New Concepts in Diabetes and its Treatment

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Introduction

  In contrast to the most common form of type 1 diabetes, linked to environmental factors (formerly called type IA), in approximately10% of all cases of type 1 diabetes (more frequently in females, with HLA-DR3, from 30 to50 years of age), the disease is a primary autoimmune disorder(previously called type IB) and is associated to other endocrine and nonendo- 65 (autoantibodies to tyrosine phosphatase). Manifest type 1 diabetes is characterized by symptoms linked to the marked hyperglycemia, such as polyuria (due to the osmotic effect of glucose), polydipsia (to compensate for the water lost with polyuria),polyphagia (to compensate for the energetic substrate glucose lost in the urine), weight loss and fatigue (due to loss of glucose in urine and to dehydration),and blurred vision (due to lens osmotic disturbances).

Any disease process affecting the pancreas may involve the islets and pro- duce diabetes (table 1). May we recall the fibrocalculous pancreatopathy, that

  According to the revised criteria by the Expert Commit- tee [1997], the ‘normal values’ and the ‘diagnostic values’ for diabetes (whichdo not coincide with the goals of therapy) are as follows (values given in the text refer to venous plasma glucose which is the preferred measurement;equivalents for whole blood and capillary glucose estimations, according to the IDF guidelines [1999] to type 2 diabetes, are indicated in footnotes). FPG and 2-hour OGTTvalues are equivalent for the diagnosis of diabetes (even if not perfectly corre- lated with each other), and actually the FPG alone is preferable for its betterreproducibility (6% variation) whereas OGTT, repeated in adults during a 2- to 6-week interval, presents an intraindividual coefficient of variation of 17%for the 2-hour value.

Acute or chronic illness: OGTT should not be performed in patients affected by acute infections, acute cardiovascular and cerebrovascular diseases

  According to the IDF guidelines [1999] to type 2 diabetes, HbA can be useful for the diagnosis 1c provided that confirmatory venous plasma glucose estimations are obtained, the assay is DCCT standardized, an HPLC chromatogram is reviewed forpresence of abnormal hemoglobins, and erythrocyte turnover is not abnormal. Suggested ReadingExpert Committee on the Diagnosis and Classification of Diabetes mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes mellitus.

Chapter II Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 20–37 . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin Secretion and Its Pharmacological Stimulation F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Insulin Secretion Introduction Pancreatic b-cells synthesize a large polypeptide chain, the proinsulin

  Its presence in the liver allows this organ to take up glucose when glycemia in the portal vein increases (such as during the absorption In order to stimulate insulin release, glucose must first be transported into the b-cell by the glucose transporter (GLUT-2 isoform), and then phos-phorylated by GK to produce glucose-6-P. The parasympathetic innervation of the pancreas may also trigger the release of vasoactive intestinal polypeptide (VIP), which stimulates thesecretion of insulin (and glucagon) while increasing the blood flow to the pancreas and the external pancreatic secretion.

MAX mal b-cell sensitivity to the potentiation effect of glucose

  Studies of genes involved in insulin secretion or insulin action havebeen successful to a certain extent by showing the implication of the insulin- receptor substrate-1 (IRS-1) gene, the ras associated with diabetes (rad) gene,the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (among others) in a low percentage of cases of type 2 diabetes in particular populations. Prostaglandins may also be implicated, as suggested by the improvement of insulin response to intravenous glucose and the increase of the slope of It has been proposed that at least one factor contributing to the pathogen- esis of type 2 diabetes is desensitization of the GLP-1 receptor on b-cells.

Side or Adverse Effects of Sulfonylureas. The most important adverse effect

Other sulfonylurea side effects or toxic reactions occur at low rate (1.5% for glyburide) (table 5) and appear within the first 2 months of treatment. The

  However, by increasing the insulin level, the number of insulin molecules that bind tothe receptors can be increased toward the normal and therefore the insulin effects can be restored; moreover, by increasing further the insulin level, themaximum effect can be reached. On the other hand, when the insulin resistance is due to defects in postreceptor steps of insulin action (see below), the dose-response curve isflattened and the maximum insulin effect is not reached even at very high insulin concentrations.

In particular, insulin (or, better, its prevalence over the counterregulatory hormones) exerts the following effects (fig. 1):

  Thus, the overall action of insulin is (1) to increase glucose utilization in muscle, liver and adipose tissue while depressing glucose production in theliver, which results in blood glucose lowering; (2) to lower FFA level by refraining lipolysis, and (3) to prevent ketone formation in the liver by opposingketogenesis. In type 2 diabetic patients, insulin resistance is due to impaired insulin action either at receptor and postreceptor level, and may result from twoetiological components, the genetic background and some acquired factors, of which overweight and obesity are certainly the most important ones.

VLDL-ApoB production. Resistance to the normal suppressive effect of insulin, in addition to other metabolic abnormalities associated with insulin resistance

  In fact, the utilization of FFA (tendencially enhanced in obesity, because of the trend to high plasma FFA levels) leads to the formation of long-chainCoA or acyl-CoA (LC-CoA) in the cytosol, followed by the entry of LC-CoA into the mitochondria through the action of the enzyme carnitine palmitoyltransferase-1 (CPT-1) and by the b-oxidation of LC-CoA to acetyl-CoA. On the other hand, in a prospective (15 years) study it was found that capillary density was increased rather than decreased in subjects with impaired In healthy young men, there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity (clamp technique) asa part of the insulin resistance syndrome, which supports the hypothesis that insulin resistance has a hemodynamic component.

Upon insulin administration, some degree of ‘resistance’ (reduced effect) may occur until the enzyme balance is normalized, i.e. until the amount of those

  When the type 1 diabetic patient becomes severely decompensated and ketoacidosis supervenes, the insulin action may be further disturbed by theinterference of the acidosis with insulin binding to its receptor as well as by the reduced response of the intracellular enzymes caused by the hyperosmolality. Metformin action on fibrinolysis and von Willebrand factor(vWF) was evaluated in the ‘Biguanides and the Prevention of the Risk ofObesity (BIGPRO)1’ trial; weight loss was the main factor associated with the decrease in PAI-1, in accordance with the recent demonstration of produc-tion of PAI-1 by adipocytes.

Chapter IV Diet and Modification of Nutrient Absorption S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Diet Introduction In the treatment of diabetes mellitus, changes in lifestyle play a major

  It has also been estimated that a waist girth of approximately 95 cm in both sexes, WHR values of 0.94 in men and of 0.88in women, and sagittal diameters of 22.8 cm in men and 25.2 cm in women correspond to a critical amount of visceral adipose tissue, equal to a fat area 2 of 130 cm . After the caloric content and the composition of the diet are established, the prescription of adiet was in the past made by utilizing the data in the Exchange Lists for MealPlanning published by the American Diabetes Association.

It is well established that equimolar amounts of carbohydrate in different foods induce different glycemic postprandial excursions. Jenkins et al. [1981]

  However, threeconsiderations speak against an excessive intake of fish or fish oil: (a) fishes of coastal waters and lakes accumulate a large quantity of mercury and chlori-nated hydrocarbons; (b) in some type 2 diabetic patients, 3-omega fatty acids may deteriorate glycemia (both increasing hepatic glucose production andimpairing insulin secretion), and (c) in patients with hypercholesterolemia but without hypertriglyceridemia the metabolic effects of fish oil are uncertain. Leucine and arginine have important biologic effects, stimulating insulin The role of dietary protein in the development and progression of diabetic nephropathy is debated while it is clearly defined that a moderately low proteindiet is the best approach for treating renal disease of diabetic patients (see chapter on Diabetic Nephropathy).

It is interesting that fibers have the best effects when naturally contained in aliments while they have poorer effects when added as pharmaceutical

  Hypocaloric Diet in Overweight Type 2 DiabetesIn type 2 diabetes, caloric restriction should be correlated with the degree of overweight or obesity, and the calculation of appropriate calories dependsupon the body weight and the physical activity of the patient. On the otherhand, a proper nutritional management of obese diabetic patients is the most Modification of Nutrient AbsorptionAgents capable of modifying the absorption of complex carbohydrates or lipids, such as a-glucosidase inhibitors and Orlistat, will be discussed in Chapter VI (Overview of Diabetes Management).

Species: Bovine insulin differs from human insulin because it contains

  It is effective in blunting elevations in glucose following meals and for rapid adjustments in insulindosage, but the pharmacokinetics of rapid-acting insulins entails that a definite time interval is observed between insulin injection and eating. Intermediate-acting NPH insulin presents a delayed onset of action(3–4 h), a delayed peak of activity (8–12 h) and a duration of action of 20–24 h; similar activity is possessed by the lente insulin.

Recently, to improve the outcome of insulin therapy and to use human insulin products with more physiological effect, a short-acting monomeric

  The insulin lispro in appropriate dosage may result in a profile of insulin close to the physiological one and is suitable for treating both type1 and type 2 diabetic patients under intensive insulin therapy. When a mixture of lente and regular insulins is used, the excess of zinc tends to bindto regular insulin and may cause precipitation of regular insulin out of solution, delaying its absorption and blunting its quick-acting effect.

Patients should inject insulin in the different locations at the same time each day, i.e. in the abdomen in the morning to optimize insulin delivery and in

  It should be underlined that the physiologically secreted insulin enters the portal vein and is taken up in substantial amount by the liver, so thatonly the remaining amount reaches the general circulation and is distributed to the peripheral tissues. Some patients (about 1/3 of type 1 diabetic patients) may experience early in the course of disease a brief honeymoon period, during which there is apartial recovery of b-cell function and a transient or a prolonged fall in the exogenous insulin requirement (=0.5 U/kg/day).

In sufficiently motivated diabetic patients, an alternative that provides a greater flexibility of insulin treatment (minimizing variations in its absorp-

  Very fewcases were reported with recombinant human insulins, and the reason why it Insulin Lipohypertrophy It consists of visible or palpable increase of localized subcutaneous fat(most prevailingly in the anterior or lateral part of thighs) at the site of insulin injection, sometimes coexisting with lipoatrophy. The aim of education and training is to provide adequateinformation in a simple form suitable to the ability of the subject, in order to allow the diabetic patients to develop the required knowledge to self-managetheir disease and to ensure an optimal and appropriate use of insulin therapy(and other therapeutical measures).

HLA phenotype DR3/DR4, characteristics which suggest that these diabetic patients may actually be affected by late-onset type 1 diabetes. Among the first-

  This intervention is suggested in the predia- betic state (before the autoimmune b-cell destruction) and is directed to the following goals: to prevent the induction of diabetogenic T lymphocytes (orto delete these cells), to induce regulatory cells which inhibit these diabetogenic lymphocytes, and to induce immunological tolerance to autoantigens. Gene Therapy It is the frontier of immunological therapy in diabetes mellitus and is directed to express regulatory cytokines (such as IL-4, IL-10 and TGF-b) orautoantigens in the thymus (selection of T cells in the thymus results in deletion of cells that cause autoimmunity), thus preventing or delaying type 1 diabetes.

Chapter VII Clinical Emergencies in Diabetes. 1: Diabetic Ketoacidosis and Hyperosmolar Nonketotic Syndrome F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Diabetic Ketoacidosis Diabetic ketoacidosis (DKA) is the classical acute metabolic complication

  In DKA, the increased anion gap is due to thefall in bicarbonate (6–10 mmol/l) caused by the accumulation in the blood of the ketone bodies (acetoacetate and b-hydroxybutyrate), with minimal contri-+ bution of lactate and FFA. Since lipolysis is more sensitive toinsulin than the glucose homeostatic mechanisms, it is possible that the residual insulin secretion, while unable to stimulate glucose utilizaton and to represshepatic glucose production, is able to refrain lipolysis, thus limiting the FFA afflux to liver and therefore the ketogenic process.

DKA). (4) There may be an enhanced activity of the Cori cycle, with increased afflux of lactate to the liver, where it may be in part metabolized to malonyl-

  Therapy may be started by intravenous infusion of saline at the rate of 1.5 liters/h for the first 2 h, followed by infusion of 0.5liter/h of half-normal saline (0.45%) adjusted according to the clinical and laboratory response. Attention should also be paid to the possible development of infections or thrombosisor DIC to start timely the appropriate therapy.

Chapter VIII Clinical Emergencies in Diabetes. 2: Hypoglycemia F. Belfiore, S. Iannello Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy Definition The term hypoglycemia refers to a biochemical condition resulting from an

  (2) Artifactual hypoglycemia as it may occur in hemolytic anemia or in leukemia and leukemic reactions (due to overutilization of glucose in the testtube by young erythrocytes or leukemic leukocytes) or in the presence of marked hyperlipemia (which may cause a 15% – or more – underestimationof glucose concentration). (4) Assay of sulfonylurea compounds in plasma or urine to diagnose factitious hypoglycemia induced by these drugs.(5) Five-hour oral glucose tolerance test (5h-OGTT), useful for the diag- nosis of reactive hypoglycemia in about 50% of cases (it is not a specific test,as it may be positive both in normal persons and in subjects with pseudohypo- glycemia).

Chapter IX Mechanisms of Diabetic Complications (Nephropathy) as Related to Perspectives of Treatment Mark E. Cooper Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre (Repatriation Campus), West Heidelberg, Vic., Australia Introduction Diabetic nephropathy (DN) is characterized by a number of functional

  Although the renal complications of diabetes hadalready been described in the 18th century, it is only over the last 20 years that the mechanisms linking chronic hyperglycemia to the development of DNhave begun to be unravelled (fig. 1). The first binding site to be cloned has been termed RAGE, this proteinhaving been detected by immunohistochemistry by our group in the kidney, primarily in distal tubules and to a lesser extent in glomeruli.

Since aminoguanidine also inhibits other biochemical pathways and in particular acts as an inhibitor of inducible NO synthase, it has been difficult

  The increased formation andaccumulation of sorbitol in these tissues is accompanied by a depletion of free + + +myoinositol, loss of Na ,K -ATPase activity, and increased consumption of the enzyme cofactors NADPH and NAD , leading to changes in cellular redoxpotential. This would imply an imbal-ance in the actions of vasoconstrictors and vasodilators in the diabetic kidney and has resulted in a large body of research focusing on a range of vasoactivehormones and their receptors in the genesis not only of the initial hemodynamic abnormalities but also on the subsequent glomerular ultrastructural injury.

Evidence of a role for the RAS in the genesis of diabetic complications has been provided by a range of studies using different experimental techniques

  Indeed, in a series of experi-ments using molecular biological and immunohistochemical techniques in an animal model of renal disease, the subtotal nephrectomy model, which hasmany functional and structural similarities to diabetic nephropathy, our group has shown that with renal injury there is de novo expression of various compo-nents of the RAS including renin and AII within the kidney. More recent studies have suggested that other vasoactive hormone systems including the natriuretic hormones such as atrial natriuretic peptide, the kal-likrein-kinin system and the potent vasoconstrictor, endothelin (ET), may also have important roles in the genesis of the hemodynamic and trophicabnormalities which are observed in organs undergoing diabetic vascular injury such as the kidney.

In some cases the vasostimulatory cytokines released in the retinal periph- ery diffuse to the anterior eye chamber to cause neovascularization in the iris

  When the oedema, the exudates, and the haemorrhages extendtowards the fovea, central vision may become threatened, partly by blocking light access to the retinal photoreceptors, and partly because of a direct de-structive effect on the neuronal components of the retina. The disadvantages of this method is that the severity of the retinal lesions cannot be documented in detail, that the retinal changes are difficult to quan-tify, and that the quality and conclusion of the examination depend on the experience and attitude of the examiner.

During the last decades, increasing focus has been directed at a different technique to screen for diabetic retinopathy by examination of the ocular back-

  Organization In order to ensure that screening efforts are efficient it is necessary that:(1) the health system is organized to permit the establishment of efficient screening programmes; (2) sufficient resources are made available in the short term (theywill always pay back in the long term); (3) qualified personnel is available to carry out the screening examinations and evaluations, and (4) patients are taught aboutthe advantages of screening, and are given motivation to participate. One of the most promising of thesemethods is optical coherence tomography that detects the phase shift of light reflected from different surfaces in the retina and transforms this signal to acolour code that expresses the reflectivity and depth of different retinal levels.

In diabetic maculopathy, laser treatment is applied corresponding to the lesions in the macular area. The treatment is performed differently dependent

  Theprinciple of the treatment strategy is to apply a laser grid pattern corresponding to the area with retinal oedema, however sparing a central zone out to approxi-mately 500 lm from the fovea. When the purpose of the operation is only to remove a vitreous haemorrhage, full restitution of the visual function to the level before the haemorrhage developed will often result, while permanent damage to the visual function will most often have developed when there is tractional retinal detachment.

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