Abc do diabetes

Abc do diabetes

(Parte 2 de 19)

Diabetes mellitus*

Impaired glucose tolerance

*In the absence of symptoms at least one additional abnormal blood glucose concentration is needed to confirm clinical diagnosis—for example, 1 hour value of 11mmol/l or more

ABC of Diabetes

Comparison of Type 1 and Type 2 diabetes

Type 1 diabetesType 2 diabetes

Inflammatory reaction in isletsNo insulitis Islet B-cells destroyedB-cells function

Islet cell antibodiesNo islet cell antibodies HLA relatedNot HLA related

Not directly inheritedStrong genetic basis (some cases)

Other specific types of diabetes

•Genetic defects of cell function—chromosome 12 hepatic nuclear factor-1 (HNF-1 ) (formerly maturity onset diabetes of the young (MODY) 3), chromosome 7 glucokinase defect (formerly MODY 2), chromosome 20 HNF-4 (formerly MODY 1), mitochondrial DNA mutation

•Genetic defects in insulin action—Type A insulin resistance (genetic defects in insulin receptor), lipoatrophic diabetes, genetic defects in the PPAR receptor • Gestational diabetes

•Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, carcinoma of pancreas, cystic fibrosis, fibro-calculous pancreatopathy, haemochromatosis

•Endocrinopathies—acromegaly, Cushing’s disease, Conn’s syndrome, glucagonoma, phaeochromocytoma, somatostatinoma

•Drug induced(these agents in particular exacerbate hyperglycaemia in patients with established diabetes)—corticosteroids, diazoxide, adrenergic agonists (for example, intravenous salbutamol), thiazides, interferon

•Uncommon forms of immune mediated diabetes—stiff man syndrome, anti-insulin receptor antibodies (Type B insulin resistance) • Infections—congenital rubella, cytomegalovirus

•Other genetic syndromes sometimes associated with diabetes—Wolfram syndrome, Down’s syndrome, Turner’s syndrome, Klinefelter’s syndrome, Prader-Willi syndrome elderly people, but diet, exercise and weight reduction are advisable in younger subjects. Over 10 years, approximately half of those with impaired glucose tolerance will develop diabetes, one-quarter will persist with impaired glucose tolerance, and one-quarter will revert to normal. Pregnant women with “impaired glucose tolerance” must be treated as if they were diabetic; for interpretation of the test in pregnancy seen page 80.

Types of diabetes

Type 1 diabetes (previously insulin dependent diabetes) is due to B-cell destruction, usually leading to absolute insulin deficiency). It can be immune mediated or idiopathic.

Type 2 diabetes (previously non-insulin dependent diabetes) ranges from those with predominant insulin resistance associated with relative insulin deficiency, to those with a predominantly insulin secretory defect with insulin resistance.

Type 1 and Type 2 diabetes are the commonest forms of primary diabetes mellitus. The division is important both clinically in assessing the need for treatment, and also in understanding the causes of diabetes which are entirely different in the two groups.

Type 1 diabetes Type 1 diabetes is due to destruction of B-cells in the pancreatic islets of Langerhans with resulting loss of insulin production. A combination of environmental and genetic factors that trigger an autoimmune attack on the B-cells is responsible, occurring in genetically susceptible individuals. Thus, among monozygotic identical twins only about one-third of the pairs are concordant for diabetes in contrast to the situation in Type 2 diabetes where almost all pairs are concordant. The process of islet destruction probably begins very early in life and is known to start several years before the clinical onset of diabetes.

HLA status The major histocompatibility complex antigens are adjuncts to several types of immunological activity. Ninety percent of Type 1 diabetic patients show either DR3 or DR4, or both together, while DR2 is protective against diabetes.

Autoantibodies and cellular immunity Islet cell antibodies are present at diagnosis in most Type 1 diabetic patients and gradually decline and disappear during the following years. Antibodies to specific proteins have more recently been identified: these include antibodies to glutamic acid decarboxylase (GAD, a 64-kDa antigen); and even closer association is found in the presence of antibodies to tyrosine phosphatase (37kDa, IA-2). The presence in a non-diabetic individual of three or more antibodies (islet cell antibodies, anti-GAD antibodies, anti-IA-2 antibodies, anti-insulin autoantibodies) indicates an 8% chance of developing diabetes within 10 years.

The presence of insulinitis at the onset of Type 1 diabetes represents the role of inflammatory cells (for example, cytotoxic T cells and macrophages) in B-cell destruction. Macrophages also produce cytokines leading to activation of lymphocytes known to be present at the onset of Type 1 diabetes.

Attempts have been made to prevent the onset of Type 1 diabetes. Immune suppression can to some extent preserve islet function, but permanent remissions are not normally achieved and the treatment is in any case too dangerous for routine use.

An islet with lymphocytic infiltration (insulitis)

The use of nicotinamide to prevent diabetes by altering macrophage function has not proved to be of benefit. Giving insulin itself may conserve islet function; the results of trials are awaited.

Associated autoimmune disorders The incidence of coeliac disease, Addison’s disease, hypothyroidism, and pernicious anaemia are increased in Type 1 diabetic patients, and appear to occur especially in those with persisting islet cell antibodies.

Risks of inheriting diabetes A child of a mother with Type 1 diabetes has an increased risk of developing the same type of diabetes, amounting to 1-2% by 25 years; the risk is about three times greater if the father has this disease. If both parents have the disease the risk is further increased and genetic counselling should be sought by these rare couples.

Type 2 diabetes There are numerous causes of Type 2 diabetes, which is now known to include a wide range of disorders with differing progression and outlook. The underlying mechanism is due either to diminished insulin secretion—that is, an islet defect, associated with increased peripheral resistance to the action of insulin resulting in decreased peripheral glucose uptake, or increased hepatic glucose output. Probably as many as 98% of Type 2 diabetic patients are “idiopathic”—that is, no specific causative defect has been identified. Whether decreasing insulin secretion or increasing insulin resistance occurs first is still uncertain, but the sequence of events may vary in different individuals. Obesity is the commonest cause of insulin resistance. Other rare insulin resistant states are shown in the table.

Some adults (especially those not overweight) over 25 years of age who appear to present with Type 2 diabetes may have latent autoimmune diabetes of adulthood (LADA) and become insulin dependent. Autoantibodies are often present in this group of patients.

Type 2 diabetes is a slowly progressive disease: insulin secretion declines over several decades, resulting in an insidious deterioration of glycaemic control which becomes increasingly difficult to achieve.

Obesity Relative insulin resistance occurs in obese subjects, perhaps because of down regulation of insulin receptors due to hyperinsulinaemia. Obese subjects have a considerably increased risk of developing Type 2 diabetes. Fat distribution is relevant to the development of diabetes, so that those who are “apple shaped” (android obesity, waist-hip ratio 0·9) are more prone to Type 2 diabetes than those who are “pear shaped” (gynoid obesity, waist-hip ratio 0·7).

The importance of leptin in the evolution of lifestyle related obesity is unclear. Leptin is a single chain peptide produced by adipose tissue and its receptors are expressed widely throughout the brain and peripheral tissues; when injected into leptin deficient rodents it causes profound hypophagia and weight loss. Plasma leptin levels rise in parallel with body fat content. Although very rare cases of morbid obesity due to leptin deficiency have been reported, and are shown to respond to leptin injections, there is in general an absence of measurable biological responses to leptin, which at present has no role in the management of obesity.

What is diabetes?

A pancreatic islet after 50 years of Type 1 diabetes: (Top) in this slide A-cells stained for glucagon are intact; (Bottom) in this slide, which is stained for insulin, B-cells are completely absent

Increased risk for Type 2 diabetes

•People over 40 years of age •People of Asian or African-Caribbean ethnic origin

•Overweight people

•Family history of diabetes

•History of gestational diabetes

•History of large baby (birth weight exceeding 4kg)

Rare syndromes

Polycystic ovary syndrome Syndrome x* hypertension

* Syndrome x includes hyperlipidaemia, hyperinsulinaemia, and glucose intolerance Obesity

Type 2 diabetes

Insulin resistance and disease

Obesity

Insulin resistance

(Parte 2 de 19)

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