in patients with type 2 diabetes mellitus (DM), 27 of the deaths in patients with type 1 diabetes for 35 years or less, and 67 of the deaths in patients with type 1 diabetes for 40 years or more (1,2). The rapid progression of macroangiopathy in patients with type 2 diabetes may reflect diverse phenomena some intrinsic to the vessel wall angiopathic factors such as elevated homocysteine and hyperlipidemia deleterious effects of dysinsulinemia and excessive or persistent microthrombi with consequent acceleration of vasculopathy secondary to clot-associated mitogens (3,4). As a result of these phenomena, cardiovascular mortality is as high as 15 in the 10 years after the diagnosis of DM becomes established (5). Because more than 90 of patients with diabetes have type 2 diabetes and because macrovascular disease is the cause of death in most patients with type 2 as opposed to type 1 (insulinopenic) diabetes, type...

Platelet function in subjects with diabetes mellitus

The activation of platelets and their participation in a thrombotic response to rupture of an atherosclerotic plaque are critical determinants of the extent of thrombosis, incremental plaque growth, and the development of occlusive thrombi. Increased adherence of platelets to vessel walls manifesting early atherosclerotic changes and the release of growth factors from a-granules can exacerbate the evolution of atherosclerosis. Patients with diabetes, particularly those with macrovascular disease, have an increased circulating platelet mass secondary to increased ploidy of megakaryocytes (28). Activation of platelets is increased with type 2 diabetes. This is reflected by increased concentrations in urine of a metabolite of thromboxane A2, thromboxane B2, and by the spontaneous aggregation of platelets (29-31) in blood. The prevalence of spontaneous aggregation of platelets correlates with the extent of elevation of concentrations of hemoglobin (Hb)A1c (30). Stringent glycemic control...

Characteristics of Routinely Administered Insulin Preparations

Common classes and examples of routinely administered insulin preparations that are often mixed on individual daily dosing schedules to permit the most precise therapeutic maintenance of euglycemia in Type (juvenile diabetes) and Type II (adult-onset diabetes) insulin-dependent diabetics. Class of Insulin Preparations

Mechanisms responsible for hyperreactivity of platelets in people with diabetes

Increased expression of the surface GPs Ib and IIb IIIa has been observed in platelets from subjects with both type 1 and type 2 diabetes (43). GP Ib-IX binds to von Willebrand factor in the subendothelium and is responsible for adherence of platelets at sites of vascular injury. Interaction between GP Ib-IX and von Willebrand factor leads to activation of platelets. Activation of GP IIb IIIa leads to the binding of fibrinogen and aggregation of platelets. Thus, increased expression of either or both of these two surface glycoproteins is likely to contribute to the increased reactivity that has been observed platelets from people with diabetes. Winocour and his colleagues have shown an association between decreased membrane fluidity and hypersensitivity of platelets to thrombin (34). Reduced membrane fluidity may be a reflection of increased glycation of membrane proteins. A reduction in membrane fluidity occurs following incubation of platelets in media containing concentrations of...

Antiplatelet therapy and diabetes

Beneficial cardiovascular effects of aspirin are particularly prominent in people with diabetes. In the Physicians Health Study, prevention of MI was greater in those with compared with those without diabetes (65). Treatment with aspirin decreased mortality in the Early Treatment Diabetic Retinopathy Study (66). Because of the marked beneficial effects of aspirin, the American Diabetes Association has recommended treatment with aspirin of all patients with type 2 diabetes without specific contraindications. Considered together, data acquired in vitro and in vivo suggest that platelets from subjects with diabetes are hypersensitive to diverse agonists. Unfortunately, currently available antiplatelet therapy does not restore normal responsiveness to platelets from subjects with diabetes. In animal preparations simulating selected aspects of diabetes, platelets remain hypersensitive to thrombin despite administration of aspirin (67). This observation suggests that the hypersensitivity is...

The coagulation system and diabetes mellitus

The increased concentrations of FPA seen in association with diabetes reflect an altered balance between prothrombotic and anti-thrombotic determinants in subjects with DM favoring thrombosis. This interpretation is consistent with other observations suggesting that generation of thrombin is increased with diabetes resulting in increased concentrations in blood of thrombin-anti-thrombin complexes (75). The steady-state The increased generation of thrombin in people with diabetes is likely to be dependent on increased activity of factor Xa. This has been observed in patients with type 1 diabetes (76). Factor Xa, a major component of the prothrombinase complex, is formed from components including circulating coagulation factor X assembled on phospholipid membranes in association with the tissue factor VIIa complex. Thrombin is generated by the prothrombinase complex comprising factors Xa, Va, and II assembled on phospholipid membranes. The activity of this complex is reflected by...

Mechanisms responsible for a prothrombotic state associated with diabetes

Patients with DM have increased concentrations in blood of the prothrombotic factors fibrinogen, von Willebrand factor, and factor VII coagulant activity (77-79). Among the three coagulation factors, fibrinogen has been most strongly associated with the risk of development of CVD (80). Although the mechanisms responsible for increased concentrations of fibrinogen and von Willebrand factor have not yet been fully elucidated, elevated concentrations in blood of insulin and proinsulin may be determinants in people with type 2 diabetes. This possibility is suggested by the close correlation between concentrations of fibrinogen with those of insulin and proinsulin in healthy subjects (81). Because prediabetic subjects and people with early stages of diabetes have marked insulin resistance that leads to a compensatory increase in the concentrations in blood of insulin and proinsulin (82-84), the hyper(pro)insulinemia of type 2 diabetes is likely to underlie, at least in part, the typically...

Diabetes and fibrinolysis

Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95) that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96) and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched subjects who had not experienced any manifestations of overt CAD (97). We found that impaired fibrinolysis in subjects with type 2 DM, not only under baseline conditions but also in response to physiological challenge, was attributable to augmented concentrations in blood of circulating PAI-1. Furthermore, obese diabetic subjects exhibited threefold elevations of PAI-1 in blood compared with values in nondiabetic subjects despite tissue-type plasminogen activator (t-PA) values that were virtually...

Mechanisms responsible for the overexpression of pai1 in diabetes

Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo (93,94,96,100-103,106). Triglycerides and their constituents (fatty acids) appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro (105,107-109). Liver steatosis is another determinant of elevated concentrations of PAI-1, perhaps indicative of the response of both to derangements in the tumor necrosis factor signaling pathway (110). Insulin and triglycerides exert a synergistic increase in accumulation of PAI-1 in conditioned media when both are present in pathophysiological concentrations (105). Analogous results are obtained with insulin in combination with very low-density lipoprotein-triglyceride, emulsified triglycerides, or...

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women. The effects of estrogen on lipid parameters are discussed in detail in the first part of this chapter. A number of observational studies have also reported that estrogen improves insulin resistance in postmenopausal women, a factor that is predictive for the development of type 2 diabetes (125,129). Estrogen therapy also appears to prevent central fat distribution, a factor that is strongly associated with insulin resistance (126). Thus, estrogen can potentially prevent the insulin resistance associated with central obesity...

Effects of HRT on Carbohydrate Metabolism in Women With Diabetes

There is a degree of reluctance among health care professionals to prescribe HRT to women with diabetes. A community-based survey in London found that diabetic postmenopausal women were less than half as likely as the general population to be prescribed HRT (137). Doctors and health care professionals perceive HRT as detrimental for diabetic women because of fear about glycemic control as is also the case with the oral contraceptive pill (138). Yet there is no evidence that HRT results in deterioration of glycemic control in women with diabetes. In general, the available data indicate that HRT either improves or has neutral effects on carbohydrate metabolism in women with diabetes depending on the estrogen and or progestogen formulation used (Table 2). Oral estradiol has been shown to improve glucose metabolism and insulin sensitivity in diabetic women (132,139), whereas transdermal estradiol was found not to affect glycemic control (140). The addition of norethisterone does not...

Combination therapy with insulin and oral agents

Insulin has been used in combination with every other type of pharmacological therapy for glycemic control in T2DM. Combination therapy with a sulfonylurea has been extensively studied, with overall improved glycemic control in individuals on a bedtime dose of intermediate or long-acting insulin.79,80 The concurrent use of insulin and metformin can modestly decrease HbA1C values and may also decrease the amount of weight gain associated with insulin alone. Thiazolidinediones maintain or slightly lower HbA1C levels when used with insulin, and further decrease the required insulin dose, but may result in additional weight gain. A clinical study investigating the use of acarbose with insulin therapy showed a 0.5 decrease in HbA1C values, which is likely due to an improvement in postprandial hyperglycemia.

Effects of HRT on Lipids in Women With Diabetes

Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in triglycerides with oral CEE (149), although one showed a greater increase among women with diabetes Regarding Lp(a), no significant differences were found among the groups studied in the NHANES III survey. However, in a randomized controlled study combined continuous HRT (CEE + MPA) has shown beneficial effects on Lp(a) in postmenopausal women with type 2 diabetes (153). Also, a significant reduction in Lp(a) and triglycerides has been reported following treatment with tibolone (154). Overall, the use of...

Side effects of insulin

The most significant adverse effect of insulin therapy is hypoglycemia. This is especially the case for treatment of T1DM, but is also true for T2DM. Insulin allergy and lipoatrophy were commonly seen with the use of animal insulin before 'pure' and biosynthetic preparations became available. Both reactions are now rare, but can be seen, probably because there is some degradation during storage and or with depot injection into tissues that can induce an immune response. Weight gain commonly occurs following improved glycemic control with insulin therapy. In the UKPDS, individuals receiving insulin therapy had an average weight gain of 4.0 kg over the course of the study.81

Type 2 diabetes mellitus

Although the diagnosis of T2DM is straightforward, it is extremely difficult to monitor and to treat successfully long-term. Therapy and the monitoring of its effectiveness are complex, invasive, and expensive. Lack of patient education and resources compounds the problem and contributes to non-compliance and suboptimal glycemic control. The asymptomatic nature of chronic hyperglycemia does not allow the patient to truly understand the risk of diabetic complications until irreversible damage has developed. Therapies that have been added to available options in recent years have new and different mechanisms of action. However, when used as monotherapy, none of them (save insulin and its analogs) sustain optimal control for long intervals of time in the majority of patients.

Incretin Augmentation of Insulin Secretion

The observation that food ingestion or enteral glucose administration provoked a greater stimulation of insulin release than similar amounts of glucose infused intravenously led to the recognition of gastrointestinal hormones known as incretins. Although a number of neurotransmitters and gut hormones possess incretin-like activity, several lines of evidence (immunoneutralization, administration of antagonists, and knockout studies) suggest that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) represent the dominant peptides responsible for nutrient-augmented stimulation of insulin secretion. Exenatide, the first GLP-1 agonist, has recently received FDA approval for adjuvant therapy in T2DM (see Section 6.19.6.7) Dipeptidyl peptidase-IV (DPP-IV) is a membrane-associated peptidase that is widely distributed in tissues and also exists as a soluble circulating form. Several DPP-IV inhibitors have been characterized and shown to lower blood glucose via...

Alternative Methods of Insulin Delivery

Delivery of insulin via the pulmonary route can potentially provide the benefits of bolus insulin therapy without injections. Pulmonary delivery of insulin uses the well-vascularized, highly permeable alveoli of the lungs as the port of entry for macromolecules. Several formulations of inhaled insulin are in clinical trials or awaiting regulatory approval. Skyler et al.93 provided the proof-of-concept study that illustrates the efficacy of mealtime use of inhaled insulin in individuals with T1DM. Glycemic control was similar in subjects receiving preprandial inhaled insulin plus subcutaneous ultralente insulin at bedtime (HbA1C 7.9 at 12 weeks) or a usual insulin regimen of two to three injections per day (HbA1C 7.7 ). Similarly, Cefalu et al 4 showed similar efficacy of inhaled insulin in individuals with T2DM whose treatment with combination oral agents had failed. In both these studies inhaled insulin was well tolerated without adverse pulmonary effects. However, due to its...

HRT and Risk of Cardiovascular Disease in Women With Diabetes

CVD is the most common cause of death in type 2 diabetes. This increased risk is particularly apparent in women with diabetes in which the relative protection afforded by the female sex is lost (107). For women without diabetes, prospective cohort surveys such as the Nurse's Health Cohort Study, suggest that estrogen therapy decreases the risk of CHD in postmenopausal women who were initially healthy at the time of enrollment (5). However, data from the HERS and WHI clinical trials have questioned the validity of epidemiological evidence by reporting an increased risk of CHD among women assigned to HRT (6,7). Little is known about the effect of HRT on CHD in women with diabetes. Secondary analyses among small subgroups of women with diabetes from case-control studies have been equivocal, some reporting a non significant reduced risk (168,169) and others nonsignificant increased risk of CHD with exposure to HRT (170). In a 3-year follow-up observational study of a cohort of25,000...

Relationship to Insulin Resistance and Diabetes

Although the exact mechanisms that lead to the development of PCOS are not clear it has been shown that insulin resistance and compensatory hyperinsulinemia possess the central role in the pathophysiology of the syndrome. Women with PCOS have both basal and glucose-stimulated hyperinsulinemia compared with weight-matched women and the high levels of insulin are thought to mediate the development of hyperandrogenemia, anovulation, and infertility. At the same time, insulin resistance and compensatory hyperinsulinemia are responsible for the cardiovascular risk factors. The hyperinsulin-ism correlates with the hyperandrogenism and occurs independent of obesity (180,181). The insulin resistance in at least 50 of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor (182). This abnormality is caused by a factor extrinsic to the insulin receptor, which is presumably a serine threonine kinase. Serine phosphorylation appears to modulate the activity of...

Classification Insulin concentrated

See also Antidiabetic Agents Insulins. Action Kinetics Concentrated insulin injection (500 U mL). Depending on response, may be given SC or IM as a single or as two or three divided doses. Not suitable for IV administration because of possible allergic or anaphylactoid reactions. Uses Insulin resistance requiring more than 200 units insulin day. Contraindications Allergy to pork or mixed pork beef insulin (unless client has been desensitized). Special Concerns Use with caution during lactation. Additional Side Effects Deep secondary hypoglycemia 18 24 hr after administration.

Classification Insulin rDNA origin

See also Antidiabetic Agents Insulins. Action Kinetics Absorbed faster than regular human insulin. compared with regular insulin, has a more rapid onset of glucose-lowering activity, an earlier peak for glucose lowering, and a shorter duration of glucose-lowering activity. However, is equipotent to human regular insulin (i.e., one unit of insulin lispro has the same glucose-lowering capacity as one unit of regular insulin). May lower the risk of nocturnal hypogly-cemia in clients with type I diabetes.H I Onset 15 min. Peak effect 30-90 min. tJ 2 1 hr. Duration 5 hr or less. Uses Diabetes mellitus. Contraindications use during episodes of hypoglycemia. Hypersensitiv-ity to insulin lispro. Special Concerns Since insulin lis-pro has a more rapid onset and shorter duration of action than regular insulin, clients with type I diabetes also require a longer acting insulin to maintain glucose control. Requirements may be decreased in impaired renal or hepatic function. use with caution during...

When blood pressure is too high in people with diabetes

In people with Type 1 diabetes, blood pressure usually rises only as a result of kidney damage. Whereas previously mainly normal blood pressure readings were obtained, as soon as microalbuminuria appears, the blood pressure begins to rise, although at first it may stay in the normal range. For example, if under normal albuminuria it was 125 80 mmHg, after the onset of microalbuminuria it might rise to 130 85 mmHg, then later to 135 90 mmHg. This is why there is no 'official' value for hypertension, but a rise in blood pressure compared with earlier values indicates increased stress for the heart, kidneys and blood vessels. Should macroalbuminuria then develop, or even renal failure, the blood pressure rises sharply if it is not treated promptly. As well as people with Type 1 diabetes, every second or third person with Type 2 diabetes shows raised blood pressure as soon as metabolic disease begins. Because there is often no visible cause for the high blood pressure, people talk about...

The BB Rat as a Model of Human Insulin Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) in humans is a disorder characterized by severe hyperglycemia, weight loss, glycosuria, and ketoacidosis. These signs and symptoms are the result of severe insulin deficiency. IDDM results from selective destruction of the insulin-producing P cells in the pancreatic islets of Langerhans in the context of an inflammatory infiltrate. Its pathogenesis is believed to be autoimmune in origin. Affected individuals require chronic treatment with exogenous insulin for survival. Knowledge of IDDM advances steadily, but the disorder remains difficult to study in humans. The diseased organ is inaccessible, and ethical considerations limit procurement of biological samples and testing of treatment modalities. Use of the BioBreeding (BB) rat to model human IDDM offers numerous advantages. Characteristics of diabetes in the BB rat closely parallel those observed in human IDDM. Diabetic animals can be biopsied, autopsied, and bred to study the genetic basis...

Maintenance And Diagnosis Of Spontaneous Iddm In Diabetesprone Bb Rats

This protocol describes the procurement and husbandry of BB rats, diagnosis of insulin-dependent diabetes mellitus (IDDM), treatment and care of diabetic animals, and his-topathological evaluation of insulitis. The methods in this protocol are common to all the models of IDDM in this unit. Diabetes is diagnosed clinically by documenting a sustained increase in blood glucose concentration. Insulitis invariably precedes the development of diabetes, but does not always progress to diabetes. Insulitis is diagnosed morphologically by assessment of mononuclear cell infiltration of pancreatic islets (see Support Protocol 1). Overt hyperglycemia occurs only when > 90 of the P cell mass in the pancreas has been destroyed.

Prevention Of Iddm In Diabetesprone Bb Rats

Spontaneous diabetes in diabetes-prone (DP)-BB rats can be prevented by a single transfusion of T cells from the peripheral lymphoid tissues of histocompatible nonlym-phopenic rat strains. Prevention by this method requires early intervention, before the onset of spontaneous insulitis it is generally ineffective after 60 days of age (Burstein et al., 1989). Engraftment of RT6+ T cells, which are absent in the unmanipulated DP-BB rat, is required for protection from disease. In this protocol, 21- to 30-day-old DP-BB rats are administered unfractionated spleen cells from coisogenic diabetes-resistant (DR)-BB rats. Although T cells mediate protection from IDDM, purification of T cells prior to transfer is not required. Because RT6 is a maturational alloantigen that is not fully expressed in young rats, donor DR rats are used at 8 weeks of age or older, when the cohort of RT6+ T cells is fully developed. The degree of protection is a function of the number of cells transfused > 90...

Insulin Therapy For Diabetic Rats

Two methods of insulin therapy are described daily subcutaneous injections of insulin for short-term maintenance and subcutaneous implantation of timed-release pellets of bovine insulin for long-term maintenance. The goal of treatment is not to produce a normal blood glucose concentration, as such tight control poses the risk of death from hypoglycemia, but rather to maintain growth and prevent ketoacidosis for the duration of the experiment. The dose of insulin is chosen on this basis. It is not necessary to monitor blood glucose concentrations in treated animals unless this parameter is a variable in an experimental study.

Oxidative and Nitrosative Stress in Diabetes Induced Vascular Dysfunction

Various neurohumoral mediators and mechanical forces acting on the innermost layer of blood vessels, the endothelium, are involved in the regulation of the vascular tone. The main pathway of vasoregulation involves the activation of the constitutive, endothelial isoform of NO synthase (eNOS) resulting in NO production (53). Endothelium-depen-dent vasodilatation is frequently used as a reproducible and accessible parameter to probe endothelial function in various pathophysiological conditions. It is well established that endothelial dysfunction, in many diseases, precedes, predicts, and predisposes for the subsequent, more severe vascular alterations. Endothelial dysfunction has been documented in various forms of diabetes, and even in prediabetic individuals (52,54-58). The pathogenesis of this endothelial dysfunction involves many components including increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol, and the subsequent activation of...

The NOD Mouse A Model For Insulin Dependent Diabetes Mellitus

Nonobese diabetic (NOD) designates an inbred, genetically well characterized mouse strain. Like the DP-BB Wor rat (unit 15.3), NOD mice spontaneously develop autoimmune T cell-mediated insulin-dependent diabetes mellitus (IDDM). However, the two models are sharply contrasted in that NOD mice, unlike BB rats, do not exhibit T lymphocytopenia, but rather the inverse (Serreze and Leiter, 1995). NOD mice are very easy to breed and are available from suppliers in the United States, Europe, and Japan. In addition to the extensive genetic characterization of the NOD genome, the availability of monoclonal antibodies to murine leukocyte antigens as well as the availability of a variety of congenic and transgenic stocks of NOD mice makes these mice especially useful for the immunologic dissection of autoimmune IDDM. Diabetogenesis in NOD mice is the consequence of heritable immunodeficiencies under complex polygenic control. The penetrance of these susceptibility-contributing polygenes is...

Insulin zinc suspension extended Ultralente

Classification Long-acting insulin See also Antidiabetic Agents Insulins. Action Kinetics Large crystals of insulin and a high content of zinc are responsible for the slow-acting properties of this preparation. Products containing both 40 units mL and 100 units mL are available. Onset 4-8 hr. Peak 10-30 hr. Duration 36 hr or longer. Uses Mild to moderate hyperglyce-mia in stabilized diabetics. Not suitable for the treatment of diabetic coma or emergency situations. How Supplied Injection 100 U mL

Syndrome of Inappropriate Secretion of Antidiuretic Hormone and Diabetes Insipidus

Diabetes insipidus involves a lack of free water due to a partial or complete deficiency in ADH. The clinical symptoms include polyuria (urine output greater than 300 mL h or 500 mL 2 h), thirst, dehydration, hypovolemia, and polydipsia. Diabetes insipidus results from the destruction of at least 90 of the large neurons in the supraoptic and paraventricular nuclei. The lesion often involves the supraoptic and hy-pophysial tract rather than the neuronal bodies themselves. The laboratory criteria for the diagnosis of diabetes insipidus are as follows.

Treatment of Insulin Dependent Diabetes Mellitus

Diabetic Lunch Meal

Juvenile onset (type I) diabetes mellitus is caused by the destruction of insulin-producing B cells in the pancreas, necessitating replacement of insulin (daily dose approx. 40 U, equivalent to approx. 1.6 mg). Therapeutic objectives are (1) prevention of life-threatening hypergly-cemic (diabetic) coma (2) prevention of diabetic sequelae (angiopathy with blindness, myocardial infarction, renal failure), with precise titration of the patient being essential to avoid even short-term spells of pathological hyperglycemia (3) prevention of insulin overdosage leading to life-threatening hypoglycemic shock (CNS disturbance due to lack of glucose). Therapeutic principles. In healthy subjects, the amount of insulin is automatically matched to carbohydrate intake, hence to blood glucose concentration. The critical secretory stimulus is the rise in plasma glucose level. Food intake and physical activity (increased glucose uptake into musculature, decreased insulin demand) are accompanied by...

Pharmacodynamics and pharmacokinetics of insulin

Insulin was initially available as a soluble, clear solution. The relatively short duration of action meant that individuals had to take multiple daily injections. Combining insulin with protamine or high concentrations of zinc led to the formation of suspensions that are slowly absorbed with a longer and variable duration of action. Insulin analogs were designed with more predictable characteristics of rapid or attenuated absorption and action. The pharmacodynamic profiles of the different types of insulin and insulin analogs are summarized in Table 9. In solution, and in the b-cell where its concentration is high, insulin tends to self-associate, forming dimers, hexamers, and larger aggregates. In the b-cell, this self-association facilitates the transportation, conversion, and intracellular storage of insulin crystals. However, self-association retards absorption of soluble insulin after subcutaneous administration because hexamers must dissociate to monomers before entering the...

Longacting insulins ultralente and insulin glargine

Long-acting insulins are used to provide a basal level of insulin. Ultralente insulin reaches a peak gradually (14-18 h after injection), with a duration of action of up to 24h. Similar to lente insulin, ultralente is a suspension of large, zinc-containing crystals that have been precipitated in an acetate buffer. Insulin glargine (Lantus) contains two modifications of the human insulin molecule that change both the onset and duration of action. Two arginine residues are added to the carboxyl terminal end of the insulin B-chain, and glycine is substituted for asparagine at the end of the A-chain (position A21). The latter modification prevents deamidation and dimerization. Overall, these changes result in a stable molecule that is soluble at an acidic pH but insoluble at the neutral pH of subcutaneous tissues. When insulin glargine is injected subcutaneously, the acidic solution is neutralized. Microprecipitates of insulin glargine form in the subcutaneous tissue and are slowly...

Shortacting insulin regular insulin

Human recombinant DNA produced regular insulin has an onset of action between 30 and 60 min after and a peak effect 2-4 h after injection, with a usual duration of action of 6-8 h. Regular insulin was the shortest acting insulin available prior to the availability of the rapid-acting analogs. Its duration of action extends beyond the duration of digestion and absorption of most meals, thereby increasing the risk of hypoglycemia. 6.19.6.5.3.3 Intermediate-acting insulins Neutral Protamine Hagedorn ((NPH), lente, and insulin detemir) Neutral Protamine Hagedorn (NPH) and insulin zinc (lente) are different types of intermediate-acting insulins. NPH is a suspension of medium-sized crystals, which include zinc and protamine. Lente is a suspension of large, zinc-containing crystals that have been precipitated in an acetate buffer. These crystals dissolve slowly after subcutaneous injection. NPH and lente have similar pharmacodynamic profiles, with an onset of action approximately 2 h, a peak...

Glycemia and Quality of wellbeing in patients with diabetes

As described in the study methods, the sample included 1522 patients 634 with type 1 diabetes and 888 with type 2 diabetes who attended endocrinology, diabetes, and ophthalmology clinics at the University of Michigan Health System between June 29,1998 and March 15,2001 and had HbA1c measurements on the day of the visit. All patients were over 18 years of age or older, able to give informed consent, and able to either self-administer the questionnaires or, if visually impaired, to respond to a research assistant reading the questionnaires 1. Tabaei BP, Shill-Novak J, Brandle M, Burke R, Kaplan RM, Herman WH. Glycemia and the quality of well-being in patients with diabetes, Quality of Life Research (in press). 2. Coffey JT, Brandle M, Zhou H, Marriott D, Burke R, Tabaei BP, Engelgau MM, Kaplan RM, Herman WH. Valuing health-related quality of life in diabetes. Diabetes Care. 2002 Dec 25(12) 2238-43.

Diabetes and Insulin Resistance

Adiponectin's involvement in CVD is likely multifactorial, but one of its main roles is likely in affecting traditional risk factors associated with coronary artery disease (CAD), particularly diabetes. As one of the diabetes susceptibility genes and the adiponectin gene both localize to 3q27, mutation at this locus has been associated with both type 2 diabetes and decreased adiponectin (41). The majority of data for animal studies thus far suggest that adiponectin acts as an insulin-sensitizing hormone. Adiponectin-knockout mice develop insulin resistance either independently of diet or only after high-fat and high-sucrose diet, and treating these mice with adiponectin ameliorates their insulin resistance (35,42). The insulin resistance in adiponectin-deficient lipoatrophic and obese mice can partially be reversed via adiponectin administration and fully restored with both leptin and adiponectin supplementation (29). Furthermore, in a longitudinal study analyzing the progression of...

Endothelial dysfunction and diabetes mellitus

Although the link between diabetes and cardiovascular disease is not well understood, endothelial dysfunction may be implicated in the pathogenesis of diabetic vascular disease. The evidence of endothelial dysfunction in diabetes comes largely from studies measuring the endothelial substances that mediate fibrinolysis and coagulation. Chapters 2 and 6 give detailed descriptions of these studies. For example, plasminogen activator inhibitor-1 levels are increased, whereas fibrinolytic activity and prostacyclin levels are decreased in both type 1 and 2 diabetes (42-45).

Gestational Diabetes Mellitus

Poorly controlled gestational diabetes is associated with an increase in the incidence of preeclampsia, polyhydramnios, fetal macrosomia, birth trauma, operative delivery, and neonatal hypoglycemia. There is an increased incidence of hyperbilirubinemia, hypocalcemia, and erythremia. Later development of diabetes mellitus in the mother is also more frequent. The prevalence of gestational diabetes is higher in black, Hispanic, Native American, and Asian women than white women. The prevalence of gestational diabetes is 1.4 to 14 percent. Risk Factors for Gestational Diabetes A family history of diabetes, especially in first degree A. Screening for gestational diabetes should be performed at 24 to 28 weeks of gestation. However, it can be done as early as the first prenatal visit if there is a high degree of suspicion that the pregnant woman has undiagnosed type 2 diabetes (eg, obesity, previous gestational diabetes or fetal macrosomia, age > 25 years, family history of diabetes)....

Metabolic effects of insulin

Insulin is an anabolic hormone with widespread effects. Increased glucose entry in adipose tissue and muscle cells. Glucose entry into cells is brought about by a family of sodium-independent facilitative glucose transporters, known as GLUT-1 to GLUT-5. Insulin stimulates translocation of glucose transporters from intracellular pools to the cell membrane. Increased glycolysis in muscle and adipose tissue. Increased glycogen synthesis in adipose tissue, muscle and liver cells. Reduced gluconeogenesis and glycogenolysis in the liver. g The metabolic actions of insulin on target tissues are mediated by the specific y insulin receptor, located in the plasma membrane. It is an integral transmem-

Insulin Resistance and Nitric Oxide

Although hyperglycemia plays an essential role in the pathophysiology of DM, elevated serum insulin levels may also play an important role in atherogenesis, specifically in noninsulin DM. Furthermore, insulin resistance is a known cardiac risk factor. Insulin mediates NO production through specific pathway, which includes insulin receptor tyrosine, phosphatidyl inositol 3-kinase and its downstream effector, akt (118,119). This increase in NO release, in turn, results in vasodilation (120). This endot-helial-dependent relaxation is accompanied by an increase in glucose transport and metabolism (121,122) and may also potentially result in the removal of postprandial glucose. Therefore, endothelial dysfunction may lead to insulin resistance. This argument is further strengthened by the findings of Petrie and coworkers (123), which showed a correlation between basal endothelial function and insulin sensitivity in healthy controls. This relationship was not seen with either nitroprusside...

Patients with Diabetes

Marshall Wynngarden, a 34-year-old physician, came to Johns Hopkins in 1986, with a history of insulin-dependent diabetes since age 9 and renal failure since 1983. He was complaining of fatigue, arthritic pains, sexual dysfunction, and muscle cramps. Despite an ACE inhibitor and moderate protein restriction, his kidney function declined. In 1988 he was started on a very-low-protein diet, supplemented by amino acids alternating with ketoacids. Symptoms improved, but he continued to have difficulty with control of his diabetes. Kidney function continued to decline slowly, and he finally decided to start dialysis in 1992, after four years.

Thyroid Disease in Diabetes Mellitus

The most frequent autoimmune disease in type 1 diabetes affects the thyroid. The etiology of autoimmunity in pancreas and thyroid is a T cell-mediated disease and seems to be due to common genetic susceptibility. Two immune regulatory genes (HLA human leukocyte antigen and CTLA-4 cytotoxic T lymphocyte-associated protein 4) contribute to the susceptibility for both diseases 5, 23 . This locus, also known as the IDDM 12 gene, seems to play a major role in development of autoimmune polyglandular syndrome type 2 (APS-2). Positivity for thyroid auto antibodies in children with type 1 diabetes shows considerable variability in different countries. Incidence and prevalence numbers vary between 3 and 50 3, 18, 19, 33, 36 compared to a suggested rate of 3-10 in non diabetic children and adolescents 17, 26, 38 . The largest cohort analysis was published by Kordonouri et al. 19 reporting a rate of 21.6 of thyroid antibodies in a group of 7,097 children and adolescents with type 1 diabetes. In...

Digoxin Succinylcholine and Insulin

Before ending this section, three more drugs should be mentioned digoxin, succinylcholine, and insulin. Two of the three are medications and one is a muscle relaxant. In the older forensic literature, these were three drugs that could be used to commit murder, with a fair certainty that they could not be detected. This is no longer the case. Digoxin is a cardiac glycoside used in the treatment of congestive heart failure and other cardiac disorders. It is the most common form of digitalis prescribed. On an empty stomach, the maximum serum concentration is reached approximately 1 h after oral ingestion. Serum concentrations of over 2 ug L are generally considered toxic. Following death, there is postmortem release of digoxin into the blood. This can cause artifactually high levels. Because of this, the authors recommend that any analysis of digoxin be done on the vitreous. In the cases the authors have seen in which death was caused by an overdose of digoxin, levels in the vitreous...

Development of adult diabetes

Marcus Gunn Jaw Winking Syndrome

Compared with a normal subject, the obese subject requires a continually elevated output of insulin (orange curves) to avoid an excessive rise of blood glucose levels (green curves) during a glucose load. When the secretory capacity of the pancreas decreases, this is first noted as a rise in blood glucose during glucose loading (latent diabetes). Subsequently, not even the fasting blood level can be maintained (manifest, overt diabetes). A diabetic condition has developed, although insulin release is not lower than that in a healthy person (relative insulin deficiency). Treatment. Caloric restriction to restore body weight to normal is associated with an increase in insulin receptor number or cellular responsiveness. The releasable amount of insulin is again adequate to maintain a normal metabolic rate. Therapy of first choice is weight reduction, not administration of drugs Should the diabetic condition fail to resolve, consideration should first be given to insulin replacement...

Effects of the Renin Angiotensin System on Insulin Signaling

Bradykinin Agonist

The effects of RAS inhibition on insulin action have been attributed to changes in both the inhibition of Ang II AT1 receptor signaling and enhancement of bradykinin B2 receptor action. ACE, also called kininase II, degrades bradykinin 1-9 and thereby reduces bradykinin B2 receptor activation (Fig. 2). Several reports have shown that bradykinin B2-receptor antagonism blocks the decreases in insulin resistance and enhanced glucose uptake associated with ACE inhibition (148,149,157) and is mimicked by chronic bradykinin administration (158). Moreover, bradykinin B2 receptor deficient mice are insulin-resistant (159). Although the mechanisms responsible for the amelioration of insulin resistance by bradykinin are not fully understood, bradykinin has been shown to enhance insulin-stimulated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and its subsequent association with Phosphatidylinositol 3'-kinase (PI3K) in skeletal muscle and liver (160,161), possibly by inhibiting...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Weight reduction is of paramount importance and cornerstone of every therapeutic strategy in PCOS. Although obesity does not seem to be the primary insult in PCOS, many studies have demonstrated the beneficial impact of weight reduction on the manifestations of the syndrome and especially insulin sensitivity, risk for diabetes and adverse cardiovascular risk profile (199). The effect of weight reduction by a hypocaloric low-fat diet on the metabolic and endocrine variables was studied in obese women with PCOS (200). The insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique, which is the gold standard in evaluating insulin resistance. After the diet intervention, insulin sensitivity improved and did not differ significantly from the body mass index matched normo-ovulatory control women. In another study, the effect of dietary intervention on insulin sensitivity and lipids, fibrinolysis and coagulation was examined also in obese women with PCOS (201)....

Effects of HRT on Endothelial Function in Postmenopausal Women With Diabetes

Endothelial dysfunction is the hallmark of diabetes and is regarded as an early manifestation of atherogenesis. In postmenopausal women with diabetes, multiple pathophysiological processes may contribute to endothelial dysfunction. These are diabetes- related, as a result of hyperglycemia and obesity insulin resistance and menopause-related as a result of loss of the protective effect of estrogen, as discussed earlier. Despite the importance of the endothelium, there is limited data on the effects of HRT on endothelial dysfunction in postmenopausal women with diabetes. In a recent study comparing healthy and diabetic postmenopausal women, Lim and associates (109) found that, although cutaneous vasodilation was impaired in postmenopausal women, it was able to be improved by HRT in nondiabetic subjects, but the improvement was less apparent in the diabetic cohort. However, the use of HRT in women with diabetes was associated with lower soluble ICAM levels, suggesting an attenuation in...

Expression of the Renin Angiotensin System in Diabetes

The production and action of Ang II is regulated at multiple levels, including the availability of angiotensinogen, levels and activities of angiotensin-processing enzymes, angiotensin receptor isotype expression, and postreceptor signaling (Fig. 1). Although quantitation of Ang II levels would provide a direct measure of extracellular RAS activation, these measurements are complicated by the rapid degradation of this peptide (46,47) and its tissue-specific production (26,27,48). Reports on the effects of diabetes on plasma and tissues Ang II levels are controversial. Studies of streptozotocin (STZ)-induced diabetes in rats have reported no effect of diabetes on Ang II levels in plasma, kidney, aorta, and heart (49), reduced renal Ang II but normal levels in plasma Ang II (50), and decreased plasma Ang II in diabetes (51). Similar controversies appear for the effects of diabetes on changes in upstream components of the RAS. For example, recent studies have reported that plasma renin...

Insulindependent Diabetes Mellitus Introduction

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disorder caused by a deficiency of insulin. The deficiency is thought to occur in those individuals who are genetically predisposed to the disease and who have experienced a precipitating event, commonly a viral infection or environmental change, that causes an autoimmune condition affecting the beta cells of the pancreas. It is treated by injection of insulin and regulation of diet and activity that maintain body functions. Complications that occur from improper coordination of these include hypoglycemia and hyperglycemia which, if untreated, lead to insulin shock or ketoacidosis. Long-term effects of the disease include neuropathy, nephropathy, retinopathy, atherosclerosis, and microangiopathy.

How failing kidney function affects diabetes management

To achieve good blood sugar control in the presence of failing kidney function is a difficult task for patient and doctor. There are various reasons for this. In some people with diabetes the insulin sensitivity changes, for reasons that are often unclear the tissues no longer respond as well to insulin. This can lead to a worsening of the diabetes. Insulin - whether made by the body or injected as a drug - is partly broken down in the kidneys. When the kidneys are not functioning properly, less insulin is metabolized, so that the effect of the insulin is prolonged. This partially compensates for the reduced insulin sensitivity mentioned above, but can also result in hypoglycaemia -dangerously low blood sugar. Someone who has advanced nephropathy often also suffers from other complications of diabetes. These may include damage to the nerves that regulate the gastrointestinal tract. Then food is no longer digested and absorbed properly. Typical signs are bloating, feeling full,...

Classification of Diabetes Mellitus and the Metabolic Syndrome

In 2003, the American Diabetes Association (ADA) revised the etiologic classification of diabetes mellitus, removing the distinction between primary and secondary causes of diabetes15 (Table 1). The nomenclature now uses Arabic rather than Roman numerals to designate T1DM and T2DM. Terms such as insulin-dependent, non-insulin-dependent, juvenile-onset, maturity-onset, and adult-onset diabetes are eliminated. Thus, diabetes is now classified according to etiology and pathophysiology, without distinction as to age of onset or type of treatment. 6.19.2.1 Type 1 Diabetes Mellitus 6.19.2.1.1 Immune-mediated diabetes mellitus (Type 1A) Immune-mediated diabetes, previously referred to as insulin-dependent diabetes, type I diabetes, and juvenile-onset diabetes, accounts for 5-10 of all cases of diabetes. Immune-mediated diabetes typically develops in childhood and adolescence, but has a variable age of onset ranging from infancy to the eighth and ninth decades of life. Abnormalities in...

How does diabetes affect the kidneys

Generally, the changes produced in the kidneys by diabetes occur very slowly, taking place over years (Table 2.2, Figure 2.4). If they are recognized early, they can - with the right treatments - be reversed. The changes start, at the onset of diabetes, with an increase in the size of the kidneys and in the amount of blood passing through them. This first, early stage is known as 'the hypertrophy and hyperfunction stage' (stage 1) because of the enlarged kidneys, enriched in blood. Even at this stage, a rise in the amount of protein in the urine is often observed. If the diabetes is properly controlled, these changes can usually be reversed within weeks or months. The protein also disappears from the urine. The progression of these changes in the kidneys depends strongly on the state of the body's metabolism. If the blood composition is good - that is, if the haemoglobin A1c (HbAlc) concentration is near-normal, namely between 6 and 7 , the diabetes will barely affect the kidneys in...

Diagnosis Of Insulindependent Diabetes Mellitus Iddm

Monitoring of glycemic status should begin when NOD mice reach 10 weeks of age. Generally, this is done at weekly intervals by using Diastix (Bayer Diagnostics appendix 5) or similar reagent strips to measure urine glucose. Picking a mouse up leads to immediate urination, allowing a drop to be collected on the test area (tip) of the reagent strip. High levels of glucose in the urine (glycosuria) appear when plasma glucose is > 300 mg dl. A nonfasting plasma glucose of > 300 mg dl for 2 consecutive weeks indicates IDDM. The nonfasting plasma glucose levels of young, prediabetic NOD mice ranges between 130 and 180 mg dl. Plasma glucose can be measured directly in small samples of venous blood using glucose oxidase methods (either commercially available glucose analyzers or small portable analyzers and glucose oxidase-coated test strips see unit 15.3 for details). Onset of IDDM can also be accelerated in young prediabetic NOD mice by intraperitoneal administration (unit 1.6) of...

Classification Oral antidiabetic

See also Antidiabetic Agents Hypogly-cemic Agents. Action Kinetics Lowers blood glucose by stimulating release of insulin from pancreas. Action depends on functioning beta cells in pancreatic islets. Rapidly and completely absorbed from GI tract. Peak plasma levels 1 hr. Completely metabolized in liver with most excreted in feces. Uses Adjunct to diet and exercise in type 2 diabetes mellitus. In combination with metformin to lower blood glucose where hyperglycemia can not be controlled by exercise, diet, or either drug alone. Contraindications Lactation. Diabetic ketoacidosis, with or without coma. Type 1 diabetes. Special Concerns Use with caution in impaired hepatic function. Safety and efficacy have not been determined in children. Side Effects CV Chest pain, angina, ischemia. GI Nausea, diarrhea, constipation, vomiting, dyspepsia. Respiratory URI, sinusitis, rhinitis, bronchitis. Musculoskeletal Arthralgia, back pain. Miscellaneous Hypoglyce-mia, headache, paresthesia, chest pain,...

Induction Of Iddm In Diabetesresistant Bb Rats

Diabetes-resistant (DR)-BB rats with induced diabetes offer advantages over spontaneously diabetic diabetes-prone (DP)-BB animals. Untreated DR rats are not lymphopenic and their T cell populations are normal with respect to phenotype and function. Treatments to induce diabetes do not induce severe lymphopenia. In addition, T cells from diabetic DR-BB rats adoptively transfer IDDM with no requirement for mitogen activation (see Alternate Protocol 2). Another practical advantage is that cells can be obtained from cohorts of young DR-BB rats treated to become diabetic at approximately the same age. This simplifies experimental design and reduces costs, because, for example, DR-BB rats treated at 30 days old will become diabetic between 44 and 51 days of age, whereas DP-BB rats need to be housed and tested from 55 to 120 days of age to identify all potentially diabetic animals. Hybridoma DS4.23 cells (available from the Division of Diabetes, University of

Insulin zinc suspension Lente

Classification Intermediate-acting insulin See also Antidiabetic Agents Insulins. Action Kinetics Contains 70 crystalline and 30 amorphous insulin suspension. Considered intermediate-acting. Principal advantage is the absence of a sensitizing agent such as protamine. Onset 1-2.5 hr. Peak 7-15 hr. Duration About 22 hr. Uses Allergy to other types of insulin and in clients disposed to throm-botic phenomena in which prota-mine may be a factor. Zinc insulin is not a replacement for regular insulin and is not suitable for emergency use. Diabetes. Adults, initial 7-26 units 30-60 min before breakfast. Dosage is then increased by daily or weekly increments of 2-10 units until satisfactory readjustment is established. A second smaller dose may be given prior to the evening meal or at bedtime. Clients on NPH can be transferred to insulin zinc suspension on a unit-for-unit basis. Clients being transferred from regular insulin should begin zinc insulin at two-thirds to three-fourths the regular...

Diabetes

Constipation is also widely believed to be associated with diabetes mellitus. This association has been observed in studies by Talley's group30 in Australia, Lithner's group31 in Sweden, and Enck et al32 in Germany. However, the only population-based study specifically examining the prevalence of gastrointestinal symptoms among diabetics was performed by Locke's group33 at the Mayo Clinic. They surveyed random samples of Olmsted County residents with type 1 and type 2 diabetes as well as two age- and gender-stratified control groups without diabetes. They did not observe any difference in the prevalence of constipation among patients with type 1 (12 vs. 14 ) or type 2 (10 vs. 12 ) diabetes, when compared with controls. There was a trend toward constipation and or laxative use being more common among individuals with type 1 diabetes particularly among men (p < .15), but this difference was observed only in those individuals using calcium channel blockers, which are known to cause...

Insulin resistance

Hyperinsulinemia and insulin resistance have been shown to increase the risk of CVDs or atherosclerosis in diabetic states, and being a potential risk factor in the development of hypertension, not only in diabetic patients but also in the general population. The mechanism by which hyperinsulinemia or insulin resistance increases the risk of atherosclerosis is still unclear. Many theories have been suggested, including insulin-induced salt retention, directly enhancing proliferation of vascular smooth muscle cells (VSMCs) (22,23), and indirectly regulating of endothelial cell homeostasis via the alteration of growth factors and cytokines in cells share extensive interaction with endothelial cells, such examples include fibroblasts, epithelial cells, VSMCs, and cardiomyocytes (24-26). We have characterized insulin receptors on the vascular cells and reported that they are identical to those in the nonvascular cells with respect to binding, structure, and tyrosine Alterations of Cell...

Diabetic Nephropathy

The prevalence of diabetic nephropathy has increased dramatically and is now the first cause of end-stage renal disease requiring renal replacement therapy worldwide (72). Although the genetic background is important in determining susceptibility to diabetic nephropathy, exposure to chronic hyperglycemia leading to the subsequent activation of multiple pathogenic pathways appears to be the main initiating factor (2,3,4-6,41). Diabetic nephropathy occurs in up to 30 -40 of diabetic patients. The initial abnormalities include glomerular hyperfiltration and hyperperfusion resulting in microalbu-minuria, increased glomerular basement membrane thickening, and mesangial ECM deposition. These processes are followed by mesangial hypertrophy, diffuse and nodular glomerulosclerosis, tubulointerstitial fibrosis, and eventually progressive renal failure (73). The ability to culture cells that are affected by AGEs has provided an important insight into the mechanisms of action of these adducts,...

Diabetes mellitus

Diabetes mellitus is a very common metabolic disease that is caused by absolute or relative insulin deficiency. The lack of this peptide hormone (see p. 76) mainly affects carbohydrate and lipid metabolism. Diabetes mellitus occurs in two forms. In type 1 diabetes (insulin-dependent diabetes mellitus, IDDM), the insulin-forming cells are destroyed in young individuals by an autoimmune reaction. The less severe type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) usually has its first onset in elderly individuals. The causes have not yet been explained in detail in this type. A. Insulin biosynthesis O Insulin is produced by the B cells of the islets ofLangerhans in the pancreas. As is usual with secretory proteins, the hormone's precursor (preproinsulin) carries a signal peptide that directs the peptide chain to the interior of the endoplasmic reticulum (see p. 210). Proinsulin is produced in the ER by cleavage of the signal peptide and formation of disulfide bonds....

With diabetes

Healthy postmenopausal women undergo changes in lipoprotein and carbohydrate metabolism and in the pattern of body fat distribution similar to those of patients with diabetes. In fact, a picture resembling the metabolic syndrome emerges with the menopause (12). Replacement therapy with estrogen can improve the adverse impact of meno Postmenopausal women with diabetes are at risk of dyslipidemia, central obesity, hypertension, and accelerated atherosclerosis, all of which can contribute to an increased risk of CVD (127). Thus, postmenopausal women with diabetes could benefit from a reduced risk of CVD with the use of HRT. However, whether HRT confers cardiovascular protection in postmenopausal women with diabetes is currently unknown and remains an issue for further clinical research. An attempt is made in this section to shed some light in this issue based on current evidence. This is preceded by a brief review of the effects of estrogen on risk factors for diabetes and the metabolic...

Insulin

The essential role of insulin in the treatment of T1DM is universally accepted, whereas its use in T2DM is often considered the last resort. Insulin should be viewed as a valuable therapeutic tool for early intervention, to attain and maintain target levels of glycemic control. The evolution of insulin preparations, from those 'purified' from animal pancreases, to human-insulin produced with recombinant DNA technology, and the present use of insulin analogs, represents more than 80 years of collaboration among industry, clinical, and basic research, and millions of people with diabetes.

Sources of insulin

With the availability of human insulin, use of animal insulin declined dramatically. Currently, the biosynthesis of human insulin involves insertion of the human proinsulin gene into either Saccharomyces cerevisiae (baker's yeast) or a nonpathogenic laboratory strain of Escherichia coli, which serve as the production organism. Human insulin is then isolated and purified. Sophisticated knowledge of the structure-function aspects of insulin has led to the development and production of analogs to human insulin. The molecular structure of insulin has been modified slightly to alter the pharmacokinetic properties of insulin, primarily affecting absorption from subcutaneous tissue. The B26-B30 region of the insulin molecule is not critical for insulin receptor recognition and it is in this region that amino acids have been substituted74 (Figure 8). Thus, the insulin analogs are recognized by the insulin receptor and bind to the receptor with similar affinity as native insulin. Insulin lispro

Types of insulin

Human insulin is available in rapid, short, intermediate, and long-acting forms (regular, NPH, lente, and ultralente). In addition, five insulin analogs are currently available for clinical use (insulins aspart, lispro, glulisine, detemir, and glargine). 6.19.6.5.3.1 Rapid-acting insulin analogs (lispro, aspart, and glulisine) Changes in the amino acid sequence of the insulin analogs lispro, aspart, and glulisine reduce the tendency to self-associate into hexamers, resulting in more rapid onset and a shorter duration of action compared to regular human insulin. Insulin lispro (Humalog) has a reversal of amino acid sequence at the B28 (proline) and B29 (lysine) positions, resulting in insulin lysine-proline. Insulin aspart (Novolog) has a B28 amino acid proline substitution with aspartic acid. Insulin glulisine (Apidra) has two amino acid substitutions and differs from human insulin in that B3 asparagine is replaced by lysine, and B29 lysine is replaced by glutamic acid.78 Table 9...

Type 1 diabetes

As b-cell function fails, individuals with T1DM require exogenous insulin for survival. Daily insulin requirements are usually between 0.5 and 1.0 units kg_ 1. During the early stages of T1DM, residual levels of endogenous insulin can reduce the daily insulin requirements below this range. Intensive insulin therapy, defined as > 3 insulin injections daily, provides more flexibility of lifestyle and often better glycemic control in individuals with T1DM than is achieved with 1-2 daily insulin injections.

Insulin Therapy

Insulin Effects

Insulin is synthesized in the B- (or p-) cells of the pancreatic islets of Langerhans. It is a protein (MW 5800) consisting of two peptide chains linked by two disulfide bridges the A chain has 21 and the B chain 30 amino acids. Insulin is the blood-sugar lowering hormone. Upon ingestion of dietary carbohydrates, it is released into the blood and acts to prevent a significant rise in blood glucose concentration by promoting uptake of glucose in specific organs, viz., the heart, adipose tissue, and skeletal muscle, or its conversion to glycogen in the liver. It also increases lipogenesis and protein synthesis, while inhibiting lipo-lysis and release of free fatty acids. Insulin is used in the replacement therapy of diabetes mellitus to supplement a deficient secretion of endogenous hormone. Sources of therapeutic insulin preparations (A). Insulin can be obtained from pancreatic tissue of slaughtered animals. Porcine insulin differs from human insulin merely by one B chain amino acid,...

In Diabetes

As mentioned above there is circumstantial evidence that nitrosative stress and peroxynitrite formation importantly contribute to the pathogenesis of diabetic cardiomyopathy both in animals and humans. We have tested a novel metalloporphyrin peroxynitrite decomposition catalyst, FP15, in murine models of diabetic cardiovascular complications (92). We hypothesized that neutralization ofperoxynitrite with FP15 would ameliorate the development of cardiovascular dysfunction in a STZ-induced murine model of diabetes. To ensure that the animals received the FP15 treatment at a time when islet cell destruction was already complete and hyperglycemia has stabilized the treatment was initiated 6 weeks after the injection of STZ. Although FP15 did not affect blood glucose levels, it provided a marked protection against the loss of endothelium-depen-dent relaxant ability of the blood vessels (Fig. 1A) and improved the depression of both diastolic (Fig. 1B) and systolic function of the heart (92)....

Regular insulin

Pork Iletin II M, Insulin-Toronto M, Regular Iletin II, Regular Purified Pork Insulin. Beef Pork Iletin M, Regular Iletin I. Human Humulin-R M, Novolin R, Novolin R PenFill, Novolin R Prefilled, Velosulin Human BR OTC Classification Rapid-acting insulin See also Antidiabetic Agents Insulins. Action Kinetics Rarely administered as the sole agent due to its short duration of action. Injections of 100 units mL are clear cloudy, colored solutions should not be used. Regular insulin is the only preparation suitable for IV administration. Available only as 100 units mL. Onset, SC 30-60 min IV 10-30 min. Peak, SC 2-4 hr IV 15-30 min. Duration, SC 6-8 hr IV 30-60 min. Uses Suitable for treatment of diabetic coma, diabetic acidosis, or other emergency situations. Especially suitable for the client suffering from labile diabetes. During acute phase of diabetic acidosis or for the client in diabetic crisis, client is monitored by serum glucose and serum ketone levels. How Supplied Insulin...

Christoph Hasslacher and Sonja

Diabetic Nephropathy Information and advice for people with diabetes, their families and carers First published in German as Diabetes und Niere 1999 Verlag Kirchheim+Co GmbH, Mainz Translated into English by Dr. Joan Marsh Diabetes und Niere. English Diabetes and the kidney Christoph Hasslacher and Sonja B hm. p. cm. First published in German as Diabetes und Niere. Includes bibliographical references and index. ISBN 0-470-02158-6 (pbk. alk. paper)

Preface to the First Edition

The cause of diabetes mellitus is metabolic in origin. However, its major clinical manifestations, which result in most of the morbidity and mortality, are a result of its vascular pathology. In fact, the American Heart Association has recently stated that, from the point of view of cardiovascular medicine, it may be appropriate to say, diabetes is a cardiovascular disease (1). But diabetic vascular disease is not limited to just the macrovasculature. Diabetes mellitus also affects the microcirculation with devastating results, including nephropathy, neuropathy, and retinopathy. Diabetic nephropathy is the leading cause of end-stage renal disease in the United States, while diabetic retinopathy is the leading cause of new-onset blindness in working-age Americans. The importance of this text on Diabetes and Cardiovascular Disease is evident by the magnitude of the population affected by diabetes mellitus. Over 10 million Americans have been diagnosed with diabetes mellitus, while...

Management of diabetic kidney

4.1 The benefits of good blood sugar control 23 How failing kidney function affects diabetes management 29 When blood pressure is too high in people with diabetes 35 4.4 Smoking - a particularly dangerous habit for diabetics 51 5 Diabetics with kidney failure are threatened in other ways 61 5.1 How diabetes can affect your sight 61 in women with diabetes 85 8.1 Pregnancy and diabetic nephropathy 95 When diabetic nephropathy is already present 97 8.2 Sport and diabetic nephropathy 100 Diabetes and kidney organizations 127 Diabetes information websites in other languages 131 The treatment of diabetes mellitus has improved markedly over the past two decades. With different education programmes, very precise meters for measuring blood sugar levels and blood pressure in the clinic and at home, new drugs, new insulins, and simple injection devices (pens), doctors and patients today have many methods of controlling blood glucose concentrations. In recent years, this has undoubtedly led to a...

How can we explain such a development

There are many causes on the one hand, the longer life expectancy and the growing number of patients with diabetes certainly contribute to the higher number of dialysis patients. On the other hand, the risk of developing diabetes-associated kidney disease was certainly underestimated. Ten or 15 years ago, diabetic nephropathy was viewed almost exclusively as a complication of Type 1 diabetes. Today, we know that patients with Type 2 diabetes, who are far more numerous, face the same risk of suffering kidney failure. Now, most patients who develop kidney damage and need to undergo dialysis have Type 2 diabetes.

Activation of the Polyol Pathway

Increased activity of the polyol pathway has been documented in culture studies using vascular cells exposed to diabetic level of D-glucose and in animals with diabetes (58,59). In these studies, hyperglycemia has been shown to increase the activity of aldose reduc-tase and enhances the reduction of glucose to sorbitol, then further oxidized to fructose by sorbitol dehydrogenase. Abnormality in the polyol pathway has been suggested to cause vascular damage in the following ways (a) osmotic damage by the accumulation of sorbitol (58) (b) induction of oxidative stress by increasing nicotinamide adenine dinucleotide phosphate (NADP) NAD+ ratio and the activation of Na+ K+ adenosine triphosphate (ATP)ase (59) and (c) reduction of NO in the vasculature by decreasing cellular NADPH, a cofactor used by aldose reductase to reduce glucose to sorbitol (60). Multiple studies have shown that inhibition of aldose reductase, the key enzyme in the polyol pathway, could prevent the some pathological...

Alteration in Oxidative Stress

Several lines of evidence support a role of increased oxidative stress in the pathogenesis of diabetic vascular complications. Reactive oxygen species, an index of oxidative stress, has been reported to be increased and in diabetic patients with retinopathy (65) and other cardiovascular complications in the Framingham Heart Study (66) and correlate with the severity of these diseases. Furthermore, these results have been recapitulated in diabetic animals or even in vascular cells cultured in media containing high levels of D-glucose (59,64). Induction of oxidative stress has been suggested to induce vascular dysfunctions via multiple approaches including cellular DNA damage by activating the poly(ADP-ribose) polymerase (67,68) reduction of NO bioavailability (59), and the activation of other mechanisms known to induce vascular cell damage such as AGE formation, PKC activation, and induction of polyol pathway (69). Additionally, evidence has shown that reactive oxygen species can cause...

Activation of the Dagpkc Pathway

DAG can be generated from multiple pathways. Agonist-induced formation of DAG depends mainly on hydrolysis of phosphatidylinositol by phospholipase C (84). However, this mechanism is most likely minimally involved in diabetes, because inositol phosphate products were not found to be increased by hyperglycemia in aortic cells and glomerular mesangial cells (85,86). When the fatty acids in DAG were analyzed (87), DAG induced by high-glucose condition has predominantly palpitate- and oleic- acid-enriched composition, whereas DAG generated from hydrolysis of phosphatidylinositol has the composition of 1-stearoly-2-arachidonyl-5N-glycerol (88). In labeling studies using 6-3H - or U-14C - glucose, we have shown that elevated glucose increase the incorporation of glucose into the glycerol backbone of DAG in aortic endothelial cells (87), aortic SMCs (89), and renal glomeruli (90). These facts indicate that the increased DAG levels in high-glucose condition are mainly derived from the de novo...

What can we do about it

We know a lot about the course of diabetic kidney disease and about the factors that influence it. If we could combine that knowledge with the therapeutic opportunities currently available, diabetic nephropathy would soon cease to be a threat. Diabetic patients can do much for themselves. To say this even more clearly without the participation of patients, we will not be able to fight nephropathy. This book is primarily for people with diabetes, their families and carers. It describes the development of nephropathy and shows the possibilities for prevention, for early diagnosis and, of course, for the treatment of this complication. It also contains abundant information about 'Diabetes and the Kidney'. We hope that this book will help motivate many patients to take responsibility for the prevention and treatment of their disease.

Vascular Contractility and Blood Flow

Hemodynamic abnormalities such as blood flow and vascular contractility have been reported in many organs of diabetic animals or patients, including the kidney, retina, peripheral arteries, and microvessels of peripheral nerves. In the retina of diabetic patients and animals with a short duration and without clinical retinopathy, blood flow has been shown to be decreased (119-123). One possible explanation for the decreased retinal blood flow in early stage of diabetes is as a result of an increase in vascular resistance at the microcirculatory level induced by PKC activation. We have reported that the decreased retinal blood flow can be mimicked by intravitreous injection of phorbol esters, which are PKC activators (78). Furthermore, decreases in retinal blood flow in diabetic rats have been reported to be normalized by PKC inhibitors (90). In addition to the retina, decreases in blood flow have also been reported in the peripheral nerves of diabetic animals by most investigators...

Vascular Permeability and Neovascularization

Increased vascular permeability is another characteristic vascular abnormality in diabetic patients and animals, in which increased permeability can occur at as early as 4-6 weeks' duration of diabetes, suggesting endothelial cell dysfunctions (139). Because the vascular barrier is formed by tight junctions between endothelial cells, the increase in permeability as a result of the abnormalities in the endothelial cells. The activation PKC can directly increase the permeability of albumin and other macromolecules through barriers formed by endothelial cells, probably by phosphorylating the cytoskeletal proteins forming the intercellular junctions (140-142). Recently, PKC- 1 overexpression in human dermal microvascular endothelial cells has been reported to enhance phorbol ester-induced increase in permeability to albumin (143). Thus, the actions of phorbol ester and hyperglycemia in endothelial-barrier functions are mediated in part through activation of PKC- 1 isoform. PKC activation...

Basement Membrane Thickening and Extracellular Matrix Expansion

Thickening of capillary basement membrane is one of the early structural abnormalities observed in almost all the tissues, including the vascular system in diabetes (151). Because basement membrane can affect numerous cellular functions, such as in structure support, vascular permeability, cell adhesion, proliferation, differentiation, and gene expression, alterations in its components may cause vascular dysfunctions. Histologically, increases in type IV and VI collagen, fibronectin and laminin and decreases in proteoglycans are observed in the mesangium of diabetic patients with nephropathy and probably in the vascular endothelium in general (152,153). These effects can be replicated in mesangial cells incubated in increasing glucose levels that were prevented general PKC inhibitors (154-156). Additionally, increased expression of transforming growth factor (TGF)- P has been implicated in the development of mesangial expansion and basement membrane thickening in diabetes. Because PKC...

Melpomeni Peppa md Jaime Uribarri md and Helen Vlassara md

The incidence of diabetes, especially type 2 diabetes, is increasing at an alarming rate assuming epidemic proportions (1). Worldwide, 124 million people had diabetes by 1997, although an estimated 221 million people will have diabetes by the year 2010 (1). Diabetic patients may suffer a number of debilitating complications such as retinopa-thy, nephropathy, neuropathy, and atherosclerosis resulting in cardiovascular, cere-brovascular, or peripheral vascular disease. These diabetic complications lead to huge economic and psychosocial consequences. Although the pathogenesis of type 1 diabetes is different from that of type 2 diabetes, the pathophysiology of vascular complications in the two conditions appears to be similar. Two landmark clinical studies, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study, showed that intensive control of hyperglycemia could reduce the occurrence or progression of retinopathy, neuropathy and nephropathy...

Endogenous Advanced Glycoxidation End Products Formation

It is now appreciated that normal living is associated with spontaneous chemical transformation of amine-containing molecules by reducing sugars in a process described since 1912 as the Maillard reaction. This process occurs constantly within the body and at an accelerated rate in diabetes (5,6). Reducing sugars react in a nonenzymatic way with free amino groups of proteins, lipids, and guanyl nucleotides in DNA and form Schiff base adducts. These further rearrange to form Amadori products, which undergo rearrangement, dehydration, and condensation reactions leading to the formation of irreversible moieties called AGEs. Among all naturally occurring sugars, glucose exhibits the slowest glycation rate, although intracellular sugars such as fructose, threose, glucose-6-phosphate, and glyceraldehyde-3-phosphate form AGEs at a much faster rate (5,6,14).

Exogenous Sources of Advanced Glycoxidation End Products

Animal studies have demonstrated the close relationship between increased dietary AGE intake and development and or progression of many diabetes-related complications. Nephropathy, postinjury restenosis, accelerated atherosclerosis, and delayed wound healing were significantly inhibited by lowering dietary AGE intake (27-30). Sebekova and associates demonstrated in the remnant-kidney rat model that feeding an AGE-rich diet for 6 weeks increases kidney weight and causes proteinuria, independent of changes in glomerular filtration rate, pointing to the detrimental effect of such diet on the kidney (31). Of particular interest are studies showing that a low-glycotoxin environment can prevent or delay significantly autoimmune diabetes in successive generations of nonobese diabetic (NOD) mice (32) and to improve the insulin-resistant state in db db (+ +) mice (33). Reduction in exposure to exogenous AGEs of db db (+ +) mice, lacking in leptin receptor and thus prone to insulin resistance...

Advanced glycoxidation endproducts metabolism

Cells such as tissue macrophages can ingest and degrade AGEs via specific or nonspecific receptors (5,6,41). Mesenchymal cells such as endothelial and mesangial cells seem to participate also in AGE elimination (42). It has been postulated that insulin may accelerate macrophage scavenger receptor-mediated endocytic uptake of AGE proteins through the IRS PI3 pathway (43). Cellular removal of AGEs is processed largely through endocytosis and further intracellular degradation resulting in the formation of low-molecular-weight AGE peptides, which are released to the extracellular space and circulation (5,41,44). These peptides undergo a variable degree of reabsorption and further catabolism in the proximal nephron and the rest is excreted in the urine. Therefore, effective AGE elimination is dependent on normal renal function (5,41,44,45). We have recently found that diabetic patients with normal renal function have a significantly lower urinary AGE excretion than healthy controls. This...

Advanced glycoxidation endproducts interactions

The first cell surface AGE-binding protein receptor identified was AGE-R1, with characteristic membrane-spanning and signal domains homologous to a 48kD component of the oligosaccharyltransferase complex-48 (5,41,50-52).This component has recently been shown to be linked to AGE removal and supression of undue oxidative stress and cell-activation events (53). An 80kD protein or AGE-R2, identical to a tyrosine-phospho-rylated protein located largely within the plasma membrane was found involved in binding and forming complexes with adaptor molecules such as Shc and GRB-2. AGEs are highly efficient stimuli for AGE-R2 phosphorylation indicating its possible involvement in AGE-signaling (5,41,54-57). AGE-receptor-3 or Galectin-3, known as Mac-2 or carbohydrate-binding protein-35, is also known to interact with the P-galactoside residue of several cell surface and extracellular matrix (ECM) glycoproteins, via the carbohydrate recognition domain (5,41,54-58). AGE-R3 or Galectin-3 is only...

Advanced Glycoxidation End Product Crosslink Breakers

Recently, a promising therapeutic strategy has been to attack the irreversible intermolecular AGE crosslinks formed in biological systems providing prevention or reversal of various diabetes- and aging-related complications. This approach aims to break preaccumulated AGE and help renal elimination of resulting smaller peptides. PTB was originally studied (187) and more recently ALT-711 (8,13,188). Long-term studies are in progress to establish the safety of this new category of anti-AGE agents

Factors that influence the development of nephropathy

Whether nephropathy ever develops and how rapidly it progresses vary immensely from patient to patient. For some, the risk of kidney damage increases with the duration of diabetes, but the risk does fall when the diabetes is continuously well controlled. For others, however, hereditary factors are also important. Even among those who have high blood sugar levels for years, there are some people who never develop nephropathy. On the other hand, there are people with fairly good diabetes control who nevertheless develop kidney damage. We know that children from families with diabetes in which one member already has a renal problem have a much higher risk, from the onset, of developing nephropathy. Unfortunately, there is as yet no definite known marker in the blood or the urine that can predict the risk of developing nephropathy for an individual patient. This would naturally be a great help, as patients at higher risk could then be managed much more intensively.

Pressure and Hemodynamic Effects

Diabetic vascular complications (102), it is likely that the BP-lowering effects of ACE inhibitors are a major contributor to the reduction of vascular complications in diabetic patients with hypertension (9,93). However, there is growing evidence that ACE inhibitors may also provide beneficial vascular effects in diabetes in the absence of systemic hypertension. Several large studies have demonstrated that ACE inhibition can reduce renal, retinal, and cardiovascular complications in normotensive diabetic patients (1,5,8). Although a small reduction in systemic BP within the normotensive range may contribute to the vasoprotective effects of ACE inhibition, the magnitude of these effects is greater than that which would be predicted based on the magnitude of these BP-lowering effects alone. Local upregulation or sensitization of the RAS can result in tissue specific increases in Ang II action, which may not significantly affect systemic BP. These local changes in the RAS can affect...

Intravascular Actions of the Renin Angiotensin System

In addition to its potent effects on vasoconstriction and BP control, Ang II also exerts a variety of effects on vascular biology, which are independent of vascular tone and pressure. AT1 receptors are expressed in most vascular cell types, including endothelial and VSMCs, cardiomyocytes, and cardiac fibroblasts (23). Activation of these receptors affects a diverse array of vascular cell functions including growth, migration, oxidant production, and gene expression (100). Overproduction of Ang II and or increased Ang II sensitivity within the vasculature tissues may stimulate these cellular processes and thereby contribute to vascular remodeling, hypertrophy, fibrosis, thrombosis, and atherosclerosis. Consistent with this hypothesis, ACE inhibition and AT1 blockade have been shown to reduce perivascular fibrosis, PAI-1, and matrix metalloprotease expression in normotensive insulin-resistant diabetic rodents (112,113). Additionally, AT1 antagonism has been shown to reduce neointimal...

Endothelium Dependent Vasodilatation

Endothelial dysfunction associated with impaired production and or stability of NO occurs in both type 1 and type 2 diabetics (79,80), and in obese insulin-resistant subjects (119). Multiple mechanisms contribute to the impairment in endothelium-dependent vasorelaxation in diabetes, including the oxidative inactivation of NO, reduced eNOS expression, reduced eNOS activity, vascular insulin resistance, elevation of circulating levels of asymmetric dimethylarginine (an endogenous NOS inhibitor), and a deficiency in tetrahydrobiopterin, a cofactor for eNOS (120-126). Both ACE inhibition and ATI receptor antagonism improves acetylcholine-induced vasorelaxation in NIDDM subjects (127,128). Treatment of normotensive type 1 diabetics with an ACE inhibitor has also been shown to increase acetylcholine-induced vasorelaxation in (129,130). In these studies, no difference in vasodilatation induced by NO donors (sodium nitroprusside) was observed in diabetic vs control subjects, suggesting that...

Vicious circle of the progression of nephropathy

Figure 2.7 If the kidney corpuscles are damaged through diabetes, a vicious circle develops ever fewer corpuscles have to do ever more work higher rates of protein deposition and higher blood pressure lead to the corpuscles being destroyed more rapidly. Damage to tfie corpuscles through diabetes Figure 2.7 If the kidney corpuscles are damaged through diabetes, a vicious circle develops ever fewer corpuscles have to do ever more work higher rates of protein deposition and higher blood pressure lead to the corpuscles being destroyed more rapidly. Since this is not yet possible, patients and doctors must all try to reduce, or at least to retard, kidney damage via the factors that we can influence. The most important is good blood sugar control and good management of high blood pressure. Sometimes, it is helpful to eat less protein. If that is not enough, protein excretion in the urine and its detrimental effects can be treated with special medicines. Levels of blood fats should not be...

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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