DIABETES MELLITUS DEFINITION q a metabolic disorder of
DIABETES MELLITUS
DEFINITION q a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.
DIABETES EPIDEMIOLOGY Diabetes is the most common endocrine problem worldwide. Incidence of diabetes is alarmingly increasing all over the globe. Incidence of childhood diabetes range between 3 -50/100, 000 worldwide
WHO CLASSIFICATION 2000 Is based on etiology not on type of treatment or age of the patient. Type 1 Diabetes (idiopathic or autoimmune b-cell destruction) Type 2 Diabetes (defects in insulin secretion or action) Other specific types
WHO CLASSIFICATION/2 Both type 1 & type 2 can be further subdivided into: ü Not insulin requiring ü Insulin requiring for control ü Insulin requiring for survival Gestational diabetes is a separate entity Impaired Glucose Tolerance (IGT) indicates blood glucose levels between normal & diabetic cut off points during glucose tolerance test.
DIAGNOSTIC CRITERIA Fasting blood glucose level Diabetic ü Plasma >7. 0 mmol ü Capillary >6. 0 mmol IGT ü Plasma 6. 0 -6. 9 mmol ü Capillary 5. 6 -6. 0 mmol ü 1 mg/dl = 0. 05556 mmol/l 2 hours after glucose load (Plasma or capillary BS) IGT ü 7. 8 -11. 0 Diabetic level ü > 11. 1 (200 mg)
Types of Diabetes in Children Type 1 diabetes mellitus accounts for >90% of cases. Type 2 diabetes is increasingly recognized in children with presentation like in adults. Permanent neonatal diabetes Transient neonatal diabetes Maturity-onset diabetes of the young Secondary diabetes e. g. in cystic fibrosis or Cushing syndrome.
MODY(Maturity onset diabetes of the young ) Usually affects older children & adolescents Not rare as previously considered 5 subclasses are identified, one subclass has specific mode of inheritance (AD) Not associated with immunologic or genetic markers Insulin resistance is present
TRANSIENT NEONATAL DIABETES Observed in both term & preterm babies, but more common in preterm Caused by immaturity of islet b-cells Polyuria & dehydration are prominent, but baby looks well & suck vigorously Highly sensitive to insulin Disappears in 4 -6 weeks
PERMANENT NEONATAL DIABETES A familial form of diabetes that appear shortly after birth & continue for life The usual genetic & immunologic markers of Type 1 diabetes are absent Insulin requiring, but ketosis resistant Is often associated with other congenital anomalies & syndromes e. g. Wolcott-Rallison syndrome.
TYPE 1 DIABETES: ETIOLOGY Type 1 diabetes mellitus is an autoimmune disease. It is triggered by environmental factors in genetically susceptible individuals. Both humoral & cell-mediated immunity are stimulated.
GENETIC FACTORS q. Evidence of genetics is shown in ü Ethnic differences ü Familial clustering ü High concordance rate in twins ü Specific genetic markers ü Higher incidence with genetic syndromes or chromosomal defects
AUTOIMMUNITY Circulating antibodies against b-cells and insulin. Immunofluorescent antibodies & lymphocyte infiltration around pancreatic islet cells. Evidence of immune system activation. Circulating immune complexes with high Ig. A & low interferon levels. Association with other autoimmune diseases.
ENVIRONMENTAL INFLUENCE Seasonal & geographical variation. Migrants take on risk of new home. Evidence for rapid temporal changes. Suspicion of environmental agents causing disease which is confirmed by case-control experimental animal studies.
ENVIRONMENTAL Viruses ü Coxasckie B ü Mumps ü Rubella ü Reoviruses Nutrition & dietary factors ü Cow’s milk protein ü Contaminated sea food
OTHER MODIFYING FACTORS The counter-regulatory hormones: q glucagon q cortisol, q catecholamines q thyroxin, q GH & somatostatin q sex hormones Emotional stress
ETIOLOGIC MODEL The etiologic model of type 1 diabetes resembles that of Rheumatic fever was prevented by elimination of the triggering environ. factor (b-streptococci). Similarly type 1 diabetes may be prevented by controlling the triggering factors in high risk persons.
CLINICAL PRESENTATIONS Classical symptom triad: üpolyuria, polydipsia and weight loss DKA Accidental diagnosis Anorexia nervosa like illness
DIAGNOSIS In symptomatic children a random plasma glucose >11 mmol (200 mg) is diagnostic. A modified OGTT = oral glucose tolerance test (fasting & 2 h) may be needed in asymptomatic children with hyperglycemia if the cause is not obvious. Remember: acute infections in young nondiabetic children cause hyperglycemia without ketoacidosis. Children ingest 1. 75 g/kg body weight in a similar volume of water by ratio (max 75 g as for adults).
Glycated haemoglobin Although Hb. A 1 c testing is mainly used for monitoring blood sugar control in patients with diabetes, the WHO now recommends that Hb. A 1 c can be used as a diagnostic test for diabetes, provided that stringent quality assurance tests are in place and assays are standardised to criteria aligned to the international reference values. An Hb. A 1 c of 6. 5% is recommended as the cut-off point for diagnosing diabetes. A value less than 6. 5% does not exclude diabetes diagnosed using glucose tests.
NATURAL HISTORY Diagnosis & initiation of insulin Period of metabolic recovery Honeymoon phase State of total insulin dependency
METABOLIC RECOVERY During metabolic recovery the patient may Develop one or more of the following: Hepatomegaly Peripheral edema Loss of hair Problem with visual acuity These are caused by deposition of metabolic re-balance. glycogen &
HONEYMOON PERIOD Due to b-cell reserve optimal function & initiation of insulin therapy. Leads to normal blood glucose level without exogenous insulin. Observed in 50 -60% of newly diagnosed patients & it can last up to one year but it always ends. Can confuse patients & parents if not educated about it early.
COMPLICATIONS OF DIABETES ARE NUTRITIONAL, METABOLIC AND CHRONIC DEGENERATIVE Acute: ØDKA (Diabetic ketoacidosis ) ØHypoglycemia Late-onset: q. Retinopathy q. Neuropathy q. Nephropathy q. Ischemic heart disease & stroke
TREATMENT GOALS Prevent death Achieve biochemical control Maintain growth and development Prevent acute complications Prevent or delay late-onset complications
TREATMENT ELEMENTS 1. Insulin therapy 2. Diet and meal planning 3. Exercise Education Monitoring ü Hb. A 1 c every 2 -months ü Home regular BG monitoring ü Home urine ketones tests when indicated
EDUCATION Educate child & care givers about: q Diabetes q Insulin q Life-saving skills q Recognition of Hypo & DKA q Meal plan q Sick-day management
INSULIN A polypeptide made of 2 b-chains. Discovered by Bants & Best in 1921. Animal types (porcine & bovine) were used before the introduction of humanlike insulin (DNA-recombinant types). Recently more potent insulin analogs are produced by changing aminoacid sequence.
FUNCTION OF INSULIN § § Insulin being an anabolic hormone stimulates protein & fatty acids synthesis. Insulin decreases blood sugar By inhibiting hepatic glycogenolysis and gluconeogenesis. 2. By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue. 1.
TYPES OF INSULIN Short acting (neutral, soluble, regular) ü Peak 2 -3 hours & duration up to 8 hours Intermediate acting ü Isophane (peak 6 -8 h & duration 16 -24 h) ü Biphasic (peak 4 -6 h & duration 12 -20 h) ü Semilente (peak 5 -7 h & duration 12 -18 h) Long acting (lente, ultralente & PZI) ü Peak 8 -14 h & duration 20 -36 h
INSULIN CONCENTRATIONS Insulin is available in different concentrations 40, 80 & 100 Unit/ml. WHO now recommends U 100 to be the only used insulin to prevent confusion. Special preparation for infusion pumps is soluble insulin 500 U/ml.
INSULIN REGIMENS Twice daily: either NPH alone or NPH+SI. Thrice daily: SI before each meal and NPH only before dinner. Intensive 4 times/day: SI before meals + NPH or Glargine at bed time. Continuous s/c infusion using pumps loaded with SI. NPH insulin (or neutral protamine Hagedorn) (also known as Humulin N, Novolin N, is an intermediateacting insulin Insulin glargine, Lantus, is a long-acting basal insulin analogue that slowly release insulin, giving a long duration of action of 18 to 26 hours
INSULIN ANALOGS Ultra short acting q Insulin Lispro q Insulin Aspart Long acting without peak action to simulate normal basal insulin q Glargine
NEW INSULIN PREPARATIONS Inhaled insulin proved to be effective & will be available within 2 years. Nasal insulin was not successful because of variable nasal absorption. Oral insulin preparations are under trials.
ADVERSE EFFECTS OF INSULIN Hypoglycemia Lipoatrophy Lipohypertrophy Obesity Insulin allergy Insulin antibodies Insulin induced edema
PRACTICAL PROBLEMS Non-availability of insulin in poor countries injection sites & technique Insulin storage & transfer Mixing insulin preparations Insulin & school hours Adjusting insulin dose at home Sick-day management Recognition & Rx of hypo at home
DIET REGULATION Regular meal plans with calorie exchange options are encouraged. 45 -50% of required energy to be obtained from complex carbohydrates, 20 -25% proteins, 30% lipids Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars. Encouraged low salt, low saturated fats and high fiber diet.
CHILDREN NUMBER OF CALORIES/DAY = 1000 + (AGE x 100)
EXERCISE Decreases insulin requirement in diabetic subjects by increasing both sensitivity of muscle cells to insulin & glucose utilization. It can precipitate hypoglycemia in the unprepared diabetic patient. It may worsen pre-existing diabetic retinopathy.
MONITORING Compliance (check records) HBG tests Hb. A 1 every 2 months Insulin & meal plan Growth & development Well being & life style School & hobbies
Pancreas & Islet Cell Transplantation Pancreas transplants are usually given to diabetics with end stage renal disease. Islet cell transplants, the ultimate treatment of type 1 diabetes is under trial in many centers in the US & Europe with encouraging results but graft rejection & recurrence of autoimmunity are serious limitations.
IMMUNE MODULATION Immunosuppressive therapy for üNewly diagnosed üProlonged the honey moon üFor high risk children Immune modulating drugs ØNicotinamide Ømycophenolate
GENE THERAPY Blocks the immunologic attack against isletcells by DNA-plasmids encoding self antigen. Gene encode cytokine inhibitors. Modifying gene expressed islet-cell antigens like GAD.
PREDICTION OF DIABETES Sensitive & specific immunologic markers ü GAD Antibodies( Glutamic acid decarboxylase antibodies) ü GLIMA antibodies ( glycated islet cell ü membrane–associated protein ) ü IA-2 antibodies ( islet cell antibodies ) ü insulin autoantibodies (IAAs), Sensitive genetic markers • HLA haplotypes • DQ molecular markers
PREVENTION OF DIABETES q. Primary prevention • Identification of diabetes gene • Tampering with the immune system • Elimination of environmental factor q. Secondary prevention • Immunosuppressive therapy q. Tertiary prevention • Tight metabolic control & good monitoring
Children and young people with type 1 diabetes should be offered an ongoing integrated package of care by a multidisciplinary paediatric diabetes care team. To optimise the effectiveness of care and reduce the risk of complications, the diabetes care team should include members with appropriate training in clinical, educational, dietetic, lifestyle, mental health and foot care aspects of diabetes for children and young people.
Diabetic ketoacidosis (DKA)
POSITIVE DG OF DKA History: polydipsia, polyuria • Clinical: acidotic respiration dehydration drowsiness abdominal pain/vomiting • Biochemical: high blood glucose on finger-prick test glucose and ketones in urine
Diabetic ketoacidosis (DKA) NICE guideline - Primary fluid replacement in DKA should be with isotonic saline, not given too rapidly except in cases of circulatory collapse. - Bicarbonate should not generally be used in the management of DKA. - Intravenous insulin should be given by infusion in cases of DKA.
Potassium replacement should begin early in DKA, with frequent monitoring for the development of hypokalaemia. add 20 mmol KCl to every 500 ml bag of fluid(40 mmol per litre). Phosphate replacement should not generally be used in the management of DKA. In patients whose conscious level is impaired, consideration should be given to insertion of a nasogastric tube, urinary catheterisation to monitor urine production, and heparinisation. To reduce the risk of catastrophic outcomes in DKA, monitoring should be continuous
British Society for Paediatric Endocrinology and Diabetes (BSPED) recommended guidelines on diabetic ketoacidosis a fall in plasma sodium concentration during fluid treatment may be associated with the development of cerebral oedema. Hypotonic saline solutions should therefore not be used, and 0. 45% saline with dextrose is now the fluid of choice once the initial phase of treatment with normal saline is complete fluid rehydration should be delivered evenly over 48 hours, and that this practice may reduce the incidence of cerebral oedema
The initial intravenous insulin infusion dose is given as 0. 1 units/kg/hour. younger children (especially the under 5’s) are particularly sensitive to insulin and therefore require a lower dose of 0. 05 units/kg/hour Airway Ensure that the airway is patent and if the child is comatose, insert an airway. If comatose or has recurrent vomiting, insert N/G tube, aspirate and leave on open drainage. Breathing Give 100% oxygen by face-mask. Circulation Insert IV cannula and take blood samples (see below). Cardiac monitor for T waves (peaked in hyperkalaemia) If shocked (poor peripheral pulses, poor capillary filling with tachycardia, and/or hypotension) give 10 ml/kg 0. 9% (normal) saline as a bolus, and repeat as necessary to a maximum of 30 ml/kg.
Once rehydration fluids and potassium are running, blood glucose will already be falling. However, insulin is essential to switch off ketogenesis and reverse the acidosis. Continuous low-dose intravenous infusion is the preferred method. solution of 1 unit per ml. of human soluble insulin (e. g. Actrapid) by adding 50 units (0. 5 ml) insulin to 50 ml 0. 9% saline in a syringe pump. Attach this using a Yconnector to the IV fluids already running. Do not add insulin directly to the fluid bags. The solution should then run at 0. 1 units/kg/hour (0. 1 ml/kg/hour
Algorithm for the management of diabetic ketoacidosis Clinical history • Polyuria • Polydipsia • Weight loss • Abdominal pain • Weakness • Vomiting • Confusion Clinical signs • Assess dehydration • Deep sighing respiration (Kussmaul) • Smell of ketones • Lethargy, drowsiness Biochemical signs • Ketones in urine or blood • Elevated blood glucose (>11 mmol/litre) • Acidaemia (p. H < 7. 3) • Take blood also for electrolytes, urea
Shock Reduced peripheral pulse volume Reduced conscious level Coma Resuscitation • Airway ± N/G tube • Breathing (100% 02) • Circulation (10 ml/kg of 0. 9% saline repeated until circulation restored, max. 3 doses) Re-evaluate • Fluid balance + IV-therapy Intravenous therapy • Calculate fluid requirements • Correct over 48 hours • 0. 9% saline • Add KCl 20 mmol every 500 ml • Insulin 0. 1 U/kg/hour by infusion
dextrose 5% Observations • Continue monitoring as • Hourly blood glucose • Neurological status at least above • Consider reducing insulin hourly 0. 05 U/kg/hour, • Hourly fluid input: output • Electrolytes 2 hours after but only when p. H > 7. 3 start of Insulin IV-therapy, then 4 -hourly Start subcutaneous Blood glucose insulin then stop < 15 mmol/litre intravenous insulin Intravenous therapy 1 hour later • Change to 0. 45% saline +
cerebral oedema mannitol 1. 0 g/kg • Restrict IV fluids by 2/3 • Move to ITU • CT scan when stabilised
Mild to moderate hypoglycaemia (aware and responds to symptoms): • Immediately consume rapidly absorbed simple carbohydrate • As symptoms improve or normoglycaemia is restored consume complex long-acting carbohydrate • Recheck blood glucose within 15 minutes Severe hypoglycaemia (unable to respond, semiconscious/unconscious and requires assistance): • Use 10% intravenous glucose if in a hospital setting • Use intramuscular glucagon or concentrated oral glucose solution outside hospital or when intravenous access not practical • As symptoms improve or normoglycaemia is restored consume complex long-acting carbohydrate (if sufficiently awake) • Repeat blood glucose measurements to check if further glucose is needed • Seek medical assistance if child/young person fails to respond or symptoms persist for more than 10 minutes
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