THYROID DISORDERS AND TYPE 2 diabetes mellitus Focus: Pathophysiology

THYROID DISORDERS AND TYPE 2 diabetes mellitusFocus: Pathophysiology1LEVEL OF COMPETENCIESHyperthyroidism 3AHypothyroidism 1NIDDM (without complication) 4IDDM 3AComplication acute and chronic 3A (3B) Hypoglycemia 3B

Adrenal cortex failure 3B 2SUGESTED BOOKS READINGS Melmed; KSP Palonsky; PR Larsen; and HM Kronenberg (Eds). Williams Textbook of Endocrinology 12th ed. 2011. Elsevier, SaundersCR Kahn; GL King; AC Moses; GC Weir; AM Jacobson; and RJ Smith (eds.). Joslins Diabetes Mellitus 14th ed. 2005. One Joslin Place BostonBuku Ajar Ilmu Penyakit Dalam3THYROID DISORDERSThe function?The histology?The etiology?4IntroductionThe terms of hyper- and hypothyroidism are related to the function of thyroid glandThyrotoxicosis is clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormonesThe function of thyroid gland is synthesis of thyroid hormones: T4 (tetraiodothyronine/ thyroxine) and T3 (triiodothyronine)5Laboratory examination of thyroid functionThe function of the thyroid gland may be evaluated in many different ways: 1. test of thyroid hormones in blood, 2. evaluation of the hypothalamic-pituitary-thyroid axis, 3. assessment of iodine metabolism (bisa uptake, bisa ekskresi), 4. estimation of gland size, 5. thyroid biopsy 6. observation on peripheral tissue, and 7. measurement of thyroid autoantibodies (Greenspan, 2004)TSH (thyroid stimulating hormone), T4 (thyroxine), T3 (triiodothyronine) 6Physiologic effects of thyroid hormonesEffects on fetal development (brain development, skeletal maturation)Effects on oxygen consumption, heat production, and free radical formationCardiovascular effects (positive inotropic and chronotropic effects)Sympathetic effects (sensitivity to cathecolamine is markedly increased)Pulmonary effectsHematopoietic effects (increased production of erythropoietin)Gastrointestinal effects (stimulated gut motility)Skeletal effects (stimulated bone turnover, bone resorptionNeuromuscular effectsEffects on lipid and carbohydrate metabolismEndocrine effects7Thyroid hormones regulation

8

9Thyroid Hormone SynthesisTrapping of iodide, diffusion and transport to colloid Oxidation iodine and iodination of tyrosine residues in thyroglobulinCoupling of iodotyrosine molecules within thyroglobulinProteolysis of thyroglobulinDeiodination of iodotyrosine (MIT/DIT) form iodine to recyle 10

PrimaryHypofunctionSecondaryHyperfunctionPrimaryHyperfunctionPituitaryFailureNormal rangeTHYROTROPIN (TSH) LEVELLow Normal HighLow Normal HighTHYROID HORMONE LEVELSubclinicalHypofunctionSubclinicalHyperfunction11Etiologies of hyperthyroidismGraves disease Toxic multinodular goiter / Toxic adenoma (autonomy)De Quervains (acute/subacute) thyroiditis (thyrotoxicosis, eventually hypothyroid)Silent/painless thryroiditis (autoimmune, eg, graves, postpartum)Postpartum thyroiditisHashimotos thyroiditis (Ig involved can be stimulatory or inhibitory)Thyrotoxicosis factitia (hypothyroid, kemudian diberi hormone replacement, dose berlebihan hyperthyroid)Thyrotoxicosis due to pregnancy and trophoblastic disease (HCG homologous w/ TSH)Iodide-induced thyrotoxicosis (eg: amiodarone)Hyperthyroidism due to inappropiate TSH secretion CongenitalMetastatic thyroid carcinoma (widely spread, usually involving bone; follicular cell found in bones)Struma ovarii

12Etiologies of HypothyroidismPrimary hypothyroidism: primary idiopathic hypothyroidism, postablative/surgery/ therapeutic irradiation, sporadic athyreotic hypothyroidism (agenesis/dysgenesis), endemic cretinism, unresponsiveness to TSHGoitrous: Hashimotos thyroiditis, Reidels struma (thyroiditis yg terjadi sclerosing --> follicular cell fibrosis), endemic iodine deficiency, antithyroid drugs, inherited defect of hormone synthesisTransient: thyroid hormon treatment withdrawal, removal of the gland, DeQuervains thyroiditis (thyrotoxicosis (-) feedback transient hypothyroid), postpartum thyroiditis, postablative treatment for GravesdiseaseSecondary hypothyroidism (hypophysis)Tertiary hypothyroidism (hypothalamic)Peripheral tissue resistance to thyroid hormone action

JOD-BASEDOW PHENOMENON : low iodine intake hyperplasia n hypertrophy, some gain autonomy iodine supplementation hyperthyroid13SYNDROMES OF THYROID AUTOIMMUNITYGraves disease: goiter, exophthalmus, and hyperthyroidsm (thyroid-stimulating antibodies)Hashimotos thyroiditis: goiter and euthyroidism or hypothyroidism (thyroid-stimulating hormone blocking antibodies/TSBAG)Primary thyroid failure (cell-destructive process) Antigen: antigen thyroglobulin (TG), antigen TSH-R, microsomal antigen (thyroid peroxidase/TPO)14Antibodies to TSH-RTSI (thyroid-stimulating immunoglobulin) (in Gravesdisease)Antibodies interfere with TSH binding (thyrotrophin-binding inhibitory immunoglobulin/TBII)Prevent the action of TSH (thyrotrophin-stimulation blocking antibodies/TSBAb) (in Hashimotos thyroiditis)TSAb/TSI, TSBAb, and TBIAb are present in graves disease15TYPE 2 DIABETES MELLITUS16Type 2 Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemiaresulting from defects in: (Expert Committee on the Diagnosis and Classification of Diabetes mellitus 2002)Definition of Diabetes Mellitusb-celldysfunction

IRInsulinresistanceMacrovascular complication

Microvascular complication

17Natural History of Type 2 DiabetesRamlo-Halsted BA and Edelman SV. Primary Care. 1999;26:771-789.Insulin resistance

Hepatic glucose production

Endogenous insulinPostprandial blood glucoseFasting blood glucose

Typical diagnosis of diabetesMicrovascular complicationsMacrovascular complicationsSeverity of diabetesImpaired glucose toleranceFrank diabetesYears to decadesTimeAsymptomatic stage18More than 80% of patients progressing to T2DM are insulin resistant

Insulin resistant;low insulin secretion (54%)Insulin resistant; good insulin secretion (29%)Insulin sensitive;good insulin secretion (1%)Insulin sensitive;low insulin secretion (16%)83%Haffner SM, et al. Circulation 2000; 101:975980.19The 7-year follow-up of the San Antonio Heart Study revealed that 195 of 1,734 subjects (11%) progressed to type 2 diabetes.These 195 converters could be characterized into four groups:insulin resistant; low insulin secretion (54%)insulin resistant; good insulin secretion (29%)insulin sensitive; low insulin secretion (16%)insulin sensitive; good insulin secretion (1%).In the study, insulin resistance was most strongly associated with progression to type 2 diabetes, with 83% of converters being insulin resistant.The lowest risk of developing type 2 diabetes was in subjects who were insulin sensitive combined with good insulin secretory capacity (1%).Haffner SM, et al. Circulation 2000; 101:975980.GLUT - 4GLUT - 4GLUT - 4GLUT - 4p85IRSp110PhosphoinositideDependent-KinaseProt Kinase BAtypicalPK CPhosphoisnositide-3 KinaseAuto phosphorilationSel OtotDinding selReceptor InsulinInsulinGlukosa

PPRE

PPARg+ RXRtranscriptionmRNA20Once insulin binds to its receptor, it has immediate post receptor actions, but importantly, it also sends a transnuclear signal into the nucleus to activate transcription factors in the ribosomal matrix.Fungsi sel beta masih dapat diperbaiki selama belum terjadi ketoacidosisAuto phosphorilationSel OtotDinding selReceptor InsulinInsulinGlukosa

PPRE

PPARg+ RXRtranscriptionmRNAINSULIN RESISTANT STATE21Pada keadaan RESISTENSI INSULINSignal post reseptor tidak terjadi,Sehingga proses Transkripsi terhambat/terganggu!!!!22Islet Cell Dysfunction Leads to Abnormal Insulin and Glucagon Dynamics in Type 2 Diabetes*Insulin measured in 5 patients.Adapted with permission from Mller WA et al. N Engl J Med 1970;283:109115.Copyright 1970 Massachusetts Medical Society. All rights reserved. Glucose (mg/dL)Insulin*(/mL)from beta cellsGlucagon (/mL)from alpha cellsTime (minutes)Type 2 diabetes (n=12)Normal patients (n=11)6006012018024036033030027024011080140130120110100901209060300Meal22Islet Cell Dysfunction Leads to Abnormal Insulin and Glucagon Dynamics in Type 2 Diabetes A clinical study examined postprandial glucose, insulin, and glucagon dynamics in patients with type 2 diabetes (n=12) versus nondiabetic control subjects (n=11).1 The study also recruited 12 patients with type 1 (juvenile) diabetes; results for this group are not shown.After a large carbohydrate meal, mean plasma glucose concentrations rose from 228 mg/dL to a peak of 353 mg/dL in patients with type 2 diabetes, compared with an increase from 84 mg/dL to a peak of 137 mg/dL in nondiabetic subjects.1Insulin rose in normal subjects from a mean fasting level of 13 /mL to a peak of 136 /mL 45 minutes after the meal. The insulin response in patients with type 2 diabetes (n=5) was delayed and suppressed in comparison, increasing from a fasting level of 21 /mL to a peak of only 50 /mL at 60 minutes.1 Insulin antibodies resulting from prior insulin therapy precluded insulin immunoassay in the other 7 patients in the group.Mean plasma glucagon levels declined significantly from the fasting value of 126 /mL to 90 /mL at 90 minutes (P