Feedback systems

Negative and Positive Feedback systems

(For example, hypothalmus, pituitary, thyroid)

TRANSPORT HORMONES

Water soluble hormones circulate in free unbound forms

Some exmaples of them are?

-Pepties: GH, insulin PTH, PRL

-Glycoproteins: FSH, LH, TSH

-Polypeptides: ACTH, ADH, calcitonin, glucagon, oxytocin

-Amines: Epi, norepi

TRANSPORT HORMONES

Lipid soluble hormones are primarialy circulating bound to a carrier

Some examples of them are?

-Thyroxine

-Steroids: Estrogen, testosterone, progestins, mineralocorticoids, glucocorticoids

-Derivatives of aracadonic acid

Cellular Mechanism of Hormone Action

What happens during Up-regulation?

Low concentrations of hormone increase the number of receptors on a target cell

Cellular Mechanism of Hormone Action

What happens during Down-Regulation?

They are located in or on the plasma membrane or in the intracellular compartment of the target cell

Cellular Mechanism of Hormone Action

What is the process of a water soluble hormone?

1. A first messenger binds to the fixed receptor on the target cell.

2. Signal Transduction (GTP)

3. ATP converts into cyclic adenosine monophosphate cAMP (or Calcium, or cyclic guanosine monophosphate cGMP) which is the second messenger

4. These activate certain kinase proteins that cause cellular response to the hormone

Cellular Mechanism of Hormone Action

lipid-soluble hormones

How do they work?

Steroid hormones: adrogens, estrogens, glucocosteroids, mineralocorticoids, thyroid diffuse across the plasma membrane, they bind to the cytoplasmic or nuclear receptors and then activate RNA polymerase and DNA transcription and translation which creates a protein and an affect on the cell.

They are connected

Very close to optic and nasal pasageways

Pituitary Gland

What is stored in the anterior pituitary (4 main ones) ?

What is it called?

adenohypophysis

1.Growth Hormone GH- in the bones and muscles

2. Adrencorticotropic hormone (ACTH) in the adrenal cortex

3. Thyroid stimulating hormone (TSH) in the thyroid gland

4. Gonadotropic hormones (FSH, LH, and ICSH) in the Testes and Ovaries

5. Melanocyte-stimulating hormone (MSH) in the skin

6. Prolactin (PRL) in the mammory glands

Pitutary gland

What is stored in the posterior pituitary?

What is it called?

Neurohypophysis

1. Oxytocin (OT) in the mammory glands and the uterus

2. Antidiuretic hormone (ADH) in the kidneys

Porterior pituitary hormones are produced where?

They are stored where?

-ADH and OT are produced in thehypothalmus and stored in the pituitary

-They are synthesized with binding proteins (neurophysins) in the supratopic and paraventricular nuclei of the hypothalmus

-transported aconally to posterior pituitary where released into circulation

-Controls the plasma osmality (water concentration in the blood)

-Osmoreceptors (sense changes in the blood) of hypothalmus; intravascular volume changes in intravascular volume changes in mechanoreceptors of the left atrium (detect mechanical change, high or low volume and send info to hypothalmus)

-increases water reabsorption in kidney; no direct effect on electrolytes

-Vasocontriction if inject it into something (not at physiologic level)

it causes contractions and milk ejection in lactating women

Thyroid

What does it secrete?

-It has two lobes: isthmus

-Follicles (follicle cells surrounding colloid Secretes Thyroid hormones

-Parafollicular cells (C cells) secrete calctonin: serum calcium

Parathyroid Glands

Where are they located?

What do they do?

-Small glands behind the upper and lower poles of the thyroid gland. When calcium is low PTH is released

-They produce thyroid hormone which

           : Regulator of serum calcium

           : Antagonist of calcitonin

-They act on the thyroid gland to produce T3 and T4 (all converted to T3

-It's bound to thyroxine-binding globulin, thyroxine-binding to prealbumin, or albumin

-Affects growth and maturation of tissues (Affects all metabolic function of all cells), cell metabolism (fat, protein, glucose), heat production, and oxygen consumption; healthy metabolic processes

-Stimulates alpha myosin heavy chain, Na/K ATPase, Ca ATPase beta adrenergic receptors in the heart; hyperthyroid effects (cardiac affects)

What happens when you have low Calcium level?

Think Parathyroid (PTH)

What are the 3 main organs?

What are you going to decrease if you increase Calcium?*

1. low Ca stimulates increased PTH

2. a. Kidneys increase nephron reabsorption of Ca and decrease proximal nephron reabsorption of phospate. Kidneys also stimulate CYP1-alpha in the renal tubule which increased the production of Vitamin D. Increase in vit D causes increased absorption of Calcium in the intestines

b. Increase PTH also stimulates the bone to stimulate osteoblasts to release RANKL and M-C3F. Increased osteoclast maturation and release of enzymes cause mobilization of calcium from the bone

phosphorus (Ca and Phos are always in opposition)

-Can also eat all the calcium in the world but wont absorb if you dont have PTH and vitamin D

Pancreas

What 2 functions as an organ does it have?

1. Endocrine organ by producing glucagon,insulin (opposing) Maintain glucose

2. Exocrine organ by producing digestive enzymes

-Islets of Langerhans: Secretion of glucagon and insulin

Pancreas

What do alpha cells produce?

glucagon (is released in response to low levels of blood sugar)

Pancreas

What do beta cells produce?

INSULIN

What is it synthisized from?

What in the blood promotes it excretion?

What electrolyte does it fascillitate the transport of?

What kind of hormone is it, anabolic or catabolic?

-Regulated by chemical, hormonal, neural mechanisms

-Synthesized from preproinsulin and proinsulin

-Secretion promoted by increased blood glucose levels

-Facilitates rate of glucose uptake into body's cells (Sensitivity of insulin receptor is a key component in maintaining normal cellular function, insulin resistance)

-ANABOLIC HORMONE (BUILDS UP, produces things, stores things)

         *Synthesis of proteins, lipids, and nucleic acids

         *Liver: increased fatty acid synthesis, gluconeogenesis, glycogenesesis, glucose uptake

         * Muscle cells: increased amino acid uptake, protein synthesis, glucose uptake, glycogenesis (storing)

         * Adipose cells: increased fat storage (more insulin, more fat), glucose uptake

Glucagon

 What does it affect?

What triggers in to be secreted?

Where does the majority of it act?

-Insulin antagonis

-Secretion promoted by decreased blood glucose levels, sympathetic stimulation (fight or flight, fuel, create ATP for energy)

- Acts primarily on the liver to increase glucose via glycongenolysis, gluconeogenesis also stimulates lipolysis (increasing glucose in the serum by producing new and breaking down

CATABOLIC

ADRENAL CORTEX

Where is it located?

What nervous systems does it stimulate?

-80% of an adrenal gland's total weight ( is in the Adrenal cortex)

-Different zones

-Adrenal medulla: Produce norepinephrine and epinephrine (Innervated by the sympathetic and parasympathetic nervous systems)

Glucocorticoid (Adrenal Cortex)

Glucocorticoid hormones

What do are the two things that they do?

1. Increase blood levels of glucose (gluconeogenesis in liver and decreased glucose uptake by muscle and adipose cells) stimulates protein catabolism

2. Immune suppresant: decrease macrophage receptor activity, T helper 1 proliferation (cellular), natural killer cells, synthesis of mediators (DECREASE, can't start the inflammatory process)

Glucocorticoid (Adrenal Cortex)

CORTISOL

-It is the most potent naturally occuring

-Stimulated by adrenocorticotropic hormone (ACTH)

-Stress hormone

-(Hypothalmus produces Coricotropin-releasing hormone (CRH) which goes to the anterior pituitary and secretes Adrenocorticotropic hormone (ACTH) which stimulates the adrenal cortex to stimulate Glucocorticoids (especially cortisol)

-Hypoxia, Hypoglycemia, hyperthermia, exercise, and cortisol insufficiency also stimullate anterior pituitar to produce ACTH

CATABOLIC

Mineralocorticoids (Adrenal Cortex)

Mineralocorticoid hormones

What do they cause?

What is the most potent naturally casuing one?

-Affect ion transport by epithelial cells

         :increase the activity of the sodium pump of the epilthelial cells

         : Cause Na RETENTION and POTASSIUM and HYDROGEN LOSS

- Most potent naturally occuring one is ALDOSTERONE

and it is regulated by the renin-angiotensin-aldosterone system

Increases the Na Pump causings sodium reabsorption

Potassium and hydrogen is lost (need to get rid of it unless want to become acidotic)

-Renin is released as result of decreased renal blood flow, and LOW SODIUM. Angiotensin I is converted to Angiotensin II by ACE.

-High K, Low Na and ACTH levels increase aldosterone in the blood

Adrogens and Estrogens (Adrenal Cortex)

Does the adrenal cortex secrete a lot of this hormone?

1. No, secretion in minimal

-The adrenal cortex secretes weak androgens

-Androgens converted by peripheral tissues to stronger androgens such as testosterone

Catecholamines (Adrenal Medulla)

What kind of cells are located here and what do they secrete?

-Chromaffin cells (pheochromocytes): they secrete the catecholamine epinephrine (majority) and norepinephrine

-Release of catecholamine has been characterized as a "fight or flight" response

-Catecholamines promote hyperglycemia

Mechanism of Hormonal Alteration

Inappropriate amounts of hormone delivered

either way too much or not enough

4 ways

1. Inadequate hormone synthesis (quantity, conversion to active form) Example insulin not converted to active form

2. Failure of feedback systems (ectopic formaiton, No feedback system) example Cushings syndrome

3. Dysfunctional delivery (inadequate blood supply, inadequate carrier proteins, ectopic production of hormones) example athrosclorsis

4. Hormone inactive (inadequate free, degeneration altered, circulating inhibitors)

Mechanisms of Hormone Alterations

Inappropriate response by the target cell

1. receptor-associated disorders

(Type II DM)

1. Receptor-associated disorders

      :Decrease in # of receptors

      :Impaired receptor function

      :Presence of antibodies against specific receptors

      :Antibodies that mimic hormone action

      :Unusual expression of receptor function

Mechanisms of Hormone Alterations

Inappropriate response by the target cell

2. Intracellular disorders

2. intracellular disorders

      :Defects in post receptor signaling

      :Inadequate synthesis of second messengers

      : Altered intracellular enzymes or proteins (don't have d/t a mutation in the gene)

      : Altered nuclear regulators

      : Altered protein synethesis

Syndrome of inappropriate antidiuretic hormone

SIADH Secretion

What is the mechanism of action?

-Disease of the Posterior Pituitary

-Ectopic secretion (SO NOT from the PP) of ADH is most common cause (via tumors; cancers of lung, duodenum, stomach, pancreas, gall bladder and prostate)

-Associated with pulmonary disorders (pneumonia, asthma and CF) and CNS disorders (encephalitis, meningitis, hemorrhage, tumors, trauma)

-Also common after surgery: transient RT volume shifts

-Medications in older adults: antidepressants, antipsychotics, general anesthetics, NSAIDS

Syndrome of inappropriate antidiuretic hormone

SIADH Secretion

Pathophysiology

-Enhanced renal water retention

-Collection ducts

-Expanded extracellular fluid volume, hyponatremia, hypoosmolarity

Syndrome of inappropriate antidiuretic hormone

SIADH Secretion

CLINICAL MANIFESTATIONS

-thirst, impaired taste, anorexia, dyspnea, fatigue

-GI symptoms: vomiting, cramps,

-Confusion, lethargy, muscle twitching, convulsions

Diabetes insipidus (DI)

Mechanism of Action

What are the two causes?

-Disease of the Posterior Pituitary

-Insufficiency of ADH

- Neurogenic: Most common

      : Insufficient amount of ADH

      : Brain tumors, aneurysms, thrombosis, infection,   close-head trauma (pressing on pituitary, minimal blood flow)

      :Genetics: mutations of ADH genes or copeptides

-Nephrogenic: inadequate response to ADH (may be enough cells but don't recognize)

      :Genetic: mutation in aquaporin gene

      :Aquired: damage to renal tubules and generation of cAMP (pyelonephritis, amyloidosis, PKD, drugs)

Diabetes Insipitus (DI)

PATHOPHYSIOLOGY

-Cannot concentrate urine; large volumes of dilute urine; increased thirst, dehydration, increased plasma osmolarity, hypernatremia

-Nephrogenic: ADH levels normal but CD do not respond

-Neurogenic: Low ADH levels

Diabetes Insipitus (DI)

Clinical Manifestations

-Polyuria, nocturia, continuois thirst (losing fluids), polydipsia

-Idiopathic- abrupt onset

Hypopituitarism

Mechanism of Action

DISEASES OF THE ANTERIOR PITUITARY

-Infarction, removal or destruction, space occupying lesions (adenoma, aneurysm)

-Pituitary infarction cia ischemic pitutary necorsis (Sheehan Syndrome-post partum vasopasm of artery supplying anterior pituitary) shock, Sickle Cell Disease

-Genetic abnormalities, head trauma, pituitary tumors, infections, vascular malformations, surgical ablation

Hypopituitarism

PATHOPHYSIOLOGY

-Highly vascular and vulnerable to ischemia

-Disruption of blood flow causes, infarction and necrosis, edema, and swelling; expansion in area further impedes blood flow

Hypopituitarism

Clinical Manifestations

Panhypopituitarism

-Depends on the affected hormones

-Panhypopituitarism: cortisol deficiency (ACTH), thyroid deficiency (TSH), gonadal failure and loss of sex characteristics (FSH, LH), Dwarfism (GH), Lack of menses (LH, FSH), Inability to lactate (PRL)

Hypopituitarism

Clinical Manifestations

ACTH

Cortisol deficiency, life threatening; hypoglycemia, degressed glycogen, decreased glucogenesis, nausea/vomitting, anorexia, fatigue, weaknes (CATABOLIC, help survive flight or fight)

Hypopituitarism

Clinical Manifestations

TSH

Cold intolerance, dryness, lethargy, decreased metabolic rate

Hypopituitarism

Clinical Manifestations

FSH/LH

Amenorrhea, atrophic vagina, uterus and breasts; atrophy of testes; decreased body hair and libido

Hypopituitarism

Clinical Manifestations

GH

in children growth failure; in adults vague-- social withdrawal, fatigue, loss of motivation

Hyperpituitarism

Mechanism of Action

-Commonly due to a benign, slow-growing pituitary adenoma (secretes the hormone)

-Adenoma secretes hormones of the cell type from which arose; without regard to physiologic need or feedback response; GH and Prolactin

-Can have hyposecretion; GH, LH, FSH, related to pressure from expanding tumor.

Hyperpituitarism

Clinical Manifestations

-Headache and fatigue

-Visual changes RT tumor impringing on optic chiasm

Hyperpituitarism

Hypersecretion of Growth Hormone

Mechanism of Action

-Common Cause: primary, autonomous GH-secreting pituitary adenoma

-Hyersecretion of growth hormone during adulthood

-Slowly progressive: Mortality: cardiac hypertrophy, hypertension, atherosclerosis, type 2 DM lead to CAD

-Malginancies common

-Connective Tissues proliferation

Hyperpituitarism

Hypersecretion of Growth Hormone

Clinical Manifestations

-Acromegaly

-Enlarged tongue, interstitial edema, increase in the size and function of sebaceceous and sweat glands, coarse skin and body hair

-Bone proliferation: large joint arthropathy, periosteal vertebral growth (kyphosis)

-Enlarged facial bones and hands and feet:

        :Protrussion of the lower jaw forehead

        :Need for increasing larger sizes of shoes, hats, rings, gloves

Giantism: GH hypersecretion in children and adolescents

Hyperpituitarism

Hypersecretion of Prolactin

Mechanism of action

Causd by prolactinomas

Mostly commm a hormonally active pituitary tumor

Hyperpituitarism

Hypersecretion of Prolactin

Clinical Manifestations

In Females and in Males

Females: increased levels of prolactin cause amenorhea, galactorrhea, hirsutism, and osteopenia

Males: increased levels of prolactin cause hypogonadism, erectile dysfunction, impaired libido, oligospermia, and diminished ejactile volume

 Alterartions in the Thyroid gland

Primary VS. Secondary

Primary: Dysfunction of disease or thyroid gland: TH production

       : Graves Disease

       :Toxic multinodular goiter

       : Follicular thyroid carcinoma

       :Drugs

Secondary: Alteration of pituitary TSH production

       :RARE

       :TSH secreting pituitary adenomas

Grave's Disease

Mechanism of Action

-50-80% of cases: Women

-Multisystem syndrom: hyperthyroidism, diffuse thyroid enlargement (goiter), opthalopathy, dermopathy

-Autoimmunie: Type II hypersensitivity (modulation), T lymphocytes synthesized to thyroid antigens, stimulate B cells to produce IgG that bind to TSH receptors and stimulate synthesis and secretion of excess TH

- mutations of several MHC genes

-Supress TRH and TSH

-Goiter: hyperfunction of thyroid gland metabolism

-Pretibal myxedema: Subcutaneous swelling anterior portion of legs and erythematous skin- associated with fibroblasts and T lymphocytes

-Exothalamous: orbital fat accumulation and inflammation with edema; extraocular muscle weakness and double vision

Graves' Disease

Hyperthyroidism resulting from nodular thyroid disease

-Thyroid gland enlarges in response to secretion of TSH (puberty, pregnancy, iodine deficiency); with resolution gland returns to normal size; but can have irreversible changes in some follicular cells

-No myxedema or exothalmus

Graves' Disease

Thyrotoxic crisis

-Rare and Dangerous

-Can develop spontaneously; may occur in person with undiagnosed hyperthyroidism subjected to excess stress

Hypothyroidism

Primary and Secondary

What does it affect?

-Affects all body systems

-Insidious in onset

-Decreased energy metabolism and heat production

-Low basal metabolic rate, cold intolerance, letargy fatigue, low body temperature

Hypothyroidism

Mechanism of Action

1. Primary thyroid malfunction--> Lack of TH negative feedback on pituitary TSH secretion and hypothalamic TRH secretion--> Low levels of TH and high levels of TSH and TRH

Secondary Causes

2. Pitutiary malfunction--> Lack of negative feedback to hypothalamic release of TRH by TSH and thyroid TH--> Low levels of TSH and TH and high levels of TRH

3. Hypothalamic malfunction--> decreased TRH--> Low levels of TRH, TSH, and TH

Hypothyroidism

Myxedema

What causes it?

What is it's clinical manifestations

1. Protein mucopolysaccharide complex binds to water

2. This produces non pitting boggy edema around eyes, hands and feet, thickened tongue, laryngeal and pharyngeal mucous membranes resulting in hoarseness, slurred speech.

Hypothyroidism

Conditions

1. Iodine deficiency: most common world wide

2. Autoimmune thyroiditis (Hashimoto Disease): gradual inflammatory destruction of thyroid by infiltration of lymphocytes and circulating thyroid antibodies (antithyroid peroxidase and antithyroglobulin antibodies), activation of NK cells, cytokines, induction of apoptosis; goiter ( still being asked to make it, follicular cells increasing insize)

3. Subacute thyroiditis: nonbacterial inflammation via viral infection; hyper, followed by hypo and then eu: symptoms last 2-4 months.

4. Painless thyroiditis: time frame similar to subacute thyroiditis but pathologically like Hashimoto

5. Postpartum thyroiditis: within 6 months of delivery; course similar to painless thyroiditis (short term)

Hyperparathyroidism

PRIMARY

-Excess secretion of PTH from one or more parathyroid glands in response to low serum Calcium levels

-85% caused by parathyroid adenomas

Hyperparathyroidism

SECONDARY

-Increased in PTH secondary to chronic disease (outside the parathyroid)

-Renal Failure resulting in hyperphosphatemia decreased activation Vitamin D and hypocalcemia which stimulates PTH

-Intestinal malabsorpition; (dietary deficiency of Vitamin D, and calcium)

Hyperparathyroidism

Clinical Manifestations

-Hypercalcemia (affects GI, muscle and nervous systems) and hypophosphatemia (inverse relationship)

-Excessive osteoclast activity resulting in bone resorpiton; fractures, kyphosis and compression fractures of the vertebral bodies

-Produces hypercalcuria, metabolic acidosis, alkaline urine, increases renal excretion of phosphate (hyperphospaturia)

-Hyperphosphoturia, alkaline urine and hypercalcuria predispose to calcium stones in the kidney.

Hyperparathyroidism

Pathophysiology

1. BONE: releases Ca2 from the bone

       -Bone resorption

       -Direct effect of osteroblasts which then stimulates osteoclasts

       -transports calcium from bone to ECF (increase in serum Calcium level)

2. GIT: Increase Ca uptake

       -Acts synergistically with Vit D

       -Indirect action thru Vit D (induce a calcium-binding protein in the duodenal and jejunal mucosa)

       -Increase absorption of phosphate

               : Acts synergistally with Vit D

3. Kidney: Increase reabsorption of Calcium

       -Increase urinary excretion of phosphate

       -Reduces tubular reabsorption of phosphate

       -Formation of Vit D3 ( acts in the intestine)

      -Decrease Na and bicarbonate reabsorption from the proximal tubule

-Assess the pituitary corticotroph cell response to glucoccorticoid negative feedback inhibition of ACTH secretion

-Helps distinguish patients with Cushing's disease (Cushing's syndrome caused by hypersecraetion of ACTH) from patients with ectopic ACTH syndrome (Cushing's syndrome caused by non-pituitary ACTH secreting tumors)

-ACTH secretion can be suppressed in most patients with Cushing's Disease; most nonpituitary malignant tumors that produce ACTH ectopically are not responsive to glucocortoid negative feedback

Hypoparathyroidism

Mechanism of Action

-Abnormally low PTH levels

      :depressed serum Ca levels (hypocalcemia)

  :increased serum phosphate levels(hyperphosphotemia)

-Usually caused by parathyroid damage in thyroid surgery

-Impaired ability to reabsorb Ca from the bone and regulate Ca reabsorption from the renal tubules

hypoprarthyrodism

Clinical Manifestations

-Symptoms related to hypocalcemia: lowered threshold potential; increased excitability; muscle spasms, hyperreflexia, tonic-clonic convulsion, laryngeal spasms

-Chvosteck and Trousseau signs (puff up cuff)

Type I Diabetes Mellitus

Mechanism of Action

-immunologically mediated destruction of beta cells in pancreatic islets: can be autoimmune (type 1a) or nonimmune: secondary to other diseases such as pancreatitis or idiopathic (type 1b)

-Genetic susceptibility: (rubella, cytomegalovirus, mumps, Epstein-Barr virus); strongest association with MHC (class II HLA-DQ and HLA-DR); 5-8 x risk if these markers are present

-Enviromental factors: viral infections

Type I Diabetes Mellitus

Pathophysiology

1. Genetic or Enviromental Factors

2. autoantigens form on insulin-producing beta cells and circulate in the blood stream and lymphatics

3. Processing and presentation of autoantigen by antigen presenting cells which cause

4. Activation of T helper 1 lymphocytes and activation of helpre 2 lymphocytes

5. TH 1 activate IFN to activate macrophages with release of IL1 and TNF alpha and also the acitvaiton of IL-2 to activation of autcantigen specific T-cytotoxic (CD8) cells

6. TH 2 cells lead to the activation of B lymphocytes to produce islet cell autoantibodies and antiGAD antibodies

7. Both steps 5 and 6 lead to the destruction of beta cells with decrease insulin secretion

Type I Diabetes Mellitus

Clinical Manifestations

-Hyperglycemia (80-90% of the function of the insulin-secreting beta cells in the islet of Langerhans is lost)

-Polydipsia, polyuria, polyphagia, weight loss, and fatigue

-Protein and fat breakdown occur because of lack of insulin

Type II Diabetes Mellitus

Mechanism of Action

-Adults and Children

-Genetic and enviromental interaction

-Metabolic Syndrome: confers a high risk of T2DM

-INSULIN RESISTANCE:

1.Adipokines: produced by adipose tissue (increase insulin resistance)

2. Free-fatty acids: decrease tissue responsiveness to insulin (abdominal obesity)

3. Inflammatory cytokines, TNF alpha, II-6 (post receptor mechanisms, they have insulin but the signal is not being received)

4. obesity (hyperinsulinemia, decreased insulin receptor density, creates insulin resistance)

Type II Diabetes Mellitus

Clinical Manifestation

Recurrent infections, vision problems, neuropathy

Type II Diabetes Mellitus

What are the 5 things in this metabolic syndrome?

1. Abdominal Obesity

2. Low HDL

3. Increased fasting blood glucose

4. HTN

5. Increased triglycerides

(only need 3 of the 5 to have high metabolic syndrome)

Type II Diabetes Mellitus

Pathophysiology

1. Gentitic Disposition

2. decreased activity of amylin (co-secreted with insulin; deficiency parallels the reduction in insulin over time) and decreased activity of incretins (released from the GI tract in response to food intake; GLP-1, GIP; stimulates insuline release; inhibited by DPP-IV)

3. causes decreased beta cell mass function which caused hypoinsulimia

4. causes tissue effects and hyperglycemia (increases glucagon)

OR

1 Genetic Disposition

2. Obestiy (Diet, inactivity) leads to

3. Adiposkines, increased free fatty acids, inflammatory cytokines AND decreased activity of Ghrelein (Produced in stomach and pancreatic islets; decreased levels associated with insulin resistance) which causes

4. Insuline resistance which causes

5. Decrease in beta cell mass function and increased demand for insulin synthesis which leads to

6. hyperinsulimeia

7 Which is tissue effects without hyperglycemia

Type II Diabetes Mellitus

Diagnosis and Monitoring

-FPG > or = 126 on 2 occasions

-NFG > 200 mg/dl

-OGTT > 200 mg/dL after 2 hours

- HbA1C: glucose bind to Hb; 120 day lifespan of RBC; reflects the average level of glucose that the cell has been exposed to during its life cycle; used for screening hyperglycemia and assess effectiveness of therapy

Type I Diabetes Mellitus

Acute complication

-Hypoglycemia

- Diabetic ketoacidosis: Usually associated with type I

Illness, trauma, surgery, emotions, total body (not serum) potassium deficiency, cerebral edema (especially in children)

-Somogyi effect: Usually with Type I, hypoglycemia with rebound hyperglycemia, not as common as once thought

Type II Diabetes Mellitus

Acute Complications

-Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS): Usually associated with type II. Higher glucose level, less ketosis, Severe dehydration and potassium deficiency

-Dawn phenomenon: Early morning glucose elevation without noctunal hypoglycemia. Related to nocturnal growth hormone elevation.

Type I and Type II Diabetes

Pathophysiology of DKA and HHNKS

Diabetes Mellitus

What are Chronic Complications?

Why does this lead to atherlosclerosis?

-Hyperglycemia and nonenzymatic glycosyltion

1. nonenzymatic glycosylation: reversible attachment of glucose to proteins, lipids and nucleic acids without activation of enzymes

2. Recurrent or persistent hyperglycemia, glucose becomes irreversibly bound to collagen and other proteins in RBCs, blood vessel walls and interstitual tissues = Advanced Glycosylation End Product (AGE)

3. receptors for AGE =RAGE; with properties that cause tissue injury or pathologic conditions

       -Crosslink trap protens LDL, immunoglobulins, complement

       -Thickened basment membrane and increase permeability of BV and nerves

       -Bind to the receptors on macrophages and induce the release of GF and cytokines

      -Induce lipid oxidation, oxidative stress and inflammation

      -Inactivation of nitric oxide and decreased endothelial dysfunction

      -Procoagulation changes

Type II Diabetes Mellitus

Clinical Manifestation

Microvascular Disease

-Diabetic Retinopathy: response to retinal ischemia resulting from blood vessel changes and RBC aggregation, related to age, duration of diabetes and glycemic control

-Diabetic Nephropathy: most common cause of end stage renal disease; develops after 5-10 years; many causes; genetic factors may confer susceptibility (see slide 49)

-Diabetic Neuropathy: most common cause of neuropathy; pathology related to chronic hyperglycemia; "dying back"; axonal degeneration of sensory fibers

Type II Diabetes Mellitus

Clinical Manifestations

Macrovascular Disease

-Coronary Artery Disease: most common cause of death in someone with type 2. Prevelance increased with duration of disease, Risk equivalent, MI equivalent.

-Stroke: 2x as common in those with DM

-Peripheral Arterial Disease: Atherosclerosis appears younger, advances more rapidly that in non diabetic; gangrenous changes in lower extremities with smaller vessels with more advanced disease

Type II Diabetes

Clinical Manifestation

Infection

-Impaired vision and neuropathy diminish prevention of breaks in skin; loss of protective sensations

-Microvascular and macrovascular complications decrease oxygen supply to tissures; increased glycosylated Hb decreases release of oxygen to tissues

-Pathogens multiply rapidly; increased glucose as source of energy

-Decrease blood supply resulting from vascular changes result in decreased white cells to affected areas

-Chemotaxis and phagocytosis defective

-Inflammatory response diminished and client signals may be absent.

Disorders of the Adrenal Cortex

Adrenocortical Hyperfunction

CUSHING'S DISEASE VS CUSHING SYNDROME

Mechanism of Action

-DISEASE: Excessive anterior pituitary secretion of ACTH

- SYNDROME: excessive level of cortisol regardless of cause

Disorders of the Adrenal Cortex

Adrenocortical Hyperfunction

Cushing's Disease

Pathophysiology

-Anterior Pituitary

-Pituitary adenoma which secreting ACTH, also ectopic ACTH secreting tumors; some tumors secrete CRH; episodic secretion of ACTH from small cell carcinomas of various tissues; cortisol fails to inhibit release of ACTH from ectopic sources via negative feedback

Cushing's Disease

Clinical Manifestations

-caused by hypercortiolism

-Weight gain from accumulation of adipose tissue(trunk, face, cervical area); truncal obesity, moon face and buffalo hump

-Glucose intolerance; cortisol induced insulin resistance, increased gluconeogenesis and glycogen storage by the liver, diabetes develops.

-Protein wasting results from catabolic effects of cortisol; muscle wasting, weakness thinning of limbs

-Increased bone resorption and inhibits bone formation

-hyperpigmentation related to increased MSH

- Increased vascular sensitivity to catecholamines-vasoconstriction and HTN

Hyperaldosteronism

Primary (Conn's Disease)

-Excessive secretion of aldosterone related to abnormaility of the adrenal cortex- primary cause is aldosterone sectreting tumor. It results in HTN, hypokalemia, renal potassium wasting, neuromuclar manifestations

Hyperaldosteronism

Secondary Hyperaldosteronism:

excessive aldosterone release from extra renal stimulus-most often Angiotensin II, via decreased circulating blood volume (shock, dehydratinion, hypoalbuminemia) ; decreased delivery of blood to the kidneys( RA stenosis, HF, hepatic Cirrhoisis)

Hyperaldosteronism

Clinical Manifestations

HTN (blood volume or vasconstriction), less commonly hypokalemia and metabolic alkalosis, edema does not usually occur because of "renal escape"

1. Secreting tumor

2. Increased aldosterone

3. Increased Na retension, Increased total Sodium, Increased Extracellular fluid

4. Increased Blood Pressure

5. Plasma volume expansion

6. Decreased Renin

7. Increased K loss

Adrenocortical hypofunction

Primary adrenal insufficiency (Addison disease)

Mechanism of Action and Patho

-Autoimmune destruction of adrenal cortex is most common cause

-Other causes include infection, infilitative disease or adrenal hemorrhage.

-Hypersecretion of adrenal androgens and estrogens (Feminization, Virilization)

Adrenal Medulla Hyperfunction

Mechanism of Action

-Caused by tumors derived from the chromaffin cells of the adrenal medulla ( Pheochromocytomas)

-Secretes catecholamines on a continuous or episodic basis.

Adrenal Medulla hyperfunction

Clinical Manifestations

(related to catecholamine secretion)

-Persistent HTN, increased peripheral vascular resistance, diaphoresis, tachycardia, vascular resistance, diaphoresis, tachycardia, palpitations and severe headaches; hypermetabolism with chronic activation of adrenergic receptors in adipose tissue of the liver

-Tumors are vascular and can rupture leading to hemorrhage (potential fatal)

Secondary HTN

What could be other causes of HTN?

- Clinical Cues (Most Common):

1. Primary Aldosteronism: 10-20% of resistant HTN; unexplained, hypokalemia; 50% are normokalemic at presentation

2. Renal Artery Stenosis: due to atherosclerotic vascular disease or in younger patients, fibromuscular dysplasia

3. Chronic Kidney Disease

4. Obstructive Sleep Apnea

Evaluation

1 Screen for primary aldosternism: paired morning measure of plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to determine PAC/PRA ratio

2. 24 hour urine to evaluate Sodium excretion, creatinine clearance, and aldosterone excretion.

3. Evaluate sleep apnea

4. Imaging for RA stenosis- delay until remainder of evaluation is negative; imaging with low specificity for renal adenomas

* Less common identifiable causes: pheochromocytoma (episodic HTN, palpitations, Diaphoresis, tremor) Cushings syndrome and aortic coarction