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Diabetes MellitusDiabetes mellitus is a syndrome of disturbed energy homeostasis caused by a deficiency of insulin or of its action resulting in abnormal metabolism of carbohydrate, protein, and fatDiabetes mellitus is the most common endocrine-metabolic disorder of childhood and adolescence3Morbidity and mortality stem from metabolic derangements and from long-term complications that affect small and large vessels and result in retinopathy, nephropathy, neuropathy, ischemic heart disease, and arterial obstruction with gangrene of the extremities4ClassificationType I Diabetes (insulin-dependent diabetes mellitus, IDDM)characterized by severe insulinopenia and dependence on exogenous insulin to prevent ketosis and to preserve lifeonset occurs predominantly in childhoodprobably has some genetic predisposition and is likely autoimmune-mediated5ClassificationType II Diabetes (non-insulin-dependent diabetes mellitus, NIDDM)patients are not insulin dependent and rarely develop ketosisgenerally occurs after age 40, and there is a high incidence of associated obesityinsulin secretion generally adequate; insulin resistance is present6ClassificationSecondary DiabetesOccurs in response to other disease processes:exocrine pancreatic disease (cystic fibrosis)Cushing syndromepoison ingestion (rodenticides)7.INSULIN

Diabetes Care 2006 29:1150-1159 Type I Diabetes Mellitus: EpidemiologyPeaks of presentation occur at 5 - 7 years of age and at adolescenceNewly recognized cases appear with greater frequency in the autumn and winter12Type I Diabetes Mellitus: Etiology and PathogenesisBasic cause of clinical findings is sharply diminished secretion of insulinThe mechanisms that lead to failure of pancreatic -cell function are likely autoimmune destruction of pancreatic islets.13Type I Diabetes Mellitus: Etiology and Pathogenesis80 - 90% of newly diagnosed patients with IDDM have anti-islet cell antibodies14Plasma glucose regulation:Plasma glucose is tightly regulated by hormones: Insulin: Plasma glucose

Glucagon Epinephrine Plasma glucose Growth hormone CortisolPathogenesisBoth genetic & environmental factors are important at pathogenesis

1-Environmental Factors :

A-Viral Infections : Although the etiologic role of viral infections in human type 1 DM is controversial, coxsackie B3, coxsackie B4, cytomegalovirus, rubella, and mumps can infect human cells. Congenital rubella infection is associated with diabetes in later life. It is estimated that 1012% of patients infected with congenital rubella develop type 1 DM and that up to 40% develop impaired glucose tolerance. .B-Nutrients- e.g Cow milk Antibodies against cow insulin Closely resembles human insulin May attack cellsC-Chemicals- Drugs such as alloxan, streptozotocin (STZ), pentamidine, and Vacor are directly cytotoxic to cells and cause diabetes in experimental animals and humans. In susceptible animals, multiple subdiabetogenic doses of STZ induce primary -cell damage and subsequently immune responses against cells, providing mechanistic evidence that a -cell insult can elicit specific autoimmunity.

2-Genetic Factors

There is a close correlation between type 1 diabetes & some classes of MHC(major histocompatibility complex) genes-e.g.genes encoding HLA-DR & HLA-DQ They can either the risk of diabetes or protect against the disease Inheritance of HLA-DR3 or -DR4 antigens appears to confer a twofold to threefold increased risk for the development of type 1 DM. When both DR3 and DR4 are inherited, the relative risk for the development of diabetes is increased 710-fold.

Genetic predisposition and environmental factors lead to initiation of an autoimmune process against the pancreatic islets. The autoimmune attack on the pancreatic islets leads to a gradual and progressive destruction of cells with loss of insulin secretion. It is estimated that, at the onset of clinical diabetes, 8090% of the pancreatic islets are destroyed.Type 1 DM is more prevalent in persons with Addisons disease, Hashimotos thyroiditis, and pernicious anemia

The development of Type 1 diabetes can be broken down into five stages: Genetic predisposition Environmental trigger Active autoimmunity Progressive beta-cell destruction Presentation of the symptoms of Type 1 diabetes

Mechanism of Hyperglycemia in Diabetes: Absolute (type 1 diabetes) or relative (type 2 diabetes) insulin deficiency: increase in hepatic glucose output decrease in peripheral glucose uptake & utilization

Increase in Hepatic Glucose Output:

insulin Liver gluconeogenesis & glycogenolysis plasma glucoseDecrease in Glucose Uptake:Muscle insulin glucose & amino acid uptake and protein breakdown plasma glucose and plasma amino acidsAdipose tissue insulin lipolysis and lipogenesis plasma fatty acids

Type I Diabetes Mellitus: PathophysiologyProgressive destruction of -cells leads to a progressive deficiency of insulinAs DM evolves, it becomes a permanent low-insulin catabolic state which feeding does not reverseSecondary changes involving stress hormones accelerate the metabolic decompensation27Type I Diabetes Mellitus: PathophysiologyWith progressive insulin deficiency, excessive glucose production and impairment of its utilization result in hyperglycemia with glucosuria when the renal threshold of ~ 180 mg/dL is exceededThe resultant osmotic diuresis produces polyuria, urinary losses of electrolytes, dehydration, and compensatory polydipsia 28Type I Diabetes Mellitus: PathophysiologyDKA results in altered lipid metabolismincreased concentrations of total lipids, cholesterol, triglycerides, and free fatty acidsfree fatty acids are shunted into ketone body formation ; the rate of formation exceeds the capacity for their peripheral utilization and renal excretion leading to accumulation of ketoacids, and therefore metabolic acidosis29Type I Diabetes Mellitus: PathophysiologyWith progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes impaired, and the patient ultimately becomes comatose30Type I Diabetes Mellitus: Clinical ManifestationsClassic presentation of diabetes in children is a history of polyuria, polydipsia, polyphagia, and weight loss, usually for up to one monthLaboratory findings include glucosuria, ketonuria, hyperglycemia, ketonemia, and metabolic acidosis. 31Type I Diabetes Mellitus: Clinical ManifestationsKeotacidosis is responsible for the initial presentation of up to 25% of childrenEarly manifestations are mild and include vomiting, polyuria, and dehydration More severe cases include Kussmaul respirations, odor of acetone on the breathAbdominal pain or rigidity may be present and mimic acute appendicitis or pancreatitisComa ultimately ensue32Type I Diabetes Mellitus: DiagnosisDiagnosis of DM is dependent on the demonstration of hyperglycemia in association with glucosuria with or without ketonuriaDKA exists when there is hyperglycemia (> 300 mg/dL), ketonemia, acidosis, glucosuria, and ketonuria

33Type I Diabetes Mellitus: Diagnosis Nonfasting blood glucose greater than 200mg/dL with typical symptoms is diagnostic with or without ketonuria. Diabetes is diagnosed if a blood sugar level after fasting is greater than 126 mg/dL.Another test, the oral glucose tolerance test (OGTT), involves measuring the blood sugar 2 hours after drinking 75 grams of glucose.. Once hyperglycemia is confirmed, it is prudent to determine whether DKA is present (especially if ketonuria is found) and to evaluate electrolyte abnormalitieseven if signs of dehydration are minimal.

Type I Diabetes Mellitus: DiagnosisDKA must be differentiated from acidosis and coma due to other causes:hypoglycemia, uremia, gastroenteritis with metabolic acidosis, lactic acidosis, salicylate intoxication, encephalitis

35Diabetic ketoacidosisDiabetic ketoacidosis (DKA) is a state of absolute or relative insulin deficiency aggravated by ensuing hyperglycemia, dehydration, and acidosis-producing derangements in intermediary metabolism.The most common causes are underlying infection, disruption of insulin treatment, and new onset of diabetes. DKA is typically characterized by hyperglycemia over 300 mg/dL, low bicarbonate ( 50cc/ kg in first 4 hrs)Hypernatremia/ persistent hyponatremia

Cerebral EdemaKnow what to look forAltered mental status/ severe headacheRecurrence of vomitingChanges in pupil size, seizures, bradycardiaClinical worsening despite improving lab valuesCT/ MRI changes may not be seen in early cerebral edemaTreatment of cerebral edemaMannitol: 1 gram/ kg IV over 30 minutesElevate the head of the bedDecrease IVF rate and insulin infusion rateDo not delay treatment until radiographic evidence

2-Long term treatment of type-1 diabetes mellitusType 1 treatment must be continued indefinitely. Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication is taken. .The average glucose level for the type 1 patient should be as close to normal (80120 mg/dl) as possible. Some physicians suggest up to 140150 mg/dl for those having trouble with lower values, such as frequent hypoglycemic events. Values above 200 mg/dl are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl usually require immediate treatment and may lead to ketoacidosis. Hypoglycemia may lead to seizures or episodes of unconsciousness.

GOALS OF TREATMENTINSULIN THERAPYDIET (NUTRITION)ACTIVITYA-INSULIN THERAPYInsulin Types: Rapid-acting -Humalog , Novolog Short-acting - Regular ,Intermediate - Lente, NPH Long-acting - Ultralente, Glargine (Lantus)

.Rapid-acting analogue (clear)Onset: 1015 minPeak: 6090 minDuration: 4 5 hShort-acting (clear)Onset: 0.51 hPeak: 24 hDuration: 58 hIntermediate-acting (cloudy)Onset: 13 hPeak: 58 hDuration: up to 18 hAlthough pork, beef, and beef-pork insulins were previously used, recombinant human insulin is now available and used almost exclusively.Commercially prepared mixtures of insulin are also available. Insulin Delivery Methods:

Insulin Syringe Insulin Pen Insulin Pump Jet Injector

Insulin treatment regimens-1Optimal diabetic control requires frequent self-monitoring of blood glucose levels. Frequent monitoring allows for rational adjustments in insulin doses. Most patients with type 1 diabetes require at least a split or mixed insulin regimen (eg, a combination of NPH with rapid-acting insulin before breakfast and supper). Insulin treatment regimens-2Increasingly used are multiple-injection regimens in which a rapid-acting insulin (eg, lispro or aspart) is administered before each meal and a long-acting insulin (eg, glargine) is given once a day in the morning or evening This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and attention to the control of their diabetes. A three-injection regimen combining the basal insulin ultralente (at breakfast and supper) with a rapid analog bolus at each meal may provide good glucose control. Further compromise to a two-injection regimen may occasionally be needed. This would require NPH or lente combined with a rapid analog bolus at breakfast and supper.However, such a schedule would provide poor coverage for lunch and early morning, and would increase the risk of hypoglycemia at midmorning and early night.

Split or mixed, eg, NPH/regular, lispro (Humalog) or aspart (NovoLog) before breakfast and supper; Split or mixed variant, eg, NPH/regular, lispro, or aspart before breakfast, regular, lispro or aspart before supper, or NPH before bedtime; Multiple-injection regimen, eg, lispro or aspart before each meal, or glargine (Lantus) once a day in the morning or evening

.nsulin pump, with which small amounts of lispro or aspart insulin are infused continuously (24 h) at a basal rate, with additional boluses given before each meal.

B-NUTRITIONAL MANAGEMENT:Nutrition plays an essential role in the management of patients with type 1 DM. This is of critical importance during childhood and adolescence, when appropriate energy intake is required to meet the needs for energy expenditure, growth, and pubertal development. In outlining nutritional requirements for the child on the basis of age, sex, weight, and activity, food preferences, including any based on cultural and ethnic backgrounds, must be considered.

.Total recommended caloric intake is based on size or surface area and can be obtained from standard tables . The caloric mixture should comprise approximately 55% carbohydrate, 30% fat, and 15% protein.Approximately 70% of the carbohydrate content should be derived from complex carbohydrates such as starch; intake of sucrose and highly refined sugars should be limited. Complex carbohydrates require prolonged digestion and absorption so that plasma glucose levels increase slowlyC-PHYSICAL ACTIVITY

Regular exercise is especially important for the person with diabetes, as it helps control the amount of sugar in the blood and helps burn excess calories and fat to achieve optimal weight.Before people with diabetes begin any exercise program, they should obtain medical approval. Type 1 diabetics must take special precautions before, during and after participation in intense physical activity or exercise.MONITORINGA reliable index of long-term glycemic control is provided by measurement of glycosylated hemoglobin. HbA1c represents the fraction of hemoglobin to which glucose has been nonenzymatically attached in the bloodstream. The formation of HbA1c is a slow reaction that is dependent on the prevailing concentration of blood glucose; it continues irreversibly throughout the red blood cell's life span of approximately 120 days. The higher the blood glucose concentration and the longer the red blood cell's exposure to it, the higher is the fraction of HbA1c , which is expressed as a percentage of total hemoglobin. .Because a blood sample at any given time contains a mixture of red blood cells of varying ages, exposed for varying times to varying blood glucose concentrations, an HbA1c measurement reflects the average blood glucose concentration of the preceding 23 mo.

.It is recommended that HbA1c measurements be obtained three to four times per year to obtain a profile of long-term glycemic control. The more consistently lower the HbA1c level, and hence the better the metabolic control, the more likely it is that microvascular complications such as retinopathy and nephropathy will be less severe, delayed in appearance, or avoided. In nondiabetic individuals, the HbA1c fraction is usually less than 6%; in diabetics, values of 68.5% represent good metabolic control, values of 910%, fair control, and values of 11% or higher, poor control .

Complications of Diabetes1-Acute complicationsKetoacidosisHypoglycemiaCerebral edema 2-Chronic complications:Neuropathy: - loss of sensation due to damage of nerve fibres(e.g. heat, cold, pain) -reduced blood flow and high blood glucose changes the metabolism of nerve cellsCardiovascular disease: - atherosclerosis -high blood pressure -myocardial infarction

Retinopathy: damage of retinaCataract: damage of lensNephropathy:-has a slow onset-may result in severe kidney failure-follow up: proteinuria

Diabetic retinopathyThe risk of diabetic retinopathy after 15 yr duration of diabetes is 98% for individuals with type 1 DM and 78% for those with type 2 DM. Although the metabolic control has an impact on the development of this complication, genetic factors also have a role, because only 50% of patients develop proliferative retinopathy. .Guidelines suggest that diabetic patients have an initial dilated and comprehensive examination by an ophthalmologist within 35 yr after the onset of type 1 DM (but not before age 10 yr). Any patients with visual symptoms or abnormalities should be referred for ophthalmologic evaluation. Subsequent evaluations should be repeated annually by an ophthalmologistDiabetic nephropathy Diabetic nephropathy affects 2030% of patients with type 1 DM 20 yr after onset.The increased mortality risk in long-term type 1 DM may be due to nephropathy, which may account for about 50% of deaths. The risk of nephropathy increases with duration of diabetes, degree of metabolic control, and genetic predisposition to essential hypertension.

.Screening for diabetic nephropathy is a routine aspect of diabetes care. The American Diabetes Association (ADA) recommends yearly screening for those with type 1 DM after 5 yr duration of disease (but not before puberty). Twenty-four hour AER (urinary albumin and creatinine) or timed (overnight) urinary AER are acceptable techniques.

Future therapiesPancreas transplantation Islet cell transplantation Gene therapy The surgery and accompanying immunosuppression required is considered by many physicians to be more dangerous than continued insulin replacement therapy, and is therefore often used only as a last resort (in cases where the patient's blood glucose levels are extremely volatile). Experimental replacement of beta cells is being investigated in several research programs. Thus far, beta cell replacement has only been performed on patients over age 18.