2012סכרת נעורים נעורים • סכרת של וקלסיפיקציה איבחוןוטיפול: • הגדרה קטואצידוזיס

2005סכרת נעורים:

סכרת • של וקלסיפיקציה אבחוןנעורים

Expert Committee on the Diagnosis and classification of Diabetes Mellitus

Diabetes care, July 1997

National Diabetes Data Group (NDDG) - 1979

WHO - 1980-1985.

סכרת של סימפטומיםנעורים

פוליאוריה•פולידיפסיה•משקל • אבדן•) לעתים ) פוליפאגיה•) לפעמים ) ראיה טשטוש

Etiologic classification of diabetes• Type 1 diabetes

• Type 2 diabetes - may range from predominantly insulin resistance

with relative insulin deficiency to vice versa.

• Other specific typegenetic defects of beta-cell function

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug- or chemical-induced

Infections

Unknown forms of immune-mediated diabetes

Other genetic syndromes sometimes associated with diabetes

• Gestational diabetes mellitus (GDM)

Criteria for the diagnosis of DM1] Symptoms of diabetes plus causal plasma glucose levels > 200

mg%.

Casual defined as any time of the day without regard to time since last meal. The classic symptoms include polyuria, polydipsia, and unexplained weight loss.

O r

2] FPG > 126 mg%. Fasting: no caloric intake for at least 8 h.

Or

3] 2h PG>200 mg% during an OGTT: Glucose load of 75g.

In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day.

Impaired glucose tolerance & fasting glucose

• IFG: > 100 mg% but < 126 mg% Near the level above which acute phase insulin secretion is lost in IV-GTT. Associated with a progressively greater risk of developing micro- & macrovascular complications.

• IGT: 2h levels of BG after OGTT between 140 mg% to 200 mg%.

• IGF & IGT are risk factors for future diabetes.

• Associated with syndrome X (insulin resistance syn)

סכרת של טווח ארוכי סיבוכים(1)

• Retinopathy: potential loss of vision• Nephropathy: potential renal failure• Peripheral neuropathy: Foot ulcer

Amputation

Charcot joints• Autonomic neuropathy: Gastrointestinal

Genitourinary

Cardiovascular

Sexual dysfunction

סכרת של טווח ארוכי סבוכים(2)

• Vascular disease: Cardiovascular

Peripheral vascular

Cerebrovascular

• Hypertension

• dislypidemia

• Periodontal disease

• Psychosocial dysfunction

Changes of the new classification

• Elimination of insulin dependent vs. insulin independent

• Type 1 & type 2:

Type 1: b-cell destruction with tendency to ketoacidosis, d/t autoimmune process with autoantibodies or without (type 1 idiopathic)

• Elimination of malnutrition-related diabetes

• Addition of impaired fasting glucose (IFG) to the entity of IGT.

Type 1 diabetes• Cellular-mediated immune destruction of the b-cells

• HLA association (HLA class II): DQA, DQB, DRB

• Autoantibodies: insulin autoantibodies (IAA) Islet cells autoantibodies (ICA)

anti Glutmic acid decarboxylase (GAD65) antibodies to tyrosine phosphatase IA-2 & IA-2b

• Young age/ lean habitus/ ketoacidosis/ autoimmune

• Idiopathic diabetes• No autoimmunity, no HLA predisposition (but inherited)

• Most are of African or Asian origin

• Insulin requirement may come and go

Diabetic ketoacidosis

DEFINITIONBlood glucose > 250 mg%KetonemiapH < 7.30 and standard bicarbonate < 15

meq/L

Diabetic ketoacidosis [1]

• Dehydration

Osmotic diuresis (glycosuria) NS 20cc/kg 1st hour

vomiting maintenance + deficit

Insensible loss

(Kussmaul breathing, fever)

• Hyperglycemia

Insulinopenia Insulin 0.1 Unit/kg/hour

Insulin resistance (acidosis)

Counterregulatory hormones

Diabetic ketoacidosis [2]

• HyponatremiaWater shift to ECF NS 1st hour

Pseudohyponatremia 0.5 NS later

• HyperkalemiaAcidosis K < 3.5 meq/L: 40 meq/L

pre renal azotemia K 3.5-5 meq/L: 30 meq/L

K 5-5.5 meq/L: 20 meq/L

• Hypophosphatemia Phosphaturia ½ KCL, ½ KPO4

Diabetic ketoacidosis [3]

• AcidosisFree fatty acids (lypolysis) Insulin

Lactic acidosis Rehydration

• Hyperlipidemia• Lypolysis Insulin

Genetic defects of b-cell function• Monogenetic defects: autosomal dominant pattern

(MODY)• Onset: before 25 y, mild hyperglycemia 1] Mutations in hepatocyte nuclear factor (HNF)-1a,

chromosome 12 (MODY 3) 2] Mutations in glucokinase, chromosome 7 (MODY 2)3] Mutations in HNF-4a, chromosome 20 (MODY 1)4] Point mutations in mitochondrial DNA (mainly position

3243 in tRNA of leucine gene, similar to MELAS syndrom)5]Impaired conversion of proinsulin to insulin (IGT)6] Mutant insulin molecule with impaired receptor binding

GLUCOKINASE: YING & YANG INTERPLAY

Glucokinase loss-of-function mutations: Decreased G phosphorylation decreased Insulin

secretion MODY 2.

Glucokinase gain-of-function mutations:Hyperinsulinism: Glaser et al: NEJM 1998;338,226.Autosomal dominant (3 generations)Val455Met mutationIn vitro study: increased affinity of glucokinase for G

higher rate of glycolysis at low G concentrations GSIR threshold: about 40 mg%

Sequels: T1DM at later age

IPF1 (PDX1) deficiency linked to MODY4Stoffers et al: nature genetics 1997;17,138.

Extended-family pedigree (6 generations)

Onset of DM: 35 y (range 17-67 )

Heterozygous individuals: 6/8 Rx of diet or OH

No signs of ketosis or severe insulin deficiency

Genetic defects in insulin action

Murations of the insulin receptor with subsequent insulin resistance (acanthosis nigricans, virilization, PCOS)

• Leprechaunism: characteristic facial features, fatal

• Rabson-Mendelhall syndrome: abnormalities of teeth and nails, pineal gland hyperplasia

• Lipoatrophic diabetes: a defect in the post-receptor signal transduction pathway.

Diseases of the exocrine pancreas

• Pancreatitis

• Trauma \ pancreatectomy

• Neoplasia

• Cystic fibrosis

• Hemochromatosis

• Fibrocalculous pancreatopathy

Other genetic syndromes

• Down’s syndrome (autoimmune diseases)

• Kleinfelter syndrome

• Turner syndrome• Wolfram’s syndrome (DIDMOD)

Enedocrinopathies

• Acromegaly

• Cushing syndrome

• Glucagonoma

• Pheormacytoma

• Hyperthyroidism

• Somatostatinoma

• Aldosteronoma

Drug- or chemical-induced

• Vacor (rat poison): permanently destroy b-cells

• Pentamidine: permanently destroy b-cells

• Nicotinic acid: impair insulin action

• Glucocorticoids: impair insulin action

• Interferon-a: induce antibodies’ positive diabetes

I n f e c ti o n s

• Congenital rubella

• CMV

• Coxsackie B virus

• Adenovirus

• Mumps