HY NOTES for ENDOCRINE SYSTEM!!

ENDOCRINE SYSTEM

Pitutary Gland

• Anterior lobe (adenohypophysis)
• Acidophills (GH and prolactin)
• Basophills (ACTh and TSH, FSH and LH)
• Chromophobes
• Posterior lobe
• Pituicytes
• ADH, Oxytocin

Five cell types

• Somatotrophs – GH (acidophilic cells)
• Lactotrophs – prolatin (acidophilic cells)
• Corticotrophs – ACTH, MSH, endorphins and lipotropin (basophilic cells)
• Thyrotrophs – TSH (basophilic)
• Gonadotrophs – FSH and LH (basophilic cells)

Pitutary Disorder

• Hyperpituitarism
• Excess of pituitary hormones
• Common reason – functional adenoma
• Pitutitary adenoma
• Mainly single hormone excess in the anterior lobe (GH or PRL)
• Adenomas associated with MEN type 1 (multiple endocrine neoplasia)
• Mass lesion present in the sella turcica in pituitary adenoma
• mass effects like visual problems from pressing on the optic chiasm and prdn of prolactin or ACTH
• Uniform polygonal cells
• G-protein mutations, G-protein play a critical role in signal transduction transmitting signals
• Alpha-subunit mutation that interferes with its intrinsic GTPase activity with therefore results in constitutive activation of Gs Alpha. The alpha-subunit of Gs is encoded by the GNAS1 gene, located on chromosome 20q13
• Pituitary apoplexy
• Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy.
• Sudden onset of excruciating headache, diplopia owing to pressure on the oculomotor nerves and hypopituitarism
• Cardiovascular collapse – emergency
• Prolactinoma
• Hyperfunctioning of pituitary adenoma – hyperprolactinemia
• Dystrophic calcification ranging from isolated psammoma bodies to extensive calcification of entire tumor mass
• Galactorrhea in young women
• Mainly due to damage to the dopaminergic neurons of the hypothalamus
• Dopamine receptor antagonist such as the neuroleptic drugs can cause hyperprolactinemia
• Bbitemporal hemianopsia – visual field abnormalities due to compression of fibers in the optic chiasm
• Increased levels of prolactin – cause amenorrhea, galactorrhea, loss of libido and infertility
• Rx – bromocriptine
• Growth Hormone excess
• Gigantism (childhood) – somatotrophic adenoma appears in children before the epiphyses have closed, the elevated levels of GH. Long bones are involved
• Acromegaly (adults) – increased levels of GH after the closure of the epiphysis. Bone density is increased (hyperostosis). Enlargement of the jaw results in protrusion (prognathism). Broad hands and feets or (ACRAL enlargement)
• Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (IGF-1 or somatomedin C) causes the clinical manifestation.
• Diagnosis – elevated serum GH and IGH-1 levels
• Corticotroph cell adenomas
• Excess prodn of ACTH by the corticotroph adenoma leads to adrenal hypersecreation of cortisol and the results in hypercortisolism (Cushing syndrome)

• Posterior Pituitary disorder
• ADH and oxytocin
• Clinical relevant Posterior syndrome include Diabetes insipidus and increase high levels of ADH
• Diabetes insipidus
• ADH deficiency (Central Diabetes Insipidus)
• Inability of the kidney to reabsorb  water
• Head trauma n tumors
• Inflammatory disorders of hypothalamus
• Rx - desmopressin
• Renal tubular unresponsiveness to circulation ADH (Nephrogenic Diabetes Insipidus)
• Causes for nephrogenic  DI
• Drugs like lithium, hypokalemia (vascular nephropathy of collecting tubules, nephrocalcinosis (calcification of collecting tubules)
• Clinical – excessive thirst, polyuria, increased osmolality and serum Na+
• Test – WATER DEPRIVATION TEST
• CDI  - UOsm increase more than 50%
• NDI – Uosm increase less than 50%
• Rx – Thiazides – Vol depletion increases proximal tubule reabsorption of water
• SIADH (Syndrome of inappropriate ADH)
• Excess ADH causes resorption of excessive amonts of free water – Hyponatremia
• Cause – secretion of ectopic ADH by neoplasm
• Clinical – hyponatremia (increase serum Na+), cerebral edema, total body water is increased
• Rx – restrict water

• Hypopituitarism
• Decreased secretion of pituitary hormones (disease of  hypothalamus or pituitary)
• Causes
• Pituitary adenoma
• Sheehan’s postpartum necrosis
• Carniopharyngioma
• Pituitary apoplexy
• Lymphocytic hypophysitis
• Clinical – Gonadotropins (FSH, LH) deficiency [ delayed puberty, adult females have secondary amenorrhea, males have impotence]
• Growth hormone (GH) deficiency
• Decreased GH decreases synthesis and release of IGF-1
• Growth delay, delayed fusion of epiphyses, bone growth does not match the age of the child
• Hypoglycemia (decreased gluconeogenesis)
• Thyroid-stimulating hormone (TSH) deficiency
• Secondary hypothyroidism – decreased T4 and TSH
• Clinical – cold intolerance, constipation, weakness
• No increase in TSH after TRF stimulation
• ACTH deficiency
• Secondary hypocortisolism
• Decreased ACTH and cortisol
• Hypoglycemia, hyponatremia
• Rx –Metyrapone (inhibits adrenal 11-hydroxylase – causes a decrease in cortisol and increase in plasma ACTH and 11-deoxycortisol)

• Anterior pituitary tumor
• Sheehan syndrome [pituitary hemorrhage]
• Ischemic necrosis [postpartum]
• Happens during pregnancy
• Anterior pituitary become twice as normal size
• Lack of blood supply cause obstetric hemorrhage or shock
• No resumption of normal menstrual cycles, she become sluggish and tired
• Clinical – inability to breast feed a child, hyponatremia, hyperkalemia and hypoglycemia
• Empty sella syndrome
• Condition that destroys part or all of the pituitary gland
• Types
• Primary – defect in the diaphragm sella that allows arachnoid mater and CSF to herniated to sella. Clinicals – obese women, hyperprolactinemia, hypopituitarism
• Secondary – pituitary adenoma, enlarges the sella. Loss of pituitary function, hypopituitarism
• Hypothalamic suprasellar tumors
• Gliomas and
• Craniopharyngiomas – vestigial remnants of Rathke pouch (ectodermal derivative from oral cavity). Abnormality of the WNT signaling pathway including activating beta-catenin mutations, also visual disturbances
• Adamantinomatous carniopharyngioma – there is calcification, stratified squamous epithelium. Nests of squamous cells grandually merge into a layer of columnar cells. They contain a cholesterol-rich, thick brownish yellow fluid ‘ machinery oil’.
• Papillary craniopharyngioma -  rarely calcified.

THYROID

Hypothalamus produces TRH then pituitary produces TSH which makes thyroid to make T3 n T4.

Disorders of Thyroid

Hyperthyroidism

• Thyrotoxicosis – elevated levels of free T3 n T4 [hypermetabolic state]. Reason – diffuse hyperplasia of the gland [Graves disease], hyperfunctional multinodular goiter and hyperfunctional adenoma of the thyroid. Also due to overactivity of the sympathetic nervous system.
• Rx – Methimazone, propyl
• Clinicals - diarrhea, weight loss, mennorrhegia, tremors, changes in the skin of tibia. Atrial fibrillation, sweating, proximal muscle weakness.
• Primary – the cause is within the gland. Most common
• Secondary – if the cause is outside the gland like pituitary
• Graves disease – exophthalamos, accumulation of loose connective tissue behind the eyeballs adds to the protuberant appearance of the eyes.
• Increase porosity of cortical bone and reduced volume of trabecular bone.
• Net effect – osteoporosis,  increased risk of fractures.
• Acute elevation in catecholamine levels
• Febrile and present with tachycardia.
• Apathetic Hyperthyroidism
• Mainly in elderly
• Unexplained weight loss or worsening cardiovascular disease
• Diagnosis of Hyperthyroidism
• – measurement of serum TSH concentration using sensitive TSH assays provides the most useful single screening test for hyperthyroidism
• - Low TSH value with FREE T4.
• If there is normal elevation after the injection of TRH then secondary hyperthyroidism is excludes
• ****If there is diffusely increased uptake in the whole gland then its GRAVES DISEASE
• ****If there is increased uptake of radioactive iodine in a solitary nodule – toxic adenoma
• ****Decrease uptake of radioactive iodine by the thyroid gland– thyroiditis – hypothyroidism

GRAVES DISEASE

• Female, 20-40y
• Autoimmune
• Hyperthyroidism [hyperfunction, diffuse enlargement]
• Infiltrative opthalmopathy
• Pretibial myxedema
• Presence of MHC haplotypes, specifically HLA-B8 and DR3
• CTLA-4 = cytotoxic T-lymphocyte-associated-4 gene
• CTLA-4 is an inhibitory receptor that prevents T-cell response to self antigens
• Antibodies to the TSH receptor, thyroid peroxisomes and thyroglobulin are present in the serum
• Thyroid stimulating immunoglobulin [TSI] are specific for Graves disease
• There is infiltration of the retro-orbital space by mononuclear cells, edema and swelling of extraocular muscles, accumulation of extracellular matrix, GAGS and fatty infiltration
• Crowded number of cells, with meaty appearances
• HASHIMOTO DISEASE – eventually people become hypothyroidism.

HYPOTHYROIDISM

• decrease in adequate levels of thyroid hormone
• primary
• autoimmune hypothyroidism – Hasimoto thyroiditis
• iodine deficiency
• drugs – lithium
• Postablative – surgery, radioactive therapy or external irradiation
• Secondary
• Pituitary failure
• Hypothalamic failure – rare
• Primary
• Thyroprivic – due to absence or loss of thyroid parenchyma
• Goitrous – due to enlargement of the thyroid gland under the influence of TSH. Anto-TSH receptor autoantibodies circulating  autoantibodies
• Dyshormonogenetic goiter
• Hormone synthesis defect
• Iodine transport into thyrocytes
• Iodine organification
• Iodotyrosine coupling
• Mutations in the thyroid peroxidase gene
• Pendred syndrome
• Mutation in the SLC2644 gene whose product is pendrin
• Problem in organification of iodine
• Isolated hypothyroidism
• Inactivating fermline mutation of the TSH receptor
• CLINICALS
• CRETINISM (60 slide)
• Develops in infancy
• Mentally retarded
• Short stature
• Coarse facial features, protruding tongue
• Reduction in maternal thyroid hormone later in pregnancy, after the fetal thyroid has developed, allows normal brain development.
• MYXEDEMA or GULL disease
• Slowing of physical and mental activity
• Mental sluggishness
• Depreseeion
• Speech and intellectual functions slowed
• Constipation and decreased sweating
• Skin – cool and pale
• Weight gain
• Accumulation of matrix substance [GAGS and hyaluronic acid]
• THYROIDITIS
• Acute illiness with severe thyroid pain
• Neck pain and tenderness
• Fever chills
• Painful cervival adenopathy
• Little inflammation and thyroid dysfunction
• HASHIMOTO THYROIDITIS
• Autreactive CD4+ Tcells to thyroid antigens appears to be initiating event
• Abnormal T cell activation and subsequent B cell stimulation
• Presence of circulating autoantibodies against thyroglobulin and thyroid peroxidase
• Mononuclear inflammatory infiltrate within germinal centers
• Hurthle cells – metaplastic response of normally low cuboidal follicular epithelium to in going injury
• Prone for Non-Hodgkins lymphoma
• There is painless enlargement of the thyroid
• REIDEL’S THYROIDITIS
• Associated with sclerosing conditions
• Extension of fibrosis into surrounding tissue
• Fibrous tissue replacement of the gland
• Tracheal obstruction
• GOITRE
• Enlargement of thyroid
• Raised TSH
• They can be hyperthyroid or hypothyroid
• Diffuse and multinodular goiters caused by dietary iodine deficiency
• Types
• Diffuse nontoxic – involves the entire gland without producing nodularity. Filled with colloid.
• Multinodular goiter – irregular enlargement of thyroid, cause compression of other organs like airway obstruction. There can be cancer of thyroid – papillary carcinoma. There is colloid rich follicles

NEOPLASM OF THYROID

Cold nodule – when the nodule is taking no radioactive

Hot nodule – toxic adenomas – takes radioactive

Follicular adenoma

• Multiple nodules
• Covered by a capsule
• There is uniform appearing follicle
• There is no vascular invasion but follicular carcinoma have invasion
• Capsule will be present
• No invasion
• **** incomplete

Papillary carcinoma thyroid contain psammoma bodies. Seen in later cases

Follicular carcinoma

• Present in women
• Increased in areas of dietary iodine deficiency
• Single nodules that may be well circumscribed or widely infiltrative
• Tumor cells resemble like follicles in thyroid but its less apparent.
• With or without colloid
• Capsular and Vascular Invasion

Medullary carcinoma

• Derived from parafollicular cells or C cells of the thyroid
• Secrete calcitonin
• they are going to have amyloid stroma with Congo red staining
• polygonal to spindle-shaped cells
• Acellular amyloid deposits [ produced from altered calcitonin]

Anaplastic carcinomas of thyroid

• High mortality rate 100%
• Older people
• Undifferentiated – giants cells, spindle cells, mixed of those

Increased up take of radioactive iodine is seen in Graves and toxic nodular goitre

Decrease uptake of radioactive iodine – thyroiditis, and for people who takes thyroid hormone

PARATHYROID

• Parathyroid gland has chief cells  and oxyphills cells
• PTH
• Increase Ca+ reabsorption in early DT
• Decreases HCO-3 reclamation in the PT
• Decreases phosphorus reabsorption in the PT
• Hypocalcemia stimulate the release of Ca+ from PTH
• Antagonizes CALCITONIN
• PTH binds to osteoblasts receptor.  (SLIDES 7)
• Components of total serum Ca+ [albumin, phosphorus n citrate]
• Hypoalbuminemia
• Decreased total serum Ca+ [ due to decrease in Ca+ bound to albumin]
• Normal PTH
• Metabolic alkalosis
• Increases –ve charge on albumin
• Normal serum calcium
• Decreased ionized Ca+, incrased PTH
• Tetany development
• Carpopedal spasm [ thumbs flexes into the palm[
• Chvosteck’s sign [ facial twitch after tapping]

Parathyroid Disorder

Primary Hyperparathyroidism

• Adenoma
• Caused by sporadic parathyroid adenomas or sporadic  hyperplasia
• Parathyroid adenoma 1 [PRAD1] gene defect
• Sporadic adenomas – MEN1, type 2An2B
• Osteitis fibrosa cystic
• Cortex is grossly thinned
• Increased amount of fibrous  tissue in the marrow
• Bone turn soft and become deformed
• Bone pain, fractures
• Nephrolithiasis
• Constipation, ulcers, gallstones
• Cardiac valve calcification
• hypercalcemia
• Nephrocalcinosis – causes polyuria and renal failure
• Calcium deposit in the limbus of the eye [ band keratopathy]
• In EKG – shortened QT interval and prolonged PR interval

Secondary Hperparathyroidism

• Renal failure
• Glands are hyperplastic
• Hypercalcermia
• Increased Ca+ reabsorption in the jejunum n kidney
• Sarcoidosis – macrophages in granulomas synthesize 1-alpha hydroxylase causes hypervitamin D
• Multiple myeloma – increased secretion of osteoclast activating factor(IL-1) by malignant cells
• Thiazides – vol depletion increases renal tubule reabsorption of calcium

Hypoparathyroidism

• Hypofunction lead to hypocalcemia [tetany], circumoral numbness or paresthesias [ tingling]
• Neuromuscular irritability due to decreased serum ionized calcium concentration. Chvostek sign and Trousseau sign.
• Causes
• Previous surgery
• Digeorge syndrome – failure of descent of 3rd n 4th pharyngeal pouches. Absence of PT gland. Absent thymus [ Tcell deficiency]
• Hypomagnesemia – Mg low, which is cofactor of adenylate cyclase, causes diarrhea, diuretics, alcoholism
• Familial hypoparathyroidism
• autoimmuneHP
• Widened QT interval
• Lens calcification
• Intracranial calcification
• 
  

Pseudohypoparathyroidism

• X-linked dominant disease
• Mental retardation
• Short 4th n 5th metacarpals [knuckle-knuckle-dimple-dimple sign]
• Hypocalcemia,  normal increased PTH

Type 1a Pseudohypoparathyroidism

• Bone resorption with blunting of the 4th and 5th knuckles of the hand
• Knuckle knuckle dimple dimple sign
• Turner syndrome  is characterized by blunting of only the fourth knuckle
• Associated with multihormone resistance
• Characterized by skeletal and developmental defects
• Clinical
• Short stature
• Obesity
• Short metacarpal n metatarsal bone

Pseudopeusohypoparathyroidism

• Mutation is inherited on the paternal allele
• No hypocalcemia or hyperphosphatemia

Secondary Hyperparathyroidism

• Chronic renal insufficiency – due to decreased phosphate excretion – hyperphosphate
• Elevated PO4 decreases Ca+ and thus stimulate parathyroid gland
• There is a reduction in availability of alpha-1-hydroxylase

ADRENAL GLAND

Adrenal Cortex

Synthesis

• Glucocorticouds by Zona fasciculata
• Mineralocorticoids by Zona glomerulosa
• Sex steroids by Zona reticularis

Adrenal Medulla

• Composed of Chromaffin cells
• Synthesize n secrete catecholamines (epinephrine)
• Product of epinephrine n NOR epinephrione – metanephrine and VMA
• Metabolic product of dopamine 0 Homovanillic acid

Cushing disease

• Dude to pituitary adenoma[excess growth of pituitary gland]
• Primary hypersecretion of ACTH with cortisol
• Mainly in women
• Clinical
• Upper body obese with thin arm and legs
• 
  

Cushing syndrome

• Crooke hyaline change
• Main cause pituitary adenoma
• There is diffuse hyperplasia [ glands become bigger]
• Adrenal cortex is thickened and yellow
• Clinicals
• Central obesity
• Moon facies
• Weakness
• Hirsutism
• Hypertension
• Diabetes
• Hyper insulinism
• Buffalo hump
• Loss of collagen and resorption of bones
• Hyperglycemia, glucosuria and polydipsia
• In this syndrome there is 24hr urine free cortisol level [increased]
• High dose of dexamethasone, reduce the secretion of ACTH.
• In Ectopic tumor[outside the gland], ACTH levels are elevated[ higher than pituitary adenoma] and in adrenal tumors the ACTH levels are low
• High dose of dexamethasone difference pituitary CS from Adrenal and ectopic

Primary Aldosteronism

• Suppression of the rennin-angiotensin system
• Decreased plasmaSLIDE 41*****************

Adrenal Insufficiency

Primary

Acute

• Adrenal crisis
• A patient who has chronic or addison disease and now he has a source of stress
• Patients on exogenous corticosteroids with rapid withdrawal result is stress to adrenal crisis
• Waterhouse Friderichsen’s Syndrome
• Catastrophic syndrome
• Massive bilateral adrenal hemorrhage
• Hypotension  shock
• Bacterial infection like Neisseria meningitides, Pseudomonas, H.influenza
• Meningococcemia is the usual cause with hemorrhafe and adrenal failure
• Develops over less than 2 days
• Skin lesion

Chronic

• Addison disease
• Destruction of adrenal cortex
• Autoimmune
• Clinical –
• Weakness
• Fatigability
• Hormones from cortex is decreased
• Increase production of ACTh from anterior pituitary and also produces melanocytes with hyperpigmentation of skin
• Hyperkalemia
• Hyponatremia
• Volume depletion
• Hypotension
• Hypoglycemia due to decrease in cortisol
• Autoimmune adrenalitis
• Autoimmune polyendocrine syndrome type1(APSI)
• Abnormalities of skin, dental n nail
• Organ specific autoimmune disorders [ hypogonadism. hypoPTD]
• Mutation in AIRE gene on 21q22
• AIRE protein is in thymus, function as a transcription factor that promotes expression of many self-antigens
• Autoimmune polyendocrine syndrome type 2 (APS2)
• Early adulthood
• Thyroiditis or Diabetes type 1

Secondary adrenocortical Insufficiency

• Disorder of the hypothalamus n pituitary
• Reduction in ACTH causes hypoadrenalism
• Hyperpigmentation is lacking

Adrenogenital syndromes

• Exess androgens due to gonadal disorders or adrenal
• DHEA & Androstenedione converted to testosterone
• Androgen excess is secondary to cushing disease

• 11 hydroxlase
• Hypertension****
• Hypokalemia
• Increase in 11 deoxycorticosterone has same property as aldosterone
• Ambiguous genitalia in females

• 17-hydrozylase deficiency –
• only mineralocorticoids are found –
• more Na retention-
• K+excretion –
• Hypertension****
• No androgens – phenotypically female****

• When there is 21 hyrdroxylase enzyme deficient [congenital adrenal hyperplasia]
• Gene is present in short arm of chromosome 6
• there is no cortisol n
• no aldosterone[mineralocorticords] –
• hypotension
• ambiguous genitalia [ small penis, scrotal development]
• salt wasting*****
• low BP, low Na, high K
• adrenal hyperplasia [decrease in feedback inhibition causes secretion of adrenocorticotropic hormone]
• Female pseudohermaphroditism [female with male phenotypes]

Adrenal Medulla

• Derived from neural crest, chromaffin cells
• Synthesize and secrete catecholamines
• Cells are modified sympathetic postganglionic neurons
• Disease
• Neuronal tumors
• Ganglion cell tumors
• Chromaffin cell tumors
• Pheochromocytoma
• Excess synthesize of catecholamines
• Hypertension
• Benign or malignant
• Color – yellow tan, incubation with potassium dichromate (Zenker’s fixative) Dark brown color [due to oxidation of stored catecholamines]
• “Zellballen” pattern
• Episodic hypertension
• Tachychardia, palpitation, headache, drenching sweats, tremor
• Cardiac complications – catecholamine cardiomyopathy
• Lab – 24hrs urine for VMA and metanephrine
• Hyperglycemia
• Neuroblastoma
• Under 5 years old
• Located adrenal medulla
• Amplification of N-MYC oncogene
• Small cell tumor
• Presence of Homer-Wright rosettes
• Lab – similar to pheochromocytoma

• MEN type 1
• 3Ps (pancreastic, pituitary, parathyroidism)
• Pancreatic – gastrinomas (ulcers)
• Pituitary – prolactinomas
• Mutation MEN 1 Gene

• MEN 2A [sipple’s syndrome]
• RET gene
• Medullary thyroid carcinoma
• Parathyroid hyperplasia (hypercalcemia)
• Pheochromocytoma

• MEN2B[William syndrome]
• Medullary thyroid carcinoma
• RET gene
• No parathyroid hyperplasia
• Marfanoid habitus
• Ganglioneuromas of GIT, Lips and tongue

• Familial medullary thyroid cancer
• Only thyroid cancer nothing else

• Von Hippel-Lindau
• Pheochromocytoma
• Paraganglioma
• Renal cell carcinoma
• Hemangioblastoma
• Pancreatic endocrine neoplasm

Pancreatic Endocrine Neoplasm

Islet cell Tumors

• Rare

HYPERINSULISISM

• Tumor from beta cells of langerhans
• Hypoglycemic shock [confusion, tumor, loss of consciousness]
• 80% have MEN1
• Lab – high insulin levels, high C-peptide levels [ endogenous marker of insulin produced in Beta-islet cells]
• If patient is in sulphonyl urea[can increaseinsulin level too] – urine will contain it – for weight loss
• Zollinger-Ellsion syndrome –
• gastrin producing tumor
• hypergastrinemia [ peptic ulcer]
• ulcer in unusual locations
• [NOT TEST USMLE}Glucagonoma
• High glugagon secretion
• Mild diabetes
• Necrolytic migratory erythema rash
• [NOT TEST USMLE]Somatostatinoma
• High somatostatin
• Mild diabetes
• Cholelithiasis
• Steatorrhea
• Hypochlorhydria
• VIPoma
• Watery diarrhea
• Hypokalemia
• Hypotension
• Periorbital edema

DIABETES

3Ps

• Polyuria
• Polydypsia

• Catabolic state
• Reduction in glucose level
• Insulin requiring cells –striated and cardiac muscle, fibroblast, fat
• Non-insulin requiring – BV, nerves, kidney, eyelens
• GLUT 4 [in muscle n adipose tissue]
• In pancreatic cell – GLUT 2 mediators [ in beta cells]
• Sulfonylurea drugs make the beta cells to release insulin
• Low glucose inside cell
• High glucose outside
• TYPE 1 Diabetes Mellitus
• Autoimmune
• Pancreatic beta-cell destruction
• You will find lymphocytic infiltrate in pancrease
• Patients improve with insulin administration
• Insulitis
• Autoimmune occurs against these antigens
• Insulin
• Beta cell enzyme glutamic acid decarboxylase
• Islet cell autoantigen 512
• HLA locus on chromosome 6
• Genetic factor –occurs with transcription factor 7 like 2 [TCF7L2]
• Ketoacidosis

• TYPE 2 Diabetes Mellitus
• Peripheral resistance to insulin action
• Inadequate secretory response
• Loss of insulin sensitivity in the hepatocytes [ abdominal obesity][fat on the liver]
• No HLA association
• Under microscope you will find amyloid
• Decreased levels of adiponextin [ in obesity]
• TZDs [thiazolidinediones] activates peroxisome proliferator activated receptor gamma – it increase the adiponectin- decrease resistance
• Metformin – improves insulin sentivity – only drug – enhance the activity of the AMP-activated protein kinase (AMPK)
• Leptin improves insulin sensitivity
• Hyperosmolarnonketotic coma
• Rx – weight loss, upregulate insulin receptor synthesis
• Amyloid deposits can be seen islet of langerhans

Complications of Diabetes Mellitus

• Short term
• Hypoglycemia
• DK
• Non ketotic hyperosmolar diabetic coma
• Lactic acidosis
• Long term
• Microangiopathy
• Smaller BVs are damaged
• Excess deposition of protein
• Macroangiopathy
• Factors
• Insulin resistance
• Obesity
• Persistent hyperglycemia
• Recommended HbA1C be maintained below 7%
• Mechanism
• Formation of advanced glycation end products [AGEs]
• Its complex enzymatic reaction b/w glucose derived dicarbonyl precursor with amino group
• They gets deposited in the basement membrane
• It cross links the type 4 collagen which increases fluid filtration
• AGEs trap LDL particules and cause cardio vascular diseases
• Damages intracellular, extracellular and plasma proteins
• Activation of Protein Kinase C(PKC)
• Increase intracellular glucose increases DAG  PKC activation
• Produces profibrogenic molecules. TGF-beta
• Increases plasminogen activator inhibitor 1
• Intracellular hyperglycemia with disturbance in polyol pathways
• Leads to an increase in intracellular glucose that is then metabolized but the enzyme aldose reductase to sorbital
• NADPH is used as a cofactor- for the enzyme glutathione reductase
• Increases cellular susceptibility
• Thickening of the basement membranes of small vessels, kidneys, retina, nerves
• Peripheral neuropathy
• Bilateral
• Tingling and numbness in the extremities
• Loss of pain sensation can result in the development of ulcers that heal poorly  - diffuse vascular injury – morbidity
• Neuropathic ulcers – painless, callus, at pressure points
• Renal failure
• Lesions
• Glomerular lesions
• Capillary basement membrane thickening
• Diffuse mesangial sclerosis
• Nodular glomerulosclerosis
• Renal vascular lesion
• Pyelonephritis
• Nephropathy
• Morbidity
• Deposition of AGE {Advanced Glycosylation End-products as nodules}
• Nephritic syndrome
• End stage renal failure
• Kimmelstiel Wilson Sy
• Retinopathy
• Increased risk of cataracts and glaucoma
• Increased risk for retinal detachment and blindness
• Thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body – histological marker of DB in the eye
• Basement membrane of retinal blood vessels is thickened
• Proliferative
• Retinal detachment
• Up-regulation of VEGF
• Retinal angiogenesis

• Non Proliferative
• Microaneurysms
• Cotton wool - infarcts
• Macular edema
• Elevated levels of PAI-1
• Diabetic patients you want to reduce the LDL levels less than 70
• Diabetic Dyslipidemia
• Hepatic production of atherogenic lipoproteins
• Suppress the uptake of circulating lipids in peripheral tissues
• Prone for Candidiasis infections [FUNGAL]
• Newborn Risks
• Hyperglycemia – causes increase in release of insulin – result in muscle mass and fat
• Caudal regression syndrome [SACRRAL AGENESIS] -
• Respiratory distress syndrome
• Macrosomia
• Gestational Diabetes
• Increased placental size and anti-insulin effect of human placental lactogen
• Acanthosis Nigricans – Hyperpigmentation in axis area – insulin resistance
• Diagnosis – Estimation of blood glucose, HbA1c should be less than 7%, fructose amine – reflects for 2 weeks
• Patients with DB
• Random glucose>200 mg/dl
• Fasting glucose?126mg/dl more than one occasion