Parathyroid Path: Remember, the parathyroid gland is composed of two different cells: 1. _____ are small, round bland cells that secrete PTH. 2. _____ are large cells with abundant eosinophilic cytoplasm.

1. Chief cells 2. Oxyphil cells

Exam II Flashcards by Jesi Whitley

The _______ are located on the posterior surface of the thyroid gland. They are inside of the sheath of the thyroid, but outside of the CT capsule. They appear as small, flattened, oval structures.

parathyroid glands

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Parathyroid Histo:

The superior parathyroid glands are slightly superior to the entry site of the ________ artery.
The inferior parathyroid glands are slightly inferior to the entry site of the ______ artery.

Inferior thyroid artery (both)

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Parathyroid Histo: The number of parathyroid ranges from 2-6, with 4 glands (2 superior and 2 inferior) being the most common.

The major supply to the parathyroid glands is the inferior thyroid artery. What are other sources?

a. superior thyroid artery
b. laryngeal artery
c. thyroid ima artery
d. tracheal artery

all of the above

*esophageal artery

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Parathyroid histo: Venous drainage of the parathyroid glands occurs via

thyroid plexus of veins

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Parathyroid histo: Innervation of the parathyroid glands includes

thyroid branches of cervical (sympathetic) ganglia

*vasomotor only

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Parathyroid Histo: The parathyroid glands derive from the ____ and ____ pharyngeal pouches.

3rd and 4th pharyngeal pouches

Dorsal regions of 3rd pouch: Inferior parathyroid
Dorsal region of 4th: Superior parathyroid

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Parathyroid Histo: True/False - The dorsal region of the 3rd pharyngeal pouch forms the inferior parathyroid. It eventually loses its connection to the pharyngeal wall, and attaches to the thyroid as it migrates. This is similar to the 4th pouch, which attaches to the dorsal part of the migrating thyroid.

True

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Parathyroid Histo: The parathyroid is separated from the thyroid gland by a CT capsule which forms septa in the gland. Cells within the parathyroid gland are arranged as cords surrounded by fenestrated capillaries. What are the cells of the parathyroid?

Chief (principle)
Oxyphil

*2 fxnal variations of the same cell

*adipose in parathyroid = inc. w/ age

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Parathyroid Histo: ______ are small, pale staining cells with centrally located nuclei, lipofuscin, glycogen and lipid droplets. They are capable of dividing and play a role in secretion of PTH.

Chief (principle cells)

*most numerous cells in parathyroid

*able to divide

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Parathyroid Histo: True/False - Principle (Chief) cells differentiate during embryonic development. They become functionally active in regulating fetal Calcium metabolism.

True

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Parathyroid Histo: _______ are large, eosinophilic cells with lots of mitochondria. They appear at puberty and increase with age. They are believed to regulate chief cell numbers.

Oxyphil cells

NO PTH secretion

*minor cells of parathyroid

*inc. # w/ chronic kidney disease

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Parathyroid Histo: True/False - Adipose in the parathyroid gland increases with increasing age.

True

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Parathyroid Histo: PTH is essential for life. It binds to the PTH receptor on the surface of cells and indirectly regulates gene expression. What doe sit regulate?

Blood calcium levels
Blood phosphate levels
1,25 OH - Vitamin D3

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Parathyroid Histo: Parathyroid Hormone (PTH) elevates blood calcium levels by:

inc. bone resorption (inc. osteoclast activity)
decreasing urinary excretion of calcium
increasing intestinal absorption of calcium
Stimulates conversion of Vit. D to Calcitriol (1,25-OH) in the kidneys

How does it regulate phosphate level?

Increases excretion of phosphate

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Parathyroid Histo: PTH binds to the receptor on osteoblasts, which activates ______ to degrade bone releasing Calcium and Phosphate.

activates osteoclasts

*Ca and PO4 bind each other

*PTH induces PO4 excretion in kidney = releases Ca2+ to be absorbed in kidney

*PTH – osteoblasts – RANKL – binds osteoclast RANK-r – activation

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Parathyroid Histo: True/False - PTH stimulates Ca2+ absorption in the intestine by stimulation the expression of an enzyme that converts inactive Vit. D to its active form. This in turn increases Ca2+ absorption

True

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Parathyroid Histo: PTH is regulated by a calcium sensing receptor located on the surface of ______ cells.

When calcium is elevated, these ions bind to the Ca2+ sensing receptor and inhibit PTH.
When calcium is low (< 10mg/dL), the receptor is NOT activated, inc. PTH.

chief (principle)

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Parathyroid Histo: Rapid, acute homeostatic action on blood calcium levels occurs via _______, whereas long-term homeostatic action of blood calcium occurs via ______.

Calcitonin (dec. Ca)
PTH (inc. calcium; hours)

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Parathyroid Path: Remember, the parathyroid gland is composed of two different cells:

_____ are small, round bland cells that secrete PTH.
_____ are large cells with abundant eosinophilic cytoplasm.

Chief cells
Oxyphil cells

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Parathyroid Path: PTH stimulates ____ enzyme in the kidney, which promotes conversion of Vitamin D to Calcitriol.

1-alpha-hydroxylase

*If suspected Vit. D. deficiency, measure 25-OH vit. D (stored form)

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Parathyroid Patho: When the parathyroid glands sense low ionized calcium, they inc. PTH secretion. Increased PTH leads to elevated PO4 and Ca2+ levels. What are the effects of PTH on

Small Intestine
Kidney
Bone

SI: calcitriol inc. calcium and PO4 absorption
Bone: PTH stimulates calcium and PO4 release (via activation of osteoclasts)
Kidney: PTH stimulates calcitriol formation and Ca2+ reabsorption in the DCT; Inhibits PO4 and HCO3- reabsorption

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Parathyroid path: True/False - PTH is typically activated in the presence of dec. plasma Ca²⁺ and dec. plasma Mg²⁺. However, in cases of extremely low Mg²⁺ levels, PTH is decreased, thus leading to dec. Ca²⁺ levels. This is why Mg²⁺ levels are often ordered on hospitalized patients (ICU, pancreatitis and chronic ethanol use).

True

*hypoalbuminemia, Small intestine bypass, diarrhea, diuretics, ethanol, aminoglycosides

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Parathyroid path: Decreased ionized calcium levels causes _____ of the nerves and muscles, meaning a smaller stimulus will be required to inititate action potential.

Partial depolarization

1. Trousseau sign: carpopedal spasm

Chvostek sign

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Parathyroid path: Following occlusion of arterial blood supply using a BP cuff for 3 min, you note your patient flexes his wrist and adducts his thumb into his palm.

This is a sign of

Hypocalcemia (decreased ionized calcium levels)

*Trousseau sign (carpopedal spasm)

(the ischemia induces hyperexcitability of nerve trunk under BP cuff.)

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Parathyroid path: ______ is characterized by contraction of ipsilateral facial muscles with tapping on the facial nerve. It is not as specific (some healthy people may have + sign)

Chovstek sign

Parathyfoid path: A patient presents with complaints of **parasthesia, perioral numbness, muscle spasm** and **laryngeal spasm**. You note he is positive for Chvostek sign and Trousseau sign (carpopedal spasm). You suspect

Hypocalcemia \*convulsions, tetany \***etiologies**: Chronic renal failure (dec. calcitriol and dec. Ca2+ reabsorption), PTH deficiency, PTH resistance, Vit. D deficiency

Parathyroid path: Vitamin D is produced from UVB light exposure (30 minutes). Optimal levels vary based on clinical risk, but it is usually \> 30ng/mL. It can be tested clinically in what populations?

1. older adults (confined to indoors) 2. residents of several regions during winter months (NE/NW U.S.) \*reported as total 25-OH(D)

Parathyroid path: Individuals at risk of low dietary vitamin D levels include: a. infants fed only mother's milk b. children who do not drink fortified milk c. malabsorption syndromes d. individuals who spend little time outside

all of the above -malabsorption syndromes: pancreatic enzyme deficiency, Crohn, CF, celiac, surgical resection of stomach

Parathyroid Path: The following are common etiologies of Vit. D deficiency: 1. Severe liver disease 2. Kidney disease 3. Certain drugs (*phenytoin, phenobarbital, rifampin*) 4. High altitudes Severe liver disease decreases the conversion of Vit. D to 25-D (1st hydroxylation step) and causes malabsorption of vit. D. What are the effects of kidney disease, medications, and high altitudes?

1. **_Liver disease_** * --dec. conversion of Vit. D to 25-D * --malabsorption ot vit. D 2. **_Kidney disease_** * nephrotic syndrome = inc. urinary loss of vit. D. 3. **_Certain drugs_** * phenytoin, phenobarbital, rifampin * inc. inc. breakdown of Vit. D by liver 4. **_Higher altitudes (northern climates)_** * inc. risk deficiency -- winter (dec. UVB radiation)

Parathyroid Path: What are the effects of the following on Vitamin D? 1. Older adults 2. Decreased sun exposure (cultural) 3. Races with inc. melanin

1. _Older adults_ * dec. efficiency at producing Vit. D (w/ inc. age) * dec. Vit. D precursors 2. _Dec. sun exposure_ * due to covering 3. _inc. skin pigmentation_ * dec. vit. D conversion (50x) * inc. risk if living at high latitude

Parathyroid path: True/False - Calcitriol (D3) is inversely related to plasma Ca2+. In cases of decreases serum Ca2+, PTH activates 1-alpha hydroxylase to inc. calcitriol production.

True \*\*inc. plasma Ca2+ in cases of dec. Ca2+ levels

Parathyroid path: PTH functions to: 1. Inc. Ca2+ 2. Inc. PO4 excretion 3. inhibits HCO3- reabsorption (kidney) 4. Inc. synthesis of 1-alpha hydroxylase in the proximal tubule (promote Vit. D synthesis) If PTH is increases, Calcitriol is \_\_\_\_\_\_\_\_. If PTH is decreased, calcitriol is \_\_\_\_\_\_.

1. Inc. PTH = inc. calcitriol 2. Dec. PTH = dec. calcitriol

Parathyroid path: Hypoalbuminemia ______ total plasma calcium, with normal free ionized calcium levels and normal PTH.

Decreases \*Correct: Total plasma Ca2+ + 0.8 (4 - plasma albumin) \*see slide 16

Parathyroid path: What are the effects of alkalosis on Calcium levels?

1. Total Calcium: Normal 2. Acute decrease Ionized calcium (inc. affinity of calcium for albumin) 3. Inc. PTH (tetany) \*more calcium binds to negative charges on albumin NOTE: First step in the evaluation of a patient with hypocalcemia à measure the serum albumin concentration

Parathyroid path: DiGeorge is one of the many etiologies that can cause hypOparathyroidism. It is a disorder due to a deletion (22q11) that results in failure of the 3rd and 4th pouches to develop. As a result, there is no thymus (no T cells) and no parathyroid gland. What are other etiologies of hypoparathyroidism?

1. Surgery 2. Autoimmune 3. Significant hypomagnasemia * Mg2+ is a cofactor for adenylate cyclase -- Inc. cAMP * cAMP required for PTH synthesis/secretion

Parathyroid path: A patient presents with complaint of **tingling** of the extremities and the lips. He reports **muscle spasms**, and exhibits **tetany-like** symptoms. General appearance reveals **hooded eyes**, low set ears, and a **bulbous** nose. _Labs reveal:_ 1. Dec. Calcium 2. Dec. PTH ROS reveals **conotruncal cardiac** anomalies, **hypoplastic thymus** and hypocalcemia. You suspect

DiGeorge Syndrome \*\*Deletion 22q11.2 \*\*Failed 3rd/4th pouch development (no parathyroid, thymus)

Parathyroid path: The MC causes of hypoparathyroidism are 1. DiGeorge syndrome 2. Hereditary autoimmune syndrome 3. Removal w/ thyroidectomy \_\_\_\_\_ is due to mutation in autoimmune regulator gene (AIRE)

hereditary autoimmune syndrome

Parathyroid path: A patient presents with short stature, rounded face, and short 4th/5th metacarpals and metatarsals (brachymetatarsia). _Labs reveal:_ 1. Dec. calcitriol 2. Dec. serumcalcium 3. Inc. PTH 4. Inc.l plasma phosphate You suspect?

Pseudohypoparathyroidism \*Albright Hereditary Osteodystrophy (phenotype) \*end organ resistance to PTH

Parathyroid path: 1. Primary hyperparathyroidism is MC due to ______ or **gland hyperplasia** 2. Secondary hyperparathyroidism is most often due to **chronic renal failure, Vit. D deficiency,** or \_\_\_\_\_\_

1. functioning neoplasm (adenoma) 2. primary malabsorption

Parathyroid path: True/False - Primary hyperthyrdoidism is intrinsic within the parathyroid gland. It is usually due to the presence of an adenoma, and may be associated with hyperplasia.

True \*\*MEN1/MEN2a sporadic neoplasms = MC hyperplasia

Parathyroid path: Secondary hyperparathyroidism involves physiologic compensation for chronic hypoCa2+. It is usually due to dec. Vit. D and is associated with chronic renal failure. What labs would be seen in patients with chronic renal failure (with regard to Ca2+ and phosphate?)

1. Inc. PO4 2. Dec. Calcitriol * (loss of 1-a-hydroxylase activity in PT; loss of 2nd hydroxylation step) \*secondary to low calcium and low Vit. D

Parathyroid path: What is the MC cause of hypercalcemia?

Parathyroid adenoma \*hyperplasia \*MEN1/MEN2a

Parathyroid path: ______ is characterized by a **monotonous population of benign chief cells** w/ absent intervening adipose tissue. It MC presents in **post-menopausal** females with **high plasma calcium**.

Parathyroid Adenoma \*Most often asymptomatic

Parathyroid path: Pre-surgical diagnosis of hypercalcemia (due to primary hyperparathyroidism) often occurs incidentally and may include: 1. initial plasma PTH 2. referral to otolaryngologist (ENT/ORL) 3. radionucleotide scan (pre-operative) True/False - Pre-operative scintigraphy may be useful in localizing and distinguishing adenomas from parathyroid hyperplasia, where more than one gland would demonstrate increased uptake.

True \*\*Harp slide 28

Parathyroid path: A patient presents with painful bones, renal stones, abdominal groans and psychic moans. _Labs reveal:_ 1. Inc. plasma calcium 2. Cystic bone spaces with brown fibrous tissue 3. Nephrocalcinosis _Imaging Reveals:_ 1. Subperiosteal. bone resorption involving the phalanges You suspect primary hyperparathyroidism. What is contributing to the renal stones? The painful bones?

1. _Renal stones_ * Inc. calcium = inc. urinary calcium excretion (formation of renal stones and nephrocalcinosis - metastatic calcification) * renal insufficiency 2. _Bone pain_ * Inc. PTH = inc. bone resorption (osteoclasts; dec. bone mineral density) * Cystic bone lesions (osteitis fibrosa cystica) NOTE: MC presentation: asymptomatic hypercalcemia (Dx incidentally w/ labs)

Parathyroid path: A patient with primary hyperparathyroidism may present with abdominal issues (**constipation, pancreatitis and PUD**). What is the pathophysiology of these?

1. Hypercalcemia inc. gastrin = inc. gastric acid (PUD) inc. pancreatic enzymes = inc. pancreatitis inc. Ca2+ = constipation

Parathyroid path: Hyperparathyroidism may also present with neuropsychiatric manifestations (psychosis, confusion, anxiety). True/False - Additionally, calcium can lead to inc. SM contraction in vessels and thus inc. risk of **HTN**. It may also lead to **metastatic calcification** (excess calcium deposits within normal tissues)

True

Parathyroid Path: The following are indicative of hyperparathyroidism: 1. Inc. serum PTH, calcium 2. Chloride/phosphorus ratio \> 33 3. dec. phosphorus 4. dec. bicarbonate (lost in urine; normal anion gap metabolic acidosis) 5. Dec. calcitriol 6. Inc. Cl- What are the causes for these labs?

Primary hyperparathyroidism 1. Dec. VIt. D = hypercalcemia inhibits 1-a hydroxylase 2. Inc. Cl- = counterbalance loss of negative charges due to dec. HCO3- 3. Dec. PO4 due to PTH (dec. resorption in kidney)

Parathyroid path: Secondary hyperparathyroidism is most often due to Vitamin D deficiency. This may be associated with: 1. Chronic renal failure (MC) 2. Inadequate sun exposure 3. Fat malabsorption 4. Chronic liver disease 5. Inc. metabolism (e.g. EtOH, phenobarb) What is a means for treating secondary hyperparathyroidism

Etelcalcitide - blocks Ca2+ sensing receptors (on parathyroids) - approved for secondary

Parathyroid path: Tertiary or Refractory (autonomous) hyperparathyroidism results from longstanding chronic renal failure (end stage renal disease). It presents with: 1. Inc. PTH 2. Inc. calcium (hypercalcemia) True/False - Tertiary hyperparathyroidism may persist after renal transplant, and patients will likely need their parathyroid glands removed.

True \*may also present w/ renal osteodystrophy (bone lesions seen in secondary/tertiary)

Parathyroid path: Malignancy-associated hypercalcemia is the 2nd MC cause of hypercalcemia. It is most commonly due to PTHrP (squamous cell carcinoma of lungs or renal cell carcinoma). However, it may also be associated with: a. inc. osteoclast activity (myeloma) b. inc. calcitriol synthesis (lymphoma) c. metastatic bone destruction (lytic or plastic bone mets) d. pituitary adenoma

A-C \*lytic lesions - multiple myeloma \*dec. plasma PTH (regardless of etiology)

Parathyroid path: Other etiologies associated with hypercalcemia include: 1. Vitamin D overdose (inc. Ca2+ absorption from intestines/kidneys) 2. Thiazides 3. Lithium 4. Granulomatous disorders \_\_\_\_\_ inc. 1-alpha hydroxylasde activity of macrophages, increasing calcitriol

Granulomatous disorders

Parathyroid path: Other etiologies associated with hypercalcemia include: 1. Vitamin D overdose (inc. Ca2+ absorption from intestines/kidneys) 2. Thiazides 3. Lithium 4. Granulomatous disorders \_\_\_1\_\_ decreases calcium excretion, while \_\_2\_\_ reduces parathyroid sensitivity to calcium (Ca2+ must be at higher level to shut off PTH production)

1. Thiazides (HCTZ) --"holds calcium" 2. Lithium

Parathyroid path: Hypophophosphatemia may result from 1. Inadequate intake 2. Increased excretion (MC) 3. Hyperparathyroidism (MCC) 4. Vitamin D deficiency 5. Shift from extracellular to intracellular space True/False - Inadequate intake may be due to poor diet (seen when requirements are high - initiation of re-feeding) and/or Vitamin D deficiency.

True

Parathyroid path: Hypophophosphatemia may result from 1. Inadequate intake 2. Increased excretion (MC) 3. Hyperparathyroidism (MCC) 4. Vitamin D deficiency 5. Shift from extracellular to intracellular space In the case of hyperparathyroidism, PTH inhibits phosphorus reabsorption in PT of kidney. In Vit. D. deficiency, there is impaired intestinal absorption of phosphate as well as decreased renal reabsorption of phosphate

True

1. acute respiratory alkalosis 2. Treatment of DKA

Parathyroid path: A patient presents with **muscle weakness, ileus, RBC hemolysis, impaired cardiac contractility,** and **respiratory failure** due to lack of ATP. What is the most likely cause?

Hypophosphatemia 1. Muscle weakness (dec. ATP synthesis) 2. RBC hemolysis (ATP needed to maintain ion pumps) 3. Respiratory failure (lack of ATP)

Parathyroid path: Hyperphosphatemia may be seen in normal growth (children; inc. phosphorus and alkaline phosphatase). However, it is indicative of disease in adults. Patients tend to present **asymptomatic**, but long term hyperphosphatemia may lead to **ectopic calcification** (metastatic calcification). What are common causes of hyperphosphatemia? a. Laxatives containing phosphate b. Acute and Chronic renal failure c. Hypoparathyroidism d. Shift of phosphate outside of cells due to acidosis

all of the above 1. Inc. intake (laxatives) 2. Dec. excretion * renal failure - MC; hypoparathyroidism 3. Inc. extracellular load * shift posphate out of cells * cell lysis (tumor lysis; hemolysis; rhabdomyolisis)

Adipose: ______ is the largest endocrine organ in the body. It is **loose CT composed of lipid-filled cells** (adipocytes) that are surrounded by collagen fibers, b.v.'s, fibroblasts and immune cells.

Adipose (fat )

Pancreas - Adipose: There are two types of adipose tissue: 1. Brown Adipose 2. White Adipose True/False - Adipose stores excess energy as lipid droplets (Triglycerides). TG's are added to adipose when food intake exceeds energy expenditure, and are utilized when energy expenditure exceeds food intake.

True

Adipose: ______ adipocytes develop in the lateral mesoderm, where **perivascular mesenchymal stem cells** differentiate to become pre-adipocytes (early lipoblasts). These cells accumulate lipid droplets as multiple, individual droplets (**multi-locular**). As differentiation continues, the multiple lipid droplets fuse to form one large lipid droplet (**unilocular**).

White adipocytes

Pancreas - Adipose: White adipose composes ~10% of body weight of healthy people. MC locations of white adipose include: 1. Subcutaneous (superficial) fascia 2. CT (under skin of abdomen, buttocks, axilla, thigh, and mammary gland) 3. Cushions 4. Visceral fat True/False - White adipose can be found in the subcutaneous fascia, where it provides thermal insulation from the cold and is considered to be good fat.

True

Pancreas - Adipose: White adipose composes ~10% of body weight of healthy people. MC locations of white adipose include: 1. Subcutaneous (superficial) fascia 2. CT (under skin of abdomen, buttocks, axilla, thigh, and mammary gland) 3. Cushions 4. Visceral fat \_\_\_\_\_\_\_ include palms and soles, visceral pericardium and orbits around the eyeballs

cushions

Adipose: White adipose composes ~10% of body weight of healthy people. MC locations of white adipose include: 1. Subcutaneous (superficial) fascia 2. CT (under skin of abdomen, buttocks, axilla, thigh, and mammary gland) 3. Cushions 4. Visceral fat \_\_\_\_\_ is considered to be "bad" fat. It is found in the greater omentum, mesentery, retroperitoneal space, bone marrow, around the kidneys, and filling spaces between tissues

Visceral fat

Adipose Histo: You are brought a histological sample taken from one of your patients. The tissue has a "chicken-wire" appearance, with washed out adipocytes. These adipocytes contain flattened nuclei and cytoplasm that is pushed to the periphery of the cell due to compression by lipid. What type of adipose is this?

White adipose \*washed out (lipid extracted) \*flattened nucleus \*cytoplasm pushed to perphery

Adipose Histo: WHich of the following is a function of white adipose tissue? a. thermogenesis b. angiogenesis c. energy homeostasis d. immune responses

B-D \***energy, adipogenesis, angiogenesis, steroid metabolism, immune responses**

Adipose: White adipose as an endocrine organ secretes adipokines (hormones, growth factors and cytokines): What are examples? a. Leptin b. Adiponectin c. Visfatin d. TNF-a

all of the above Leptin, Adiponectin, Resistin, Visfatin, Angiotensinogen/Ang. II, TNF-a, PGI2

Adipose Histo: ____ is a peptide hormone secreted by adipocytes, SK muscle, intestine, brain, joint tissue and bone. It is released in a circadian rhythm and functions as a satiety factor.

Leptin (keeps you thin) \*limits food intake, inc. metabolic rate, inc. weight loss \*receptors = CNS, adipocytes, pancreatic B cells, gonads, muscle, endothelial cells

Adipose Histo: Leptin's main functions include: 1. Energy expenditure 2. Food intake 3. Hormone regulation True/False - Other functions include **bone metabolism**, regulation of **reproduction, vascular function** and **inflammation/immunity.**

True

Adipose Histo: Leptin acts in the hypothalamus (and other brain locations) to decrease food intake and increase energy expenditure. Weight gain typically results in increased adipose and increased leptin secretion. What role does insulin play in leptin secretion?

Increases leptin secretion from adipose tissue \*once secreted, leptin inhibits insulin (B cells) \*leptin resistant overweight people = insulin not inhibited leading to inc. insulin and inc. leptin (type II diabetes)

Adipose Histo: A **severely obese** patient presents with **constant hunger** (hyperphagia/overeating) and **rapid** weight gain. Her mother states she was obese beginning in the first few months of life. She has **hypogonadotropic hypogonadism** with delayed or absent puberty. Labs reveal Leptin is present, but is not secreted. You suspect

Congenital Leptin deficiency \*rare, AR \*similar phenotype w/ receptor mutations

Adipose Histo: True/False - Leptin deficiency can be treated with leptin, however, leptin does not effectively treat all forms of obesity

True

Adipose Histo: Leptin plays a role in immune function by: a. increasing cytotoxic activity of NK cells b. promoting activation of granulocytes and macrophages c. increasing proliferation of native B and T cells d. promoting switch towards pro-inflammatory T helper cells

all of the above \*also activates B cells to secrete cytokines

Adipose Histo: ______ is secreted by adipose tissue and acts as a marker for metabolic syndrome. It circulates at high concentrations in the serum, but is decreased in obesity (visceral), type II diabetes, CAD and dyslipidemia. In states of decreased fat mass, it acts locally on adipocytes to increase glucose uptake, adipogenesis and lipid storage (via inhibition of lipolysis).

Adiponectin \*Inc. w/ dec. fat mass \*marker for metabolic syndrome

Adipose Histo: Which of the following is an action of liver adiponectin? a. Dec. insulin sensitivity b. Inhibits gluconeogenesis c. Inhibits accumulation of ceramide d. Indirectly inhibits lipogenesis (inc. B-ox)

B-D \*inc. insulin sensitivity \*inc. fatty acid oxidation (SK muscle) "guardian angel against obesity"

Adipose Histo: Which of the following is an action of adiponectin on vascular endothelial cells? a. reduces foam cell formation b. inc. differentiation c. inc. migration d. dec. monocyte adhesion

B-D \*inc. survival, differentiation, migration \*dec. monocyte adhesion

Adipose Histo: Which of the following is a function of adiponectin on macrophages? a. decreases inflammatory response b. dec. foam cell formation c. dec. proliferation d. inc. differentation

A and B _Macros_: dec. foam cells, dec. inflammatory response _Vascular SM_: dec. proliferation, migration and inc. differentiation

Adipose Histo: For white adipose tissue, subcutaneous fat is better than visceral fat, which is correlated with metabolic syndrome. True/False - Brown fat is better than white fat

True

Adipose Histo: In paraxial mesoderm, SK myogenic progenitor stem cells differentiate to form pre-adipoytes (early lipoblast). Similar to the white adipocytes, the eraly brown lipoblast accumulates lipid droplets as multiple, individual droplets (multi-locular). How does the brown differ from the white adipocyte?

It remains multilocular \*abundant in newborns (2-5% newborn body weight) \*back, neck, shoulders

Adipose Histo: True/False - The quantity of brown fat decreases during **childhood** and adolescence but can still be found in **cervical, axillary, paravertebral, mediastinal, sternal and abdominal** regions. In **adults**, it is MC found around the **kidneys, adrenal glands, aorta** and **mediastinum**.

True

Adipose Histo: PET scans can be used to identify sites of high glucose metabolism (e.g. tumors). Brown adipose may be a potential source of false positive interpretations on PET scans. It typically presents on PET as bilateral and symmetrical.

True \*radioactive glucose isotope to ID sites of glucose metabolism

Adipose Histo: Compared to white adipocytes, brown adipocytes are usually smaller with a more centrally located nucleus. Brown adipocytes contain: 1. Abundant mitochondria (contribute to brown color) 2. Small lipid inclusions (multi-locular) 3. Rich vascularization 4. CT septa Brown adipocytes receive direct sympathetic innercation, enabling them to regulate metabolic activity and generate heat. Why is this important?

offsets heat loss from a newborn's high surfacde to mass ratio \*helps prevent lethal hypothermia

Adipose Histo: ________ is a protein expressed exclusively in brown adipose tissue. It is located on the inner mitochondrial membrane. It catalyzes the re-entry of protons into the mitochondrial matrix. This allows the protons to bypass ATP synthase (not produce ATP), uncoupling oxidative phosphorylation and releasing chemical energy as heat.

Uncoupling protein 1 \*NE stimulates lipolysis and hydrolysis of triglycerides \*NE stimulates expression of UCP-1

Adipose Histo: In humans, UCP-1 is responsible for the adaptive thermogenesis response. This response is stimulated by changes in the external environment and cold. Cold stimulates glucose utilzation by increasing expression of \_\_\_\_\_\_\_\_\_, leading to increased brown fat in humand during winter.

Inc. gucose trasnporters \*Heat via lipid metabolism = non-shivering thermogenesis

Adipose Histo: True/False - Brown adipose is increased in patients with pheochromocytoma, which secretes excessive NE and epinephrine. Furthermore, patients tend to have inc. UCP-1 expression in response to elevated NE

True

Adipose Histo: Transdifferentiation

Ability of adipose cells to interconvert 1. White to Brown in case of excess cold env. 2. Brown to white in case of excess energy (need to store TG's)

Adipose Histo: _______ are located in subcutaneous depots of white adipose tissue. Under basal conditions, these cells express markers similar to white adipocytes, but under sympathetic stimulations and/or cold, express UCP-1 and increase energy consumption similar to brown adipocytes.

Beige adipocytes \*recently discovered \*treatment?

Metabolic syndrome: Metabolic syndrome is characterized by a constellation of known and emerging risk factors mostly **related to CV disease** (e.g. coronary and CAD). This condition may be present in up to 25% of Americans, and is **strongly associated with insulin resistance**. What are common risk factors for metabolic syndrome? a. abdominal obesity b. insulin resistance c. atherogenic dyslipidemia (inc. TG's, small LDL, low HDL-C) d. elevated blood pressure

all of the above \*pro-inflammatory states and pro-thrombotic states

Metabolic syndrome: Metabolic syndrome is described as **abnormalities of glucose and lipid metabolism coupled with HTN + systemic pro-inflammation**. The central issue with metabolic syndrome is insulin resistance contributed to by excess \_\_\_\_\_\_\_\_. This excess _____ is at the center of the alterations that occur to the body.

Excess adiposity \*Other contributors include diet, pro-inflammatory effectors, and different types of stress.

Metabolic syndrome path: Excess adiposity contributes to a multitude of disorders including: a. HTN b. Depression c. Sleep problems d. Inability to exercise

all of the above \*osteoarthritis + knee/hip arthroplasty \*Sleep: sleep apnea \*Inability to exercise: social barriers, physical limits \*cholelithiasis, cancer, avoidance of routine health

Metabolic syndrome: What are the components associated with metabolic syndrome diagnosis/criteria?

1. Obesity - general, abdominal 2. Insulin resistance 3. Inc. b.p 4. Abnormal lipids 5. Inflammation Other: hepatic dysfunction, cholelithiasis

Metabolic syndrome: Obesity is associated with an increase in all-cause mortality. It is a known risk factor for a number of conditions including type II diabetes, cardiovascular disease and cancer. _Adiposity promotes a pro-inflammatory state via:_ a. free fatty acids b. excess levels of lipids in cells and tissues c. stimulation of IL-1 d. inc. hepatocirculation

A-C 1. _free fatty acids_ * freed from lipolysis (inc. insulin resistance) 2. _excess lipids in cells_ * favor pro-inflammatory state 3. _Inc. Il-1 release_ * systemic inflammation and inc. insulin resistance * **inc. FFA within macrophages and B-cells (inflammasome) stimulate IL-1 (inc. inflammation)**

Metabolic syndrome: Obesity is the main contributor to insulin resistance. As BMI increases, so does the risk for insulin resistance and the development of diabetes. True/False - Insulin sensitivity is the function of adiposity distribution (e.g. central vs. peripheral/gluteal/subcutaneous). In other words, depending on where the fat is distributed, there may be increased risk. Studies have shown that patients who develop diabetes w/out overt overall obesity have had mainly visceral adiposity, while patients with primarily subcutaneous adiposity have been known to be protected from diabetes.

True \*central adiposity = marker \*subcutaneous adiposity = "metabolically healthy obese"

Metabolic syndrome: Central obesity is more susceptible to increased lipolysis due to enhanced sensitivity to the stimulatory effects of counter-regulatory hormones. It is mostly associated with increased ______ receptors, and increased conversion of cortisone to cortisol (from high levels of type 1 11-B hydroxyl steroid DH).

B-adrenergic receptors \*Insulin's suppressive effect is weaker due to dec. insulin receptor affinity

Metabolic syndrome: Visceral adipose tissue drains directly into the portal vein, exposing it to high levels of free fatty acids and altered adipokine levels. The result is hepatic steatosis and insulin resistance. How does this manifest?

- increased hepatic glucose output - elevated fasting glucose levels (gluconeogenesis)

Metabolic syndrome: True/False - Increased free fatty acids can contribute to increases in lipid deposition in insulin-target tissues. Furthermore, insulin signalling can be hindered directly within skeletal muscle (peripheral tissues) resulting in impaired insulin-stimulated glucose disposal and transport (after meals). It may be dec. indirectly via pro-inflammatory cytokines.

True \*GLUT 4 transport after meal due to dec. translocation **NUTSHELL:** Inc. lipid in peripheral tissues = dec. insulin signalling and dec. glucose uptake (dec. GLUT4). Inc. inflammation = insulin resistance.

Metabolic syndrome: Studies have shown an i**nverse correlation** between fasting plasma free fatty acids and insulin sensitivity. True/False - Central adipose tissue is more lipolytic than peripheral adiopose sites. Excess secretion of FFAs can overwhelm the intracellular fatty acid oxidation pathways, leading to **accumulation of cytoplasmic intermediates.**

True \*diacylglycerol (DAG) \*phospholipids \*sphingolipids, ceramides

Metabolic syndrome: Free fatty acids are toxic metabolites that can: **1. attenuate signaling through the insulin receptor** **2. activate inflammatory pathways in islets (inc. B-cell abnormalities)** Insulin normally inhibits gluconeogenesis in hepatocytes by blocking the activity of ________ (1st enzymatic step). However, attenuated insulin signalling leads to elevated gluconeogenesis due to "ramped up" action of this enzyme.

phosphoenolpyruvate carboxykinase \*ramped up = inc. gluconeogenesis

Metabolic syndrome: True/False - Excess free fatty acids also compete with glucose as substrates for oxidation. This can further exacerbate the reduced glucose utilization

True

Metabolic syndrome contributes to hyperinsulinemia. The presence of hyperinsulinemia can contribute to elevated blood pressure via 1. sodium retention 2. expansion of blood volume 3. excess NE production 4. SM proliferation True/False - Risk of developing HTN increases proportionately with increase in weight

True \*all 4 are hallmarks of hTN

Metabolic syndrome: Atherogenic dyslipidemia is characterized by elevated triglycerides, small LDL particles and low HDL-C. _Trigliceride levels:_ 1. \< 150 = normal 2. 150-199 = borderline high 3. 200-499 = high 4. \> 500mg/dL = very high True/False - Triglycerides serve as an important biomarker for CV risk. They are not a direct factor for atherogenesis.

True

Metabolic syndrome: C-reactive protein and other pro-inflammatory cytokines (TNF) are often elevated in obese patients, particularly central adiposity. Contributions likely include

1. TG's, LDL, fatty acids 2. release of adipokines

Metabolic syndrome: Chronic inflammation is believed to contribute to a. insulin resistance b. thrombosis c. CV disease d. other metabolic changes e. cancer

all of the above

Metabolic syndrome: Adipose is an endocrine organ that releases hormones in response to changes in metabolism. Adipokines (adipose cytokines) are proteins secreted in the circulation by adipose tissue. These play a role in promoting hyperglycemia and/or decreasing blood glucose (leptin/adiponectin). Adiponectin are ______ in obesity, contributing to insulin resistance

reduced in obesity \*leptin and adipnectin inc. insulin sensitivity in peripheral tissues

Metabolic syndrome: Metabolic syndrome and obesity are associated with cancer in that they both increase insulin and \_\_\_\_\_\_, which stimulate cell proliferation (and inhibit apoptosis).

IGF-1 \*see slide 31

Metabolic syndrome: Non-alcoholic fatty liver disease is commonly associated with obesity and type 2 diabetes likely due to **visceral (abdominal) adiposity.** This disorder ranges in severity (hepatic steatosis w/out liver injury to NASH w/ inflammation and/or fibrosis). True/False - High levels of circulating free fatty acids can contribute to the accumulation of excess fat (steatosis) in hepatocytes.

True

Metabolic syndrome: True/False - Cholelithiasis is 6x more common in obese patients. This is because obesity is assocated with increased total body cholesterol. Cholesterol turnover leads to inc. biliary excretion of cholesterol in bile. Ultimately, obesity predisoposes patients to formation of cholesterol rich gallstones.

True

Metabolic syndrome: Insulin resistance is a primary mediator of other disorders including polycystic ovarian syndrome and acanthosis nigricans. It is thought to be related to \_\_\_

IGF-1

Metabolic syndrome: Majority of obese people have high insulin levels and display insulin resistance. However, most do not develop diabetes. This is because mechanisms must be present to cause ß-cell damage. This may be associated with increased susceptibility in certain individuals or families. True/False - Beta cell mass normally increases with obesity, however, mass declines in patients who develop impaired glucose tolerance and diabetes

True

Metabolic syndrome: B-cell dysfunction is probably necessary for the development of overt diabetes. In early "sporadic" type 2 diabetes, B-cell function is increased to compensate/counter insulin resistance. In later stages, B-cells exhaust their capacity to adapt to long term demands of insulin resistance, and the hyperinsulinemic state gives way to a state of relative insulin \_\_\_\_\_.

insulin deficiency \*insulin deficient for level of glucose in the blood

Metabolic syndrome: The following are causes of B-cell dysfunction: 1. Excess free fatty acids (ffa's) 2. Chronic hyperglycemia 3. Abnormal incretin 4. Amyloid deposition within islets Explain

1. _Inc. FFA's_ * compromise B-cell function * attenuate insulin release (lipotoxicicity) 2. _Abnormal incretin_ * dec. secretion of GIP and GLP (promoters of insulin release) 3. _Amyloid deposition_ * B-cell burnout

Metabolic syndrome: Primary prevention strategies include 1. Increased activity levels 2. Improve diet 3. Energy drinks? True/False - Modest weight loss can alter trajectory of diabetic and pre-diabetic patients (who are often obese). Furthermore, weight loss and exercise have a combined benefit, with different physiological effects. Ultimately, less adipose cells = less biologically active agents contributing to insulin resistance.

True

Metabolic syndrome: Exercise enhances the body's (esp. SK muscle) ability to utilize fuel sources more efficiently. How is this done? a. inc. mitochondria b. inc. surface expression of GLUT 4 receptors c. inc. collateral circulation d. inc. lipid metabolism

all of the above

Pancreas Histo: The pancreas is a retroperitoneal, elongated gland that overlies and crosses the body of **L1** and **L2** vertebrae. It is posterior to the stomach, between the duodenum and spleen. It is composed of a head, neck, body, and tail, and plays a role in exocrine function and endocrine function. Exocrine secretions exit the pancreas via \_\_\_\_\_, which carry products to the duodenum.

main and accessory pancreatic ducts

Pancreas Histo: The main arterial supply to the pancreas is via 1. ______ which arises from the **splenic artery** 2. Pancreaticoduodenal artery (**inferior anterior and posterior** branches) which arises from the \_\_\_\_\_\_\_ 3. Pancreaticoduodenal artery (**superior anterior and posterior**) which arise from the \_\_\_\_\_\_\_\_\_

1. Greater pancreatic artery 2. Superior mesenteric artery 3. Gastroduodenal artery

Pancreas Histo: Venous drainage of the pancreas involves _____ which in turn drain into the **splenic vein**.

Pancreatic veins

Pancreas Histo: THe majority of pancreatic lymph vessels drain into \_\_\_\_\_\_. However, some drain into **pyloric lymph nodes**. Efferent vessels from these lymph nodes drain into either the superior mesenteric lymph nodes or the celiac lymph nodes.

Pancreaticosplenic lymph nodes (along splenic artery)

Pancreas Histo: The pancreas is innervated by nerves derived from the _____ and abdominopelvic splanchnic nerves. *Sympathetic* innervation goes to *blood vessels*, while **SNS** and **PNS** (secretomotor) innervation go to **pancreatic acinar cells and islets**.

Vagus

Pancreas Histo: Development of the pancreas begins by formation of the dorsal and ventral pancreatic \_\_\_\_, which arise from the *caudal* region of the foregut. The duodenum then rotates to the right, carrying the pancreatic ____ along with it. This results in the movement of the ventral pancreatic ______ dorsally so that it is posterior to the dorsal pancreatic \_\_\_\_\_.

buds/bud \*all are pancreatic bud

Pancreas Histo: Formation of an annular pancreas occurs when the pancreas forms a complete ring that circles the duodenum. It occurs when the two lobes of a bilobed ventral pancreatic bud (normal variation) migrate in _____ directions around the duodenum prior to fusing with the dorsal pancreatic bud.

Opposite directions

Pancreas Histo: Islet cells begin as exocrine and endocrine cells that are mixed together in a stratified epithelium of the pancreas. 2. Next, microlumens form and fuse to generate the exocrine glands and ducts. 3. Endocrine glands _______ and aggregate in the surrounding mesenchyme forming islets. These islet will continue to proliferate during development.

delaminate \*B-cells secrete insulin by 5th month \*islets continue to proliferate until puberty

Pancreas Histo: By puberty, pancreatic islets lose the capacity to continue proliferating. When is the exception?

Pregnancy (expansion of islet volume occurs)

Pancreas Histo: Islets appear as *pale-staining areas of spherical aggregates* of cells arranged in clumps and cords. They are scattered among exocrine acini. True/False - Fenestrated capillaries surround the islet cells. Islets have 10x the amount of blood/mass compared to the exocrine pancreas

True

Pancreas Histo: The endocrine pancreas has 5 cell types, distributed randomly throughout the islet. Each cell produces one main hormone (but could produce other minor hormones). These cells are ID'd by EM or immunocytochemistry: 1. alpha (à) 2. beta (ß) 3. delta (σ) 4. PP cells \_\_\_\_\_\_ have an eosinophilic cytoplasm and are responsible for the secretion of glucagon. CCK, ACTH-endorphin, and GIP can also be seen by immunocytochemistry.

Alpha Cells NOTE: reticular fibers separate islets from exocrine acini

Pancreatic HIsto: Glucagon is secreted by alpha cells of the pancreas. It is the 2nd most abundant endocrine secretion and functions as an antagonist to insulin. True/False - It plays a role in increasing glucose, fatty acids and ketoacids when plasma glucose is decreased. It also acts by inhibiting actions of the exocrine pancreas.

True \*stimulates proteolysis, gucogenolysis, gluconeogenesis, fat mobilization

Pancreas Histo: Glucagon is either activated when blood glucose levels \< 70mg/100ml or in states of decreased fatty acids in the blood. What are inhibitors of glucagon secretion?

1. blood glucose \> 70mg/100ml 2. Insulin

Pancreas Histo: The endocrine pancreas has 5 cell types, distributed randomly throughout the islet. Each cell produces one main hormone (but could produce other minor hormones). These cells are ID'd by EM or immunocytochemistry: 1. alpha (à) 2. beta (ß) 3. delta (σ) 4. PP cells \_\_\_\_\_ stain basophilic with special staining. They make up 70% of the islet cells are are responsbile for secreting **insulin** (decreases blood glucose levels). These cells also secrete **amylin** which inhibits glucagon secretion, delays gastric emptying and acts as a satiety agent.

Beta (B) cells

Pancreas HIsto: Insulin is essential for growth and development. It acts on multiple sites including the liver, SK muscle, and adipose tissue. True/False: It acts to dec. protein catabolism (stimulate aa uptake), inhibit lipase. It also stimulates glucose uptake and stimulates glycogenesis/glycolysis.

True \*stimulates exocrine pancreas \*Dec. glucose, fa's, ketoacids, aa's NOTE: Insulin is anabolic (builds up and stores)

Pancreas Histo: True/False - Insulin secretion occurs when blood glucose levels are elevated (**\> 70mg/100ml**). It may also be stimulated by increase in *fa's, gastrin, CCK* and/or *secretin.* It promotes glucose uptake and storage by the liver and muscle resulting in removal of glucose from the blood.

True

Pancreas Histo: Amylin (islet/insulinoma amyloid polypeptide; diabetes associated polypeptide) is co-secreted with insulin from B-cells at 15:1 ratio (insulin to amylin). It acts by suppressing \_\_\_\_\_\_\_\_. The net effect is decreased blood glucose and decreased body weight.

1. food intake (brainstem) 2. glucagon release 3. gastric emptying

Pancreas Histo: The endocrine pancreas has 5 cell types, distributed randomly throughout the islet. Each cell produces one main hormone (but could produce other minor hormones). These cells are ID'd by EM or immunocytochemistry: 1. alpha (à) 2. beta (ß) 3. delta (σ) 4. PP cells \_\_\_\_\_\_\_ is secreted by D cells. It plays a role in inhibition of GH, SM contraction, and the inhibition of both insulin and glucagon (paracrine effect).

Somatostatin \*identical to hormone secreted by hypothalamus \*D cells also secrete gastrin

Pancreas Histo: Some islet tumors secrete large amounts of gastrin, resulting in excessive acid production in the stomach (Zollinger-Ellison syndrome). This leads to 1. Pancreatic/Durodenal tumors 2. Peptic ulcers 3. Gastric hypersecretions An example of these tumors is

Gastrinoma \*gastrin stimulates parietal and enterochromaffin cells \*ZE: multiple, refractory ulcers resistant to medical Tx and weird locations (jejunum)

1. Somatostatin 2. Exocrine secretions (pancreatic enzymes) 3. Bile secretion (inhibits gallbladder contraction) NET: conserves digestive enzymes and bile between meals

True

Pancreas Histo: Although islets are 1-2% of the pancreas, they receive 10-15% of pancreatic blood flow. Each islet is supplied by an arteriole, which breaks up into fenestrated capillaries that surround the cells of the islet. Blood exits the islets and then perfuses

The exocrine pancreas

Pancreas Histo: Pancreatic islets have both sympathetic and parasympathetic innervation. 10% of islet cells have nerve ending directly on the plasma membrane. Islet cells send signals to each other via **gap junctions**. In addition, autonomic nerves may have a direct effect on alpha and B cell secretion as well as PP secretion. 1. Parasympathetic (cholinergic) stimulation = increases secretion of \_\_\_\_\_\_\_ 2. Sympathetic (adrenergic) stimulation = increases \_\_\_\_\_\_, but decreases \_\_\_\_\_\_

1. PNS: inc. insulin and glucagno 2. SNS: inc. glucagon; dec. insulin \*rest and digest = inc. both \*fight or flight = mobilize energy

Pancreas path: Insulin is activated by the presence of inc. glucose in the blood. It acts to increase cellular glucose uptake, resulting in inc. synthesis of fat, glycogen and proteins. 1. In healthy patients, blood glucose levels increase following meals. Glucose enters pancreatic B-cells via **insulin independent transporter** \_\_\_\_\_\_\_. 2. Metabolism of glucose leads to **ATP production** which in turn, closes K+ channels and leads to depolarization of the cell membrane. This leads to the opening of ____ channels. 3. Ca2+ Influx results in release of stored insulin.

1. GLUT 2 2. Ca2+ channels

Pancreas path: Insulin is anabolic and stimulates conversion of glucose to glycogen (via **glycogen synthase**) in the liver, as well as conversion of glucose to fat (lipogenesis). Glucagon, on the other hand is catabolic, stimulating the production of glucose from glycogen and \_\_\_\_\_

fatty acids (to ketoacids) NOTE: Insulin promotes protein synthesis and inhibits lipolysis

Pancreas path: In the fed state there is a high ratio of insulin to glucagon. This leads to increased a. glucose uptake in muscle and adipose tissue b. glycolysis c. glycogen synthesis d. protein synthesis e. uptake of ions (K+ and PO4)

all of the above

Pancreas path: In the diabetic state, insulin levels are low compared to glucagon. Thus, there is increased a. hepatic glycogen breakdown b. fatty acid oxidation c. ketogenesis (due to excess glucagon) d. impaired transport of glucose, aa's and ions into peripheral cells

all of the above \*insulin stimulates uptake into peripheral cells \*glucagon stimulates fat/lipid conversion to ketoacids \*peripheral lipolysis = inc. fa's available for hepatic ketogenesis

Pancreas Path: _______ is a disorder of elevated blood glucose (abnormal handling/management of glucose and energy). It is distinguished by: 1. fasting plasma glucose between 100-125mg/dL (\<126mg/dL) 2. HbA1c b/t 5.7 - 6.4 % 3. trajectory towards diabetes Although glucose levels are elevated, it does not fit the diagnostic criteria of diabetes mellitus. You suspect

Pre-diabetes (glucose intolerance) ## Footnote \*inc. risk of type 2 diabetes Prevent: - Exercise - Weight loss (5-10%), - Diet (50% **carbs**, 30% **fat** (\<10% saturated) and 15-20% **protein)**

Pancreas path: True/False - Diabetes mellitus is the leading cause of **kidney failure**, **non-traumatic lower limb amputations** (gangrenous necorsis) and new cases of **blindness** amongst adults in the U.S. It is also a major contributor to **heart disease, stroke** and **macrovascular disease**.

True \*macrovascular: peripheral, CV, cerebrovascular \*microvascular: eyes

Pancreas path: A patient presents with complaints of polydipsia, polyuria, and polyphagia (excess hunger/eating). Labs reveal: 1. Random blood glucose: \> 200mg/dL w/ hyperglycemic signs 2. Fasting glucose: \> 126mg/dL (normal \< 100mg.dL) 3. HbA1c.: \> 6.5% 4. 2 hr. oral glucose tolerance test: \> 200 mg/dL (normal \< 140) Before you can confirm diabetes mellitus. What must be done?

Perform test again \*except random

Pancreas path: Monitoring diabetes aids in the goal of preventing vascular and other complications. Monitoring involves evaluation of mean blood glucose and HbA1c. True/False - Monitoring may be done to assess other CV risk factors. These include TG's, HDL, LDL, blood pressure (endothelial injury), CRP and ApoE.

True

Pancreas path: Glycated hemoglobin (HbA1c) has a good correlation with mean blood glucose and is used as a mechanism for monitoring glucose levels. It represents the glucose mean over the last ______ months, and the normal range is 4% to 5.6%. NOTE: Elevated plasma glucose + RBCs = non-enzymatic binding of glucose to Hb in RBC's = Inc. HbA1c

~3 months \*target usually 7-8% \*values dependent on red cell lifespan (may need to adjust for anemia)

Pancreas path: HbA1c that is normal or \< 6.5% is an acceptable target if achieved with diet and exercise. True/False - There is movement toward individualized Tx over aggresive pursuit of target with medications. This is based on risk-benefit evidence. Instead of targeting lab values, symptoms are targeted.

True \*medications tended to cause most harm \*consider: patient's preference, general health, life expectancy, etc.

Pnacreas path: Type I diabetes is associated with autoimmune destruction of ______ in the pancreas (antibodies against insulin, islet cells and/or other components). This destruction results in defiency in insulin, and thus, inability of peripheral cells to take up glucose.

B-cells in the pancreas

Pancreas path: In type 2 diabetes, insulin is present, but there is a post-receptor defect. In other words, insulin is present, but has no effect on cells. Over time, this may lead to progressive B-cell failure. The net result, similar to type I, is hyperglycemia

True

Pancreas Path: **Type I diabetes** is associated with **HLA-DR3** and **HLA-DR4**. It is increased in first degree relatives (genetic predisposition), however, not everyone who is susceptible manifests the disease. It requires an autommine response (failure of self tolerance in T cells) that target islet cell antigens (**GAD, Insulin, ICA512**). What is one of the best predictors of progression to type 1 DM?

Expression of autoantibodies ( - Glutamic acid decarboxylase (GAD) = B cell enzyme - Insulinoma-associated protein 2 (IA-2) - insulin autoantibodies

Pancreas Path: Type I diabetes is due to failure of self-tolerance in T cells to islet antigens. True/False - Environmental factors may play a role, specifically, viruses that share epitopes with islet antigens. Their presence may lead to immune cross-reactivity and subsequent destruction of islet tissues (**molecular mimicry**). However, it is possible that infections may be protective against type 1 diabetes.

True

Pancreas path: True/False - With regard to B-cell destruction, there is typically a lag period between the initiation of autommine processes and the appearance of the disease (despite the abrupt onset). Over time there is progressive loss of insulin reserves/release, leading to dec. glucose uptake and thus, hyperglycemia. Hyperglycemia and ketosis occur late in the process after about 90% of the B cells have been destroyed

True

Pancreas path: Type 1 diabetes mellitus accounts for 5-10% of diabetes cases. Usual onset is in kids with bimodal peak (age *5-7* and *10-14*). However, it may occur in any age. Patients with type 1 DM often present with abrupt onset of **hyperglycemia** with **polyuria, polydipsia**, and **polyphagia** (excessive hunger). They complain of **weight loss, fatigue** and **blurry vision**. Infections may co-occur (candidiasis, UTIs, etc.) Diabetic ketoacidosis is also associated.

\*sudden onset of symptoms \*DKA \*may have been rare or acutely ill

Pancreas path: A 28 year old male presents with abrupt onset of hyperglycemia with excessive urination, excessive thirst and excessive hunger. He reports weight loss despite consistently eating. He admits to fatigue and blurry vision. He reports a recent UTI from which he has recovered. After obtaining labs, you suspect type 1 diabetes mellitus. What are the causes of his clinical features?

1. _Polyuria_ * osmotic diuresis (secondary to hyperglycemia) * nocturnal enuresis (secondary to polyuria - indication in kids) 2. _Thirst_ * reponse to hyperosmolar state (inc. Posm) * dehydration 3. _Hunger_ * persistently inc. Posm = inc. hunger

Pancreas path: A 28 year old male presents with abrupt onset of hyperglycemia with excessive urination, excessive thirst and excessive hunger. He reports weight loss despite consistently eating. He admits to fatigue and blurry vision. He reports a recent UTI from which he has recovered. _Labs_: 1. fasting glucose \> 126mg/dL 2. random glucose \> 200 (+ clinical symptoms) 3. oral glucose test \> 200 mg/dL 4. HbA1C \> 6.5% After obtaining labs, you suspect type 1 diabetes mellitus. What is the cause of his fatigue, muscle cramping and blurred vision?

1. _Fatigue_ * muscle wasting (catabolism of insulin deficiency, hypovolemia, hypokalemia) 2. _Cramps_ * electrolyte imbalance 3. _Blurred vision_ * hyperosmolar state (lens/vitreous humor) * osmotic swelling of the lens (altered focal length) NOTE: Beta cell destruction likely started months/years before onset of symptoms

Pancreas path: True/False - It is not unusual for patients with type 1 DM to present with DKA, which may occur secondary to stress of illness or surgery. An explosive onset of symptoms in a young, lean patient with ketoacidosis is considered diagnostic of type 1 DM

True

Pancreas path: Over time, patients with new onset type 1 DM will lose weight despite normal or increased appetite. This is due to 1. water depletion 2. sustained catabolic state (dec. glycogen, proteins, TG's) However, weight loss may not occur if treatment is initiated promptly after onset of disease

True

Pancreas path: 1. Nausea, abdmonal discomfort/pain, and/or change in bowel movement may accompany acute diabetic ketoacidosis. These symptoms are induced by \_\_\_\_\_. 2. Right upper quadrant pain may present in DKA due to \_\_\_\_\_\_\_, which causes distension of the hepatic capsule.

1. Beta hydroxybutyrate 2. Acute fatty liver \*persistent abdominal pain may indicate serious cause of DKA (pancreatitis, peritonitis)

Pancreas path: Type 2 diabetes mellitus is associated with an interplay of **genetic and environmental factors + pro-inflammatory state** (cytokines, ffa's, adipokines). It ultimately results in **insulin resistance** +/- lack of insulin. Predisposing conditions of type 2 diabetes include: a. obesity b. sedentary lifestyle c. family Hx d. African Americans

all of the above \*Hispanics, Native Americans \*age \>45 \*obesity = inc. peripheral resistance to insulin NOTE: largely reversed by weight loss

Pancreas path: Genetics plays a role in predisposing individuals to type 2 DM. Increased concordance (\> 90%) was observed in monozygotic twins, and first degree relatives have been shown to have inc. risk of developing type 2 DM. True/False - Over 30 genetic loci have been identified that individually confer minimal to modest increase in the lifetime risk for type 2 DM

True NOTE: NOT autoimmune

Pancreas path: Type 2 DM is associated with multiple metabolic defects. Which of these is an associated problem? a. decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver to insulin b. inadequate insulin secretion due to insulin resistance and hyperglycemia (b-cell dysfunction) c. insulin resistance pre-dating development of hyperglycemia d. inability of B cells to adapt to increasing secretory needs for maintenance of euglycemia state

all of the above \*Insulin resistance: compensatory B-cell hyperfunction, hyperinsulinemia \*Inability of B-cells to adapt = chronic hyperglycemia, long standing complications

Pancreas path: In the presence of insulin, GLUT-4 normally translocates to the cell membrane and allows incorporation of glucose into the cell. In the absence of insulin, GLUT-4 remains \_\_\_\_\_\_\_\_\_. A defect in signalling results in decreased GLUT-4 on the cell surface and an ultimate decrease in glucose uptake.

Intracellular \*post-receptor defect \*mechanism of Insulin resistance

Pancreas path: Obesity, specifically central/visceral (visceral adiposity) is a top environmental risk factor for the development of type 2 DM. More than 80% of individuals with type 2 Diaetes are obese. True/False - Obesity can contribute to metabolic abnormalities and insulin resistance early in the disease. This may be improved with modest weight loss through diet.

True

Pancreas path: Sedentary lifestyle (lack of exercise) is another environmental risk factor that contributes to development of TYpe 2 diabetes. It is independent of obesity. Type 2 can be managed with weight loss and exercise which can improve insulin sensitivity. True/False - Exercise enhances the body's ability (esp. SK muscle) to utilize fuel sources more efficiently. It does so by **increasing mitochondria, increasing cell surface experssion** of **GLUT 4 receptors, promoting collateral circulation,** and **increasing lipid metabolism.**

True \*weight loss and exercise = combined benefit, different physiologic effects \*dec. amt. of adipose cells (dec. active agents causing insulin resistance)

Pancreas path: Although the majority of obese people have high insulin levels and show insulin resistance, not all go on to develop obesity. What is the key factor that contributes to development of diabetes in people?

Beta cell defect \*initial inc. in B-cell mass to compensate, then apoptosis and decline in mass

Pancreas path: Which of the following is a factor associated with Beta cell damage contributing to type 2 DM? a. Lipid accumulation in Beta cells b. Chronic exposure to hyperglycemia and inc. free fatty acids c. Abnormal incretin effect d. amyloid deposition within islets

all of the above 1. Lipid accumulation * functional impairment: activate pro-apoptotoic unfolded protein response (UPR) in ER 2. Chronic hyperglycemia, ffa's * glucolipotoxicity (dec. insulin secretion) 3. Incretin * dec. GIP and GLP-1 (promote insulin release) 4. Amyloid * characteristic histologic finding * B-cell burnout

Pancreas path: True/False - Central obesity (visceral adiposity) most closely correlates with insulin resistance because it is most susceptible to increased lipolysis. This susceptibility is due to 1. inc. sensitivity to stimulation by counter-regulatory hormones (inc. B-adrenergic receptor and conversion to cortisol) 2. weaker suppressive effect of insulin due to lower insulin receptor affinity

True \*inc. B-adrenergic receptors and inc. conversion of inactive cortison to active cortisol (due to high levels of **type 1 B-hydroxyl-steroid DH**)

Pancreas path: Visceral adipose tissue drains directly in to the portal vein, explsing the liver to high levels of free fatty acids and altered adipokine levels. This results in hepatic _____ and insulin resistance. It often manifests as increased hepatic glucose output and elevated fasting glucose levels.

steatosis - inc. hepatic glucose - inc. fasting glucose (gluconeogenesis)

Pancreas path: Increased fatty acids can lead to central obesity and contribute to development of type 2 DM. It increases lipid deposition in other insulin-target tissues (especially SK muscle). It is associated with mitochondrial dysfunction and insulin resistance, resulting in impaired insulin-stimulated glucose disposal (post-prandial) due to decreased \_\_\_\_\_

translocation of GLUT 4

Pancreas path: Type 1 vs. Type 2 DM

1. _Type I DM_ * -autoimmune destruction B cells * -Insulin always needed in Tx * -\< 30 y/o MC * -HLA DR3 and DR4 * Complications: DKA (+ lactic acidosis) * histo: islet leukocyte infiltrate 2_. Type 2 DM_ * inc. resistance to insulin, progressive B cell failure * insulin sometimes needed in Tx * \> 40 y/o * low insulin sensitivity * histo: islet amyloid polypeptide deposits * Tx: diet, exercise, oral meds, insulin * Complications: hyperosmosis

Pancreas path: Which of the following is a potential secondary cause of diabetes mellitus? a. other pancreatic diseases (CF, pancreatitis, pancreatic cancer) b. hemochromatosis (Fe deposits - free radical damage to islets) c. infection (mumps, HIV, CMV) d. genetic defects in ß-cell function (not B-loss or abs)

all of the above \*drugs (corticosteroids) \*endocrine (pheo; Cushing) \*glucagonoma, acromegaly (counter-regulatory hormones - glucagon, epinephrine, cortisol, GH)

Pancreas path: Genetic contributions/associations with diabetes mellitus include: 1. Hereditary hemochromatosis 2. Maturity onset diabetes of the young \_\_\_\_\_\_ is associated with mutations in C282Y and H63D in the HFE gene. It results in free radical damage to the islets

Hereditary hemochromatosis

Pancreas path: Genetic contributions/associations with diabetes mellitus include: 1. Hereditary hemochromatosis 2. Maturity onset diabetes of the young \_\_\_\_\_ is an AD disease that is associated with hepatocyte nuclear factor 1-alpha. It results in reduced insulin production

Maturity onset diabetes (MODY)

Pancreas path: Deficiency or absence of insulin results in a catabolic state leading to unopposed counter regulatory hormones (glucagon and epinephrine). As a result, there is decreased assimilation of glucose into the liver and muscle. The net result is hyperglycemia, or elevated glucose that eventually exceed the renal threshold. Which of the following is an acute complication of diabetes mellitus? a. absolute absence of insulin b. abrupt or marked shift toward insulin/glucagon ration (acute illness/stressor) c. macrovascular issues (e.g. anuerysm) d. microvascular issues

A and B Acute: \*C and D are chronic complications

Pancreas path: Acute complications of diabetes mellitus are associated with insulin deficiency that results in a catabolic state. This increased catabolism = decreased assmilation of glucose into the liver and muscle. What is the net result?

Hyperglycemia \*exceeds renal threshold (180) - lead to osmotic diuresis w/ volume depletion \*glycogenolysis might still occur \*gluconeogenesis will still occur

Pancreas path: Insulin is a major anabolic hormone, thus, deficiency results in a catabolic state and unopposed counter-regulatory hormones (glucagon and epinephrine). \_\_\_\_\_\_\_ is precipitated by illness leading to inc. counter-regulatory hormones and/or omission of insulin. It leads to severe volume depletion (osmotic diuresis) and possibly coma.

Diabetic ketoacidosis \*acute complication

Pancreas path: The mechanisms for hyperglycemia are: 1. Inc. protein degradation 2. Inc. gluconeogenesis 3. Inc. glycogenolysis 4. Dec. glucose uptake by muscle and adipose Gluconeogenesis and glycogenolysis both result in increased glucose from the liver. How does protein degradation in muscle affect hyperglycemia?

muscle breakdown provides amino acid substrates for gluconeogenesis \*muscle wasting

Pancreas path: A patient presents with Delirium/psychosis, rapid, deep breathing (Kussmaul respirations,) abdominal pain, nausea, vomiting and dehydration. She has a fruity odor to her breath (exhaled acetone). Labs reveal: 1. Hyperglycemia 2. Inc. H+, dec. HCO3- (inc. anion gap) 3. Inc. blood ketone levels 4. Leukocytosis 5. Hyperkalemia You suspect? How do you treat?

Diabetic Ketoacidosis \*\*serious complication of diabetes \*\*insulin non-compliance or inc. insulin requirements Tx: IV fluids, IV insulin and K+

Pancreas path: A diabetic patient presents with **anorexia, nausea, vomiting,** and **abdominal pain** (ß-hydroxybutyric acid). She exhibits **altered levels of consciousness** (coma may occur). Patient exhibits **deep, rapid breathing (Kussmaul).** You note **fruity breath** (exhalation of acetone; volatile ketoacid). You also note **decreased skin turgor** and **dry mucous membranes** (volume depletion). You suspect DKA, a state of increased ketone body. What is the mechanism of DKA?

1. Dec. Insulin = inc. hormone sensitive lipase * inc. lipolysis 2. Inc. lipolysis = inc. free fatty acids * fa's oxidized to ketone bodies (**Beta hydroxybutyric acid, acetoacetic acid, and acetate**) * (B-oxidation to acetyl coA -- oxidation of acetyl CoA = ketone bodies) \*Rate of production \> Rate of consumpion = ketonemia and ketonuria

Plasma or blood B-hydroxybutyrate

Pancreas Path: A diabetic patient with DKA presents with the following labs: 1. Hyperglycemia (**350-900** mg/dL) 2. Hyponatremia (**Dec. Na2+**) 3. Hyperkalemia w/ low total body potassium 4. Metabolic acidosis (**inc. anion gap**) 5. Increased BUN (pre-renal azotemia; **BUN:Cr \> 20**) \_\_\_\_\_ is mild and due to a dilutional effect. It occurs via osmotic effect of glucose pulling water from the intracellular fluid into the extracellular fluid

Hyponatremia

Pancreas Path: A diabetic patient presents with the following labs: 1. Hyperglycemia (350-900 mg/dL) 2. Hyponatremia (Dec. Na2+) 3. Hyperkalemia w/ low total body potassium 4. Metabolic acidosis (inc. anion gap) 5. Increased BUN (pre-renal azotemia; BUN:Cr \> 20) True/False - Excess hydrogen ions are exchanged for K+ ions. However, total body potassium may be low in DKA

True

Pancreas Path: A diabetic patient presents with the following labs: 1. Hyperglycemia (350-900 mg/dL) 2. Hyponatremia (Dec. Na2+) 3. Hyperkalemia w/ low total body potassium 4. Metabolic acidosis (inc. anion gap) 5. Increased BUN (pre-renal azotemia; BUN:Cr \> 20) Patient's with DKA tend to have an increased anion gap due to ketoacidosis (acwetoacetic and B-hydroxybutyric acids). They may also have lactic acidosis due to hypoperfusion and altered glucose metabolism.

True \*severe (pH 6.9-7.2)

Pancreas Path: A diabetic patient presents with the following labs: 1. Hyperglycemia (350-900 mg/dL) 2. Hyponatremia (Dec. Na2+) 3. Hyperkalemia w/ low total body potassium 4. Metabolic acidosis (inc. anion gap) 5. Increased BUN (pre-renal azotemia; BUN:Cr \> 20) True/False - Patient's with DKA present with pre-renal azotemia (BUN:Cr \> 20) due to decreased renal blood flow. This decrease in blood flow is associated with volume depletion secondary to osmotic diuresis

True

Pancreas path: A diabetic patient presents with **anorexia, nausea, vomiting, and abdominal pain** (ß-hydroxybutyric acid). She exhibits **altered levels of consciousness** (coma may occur). Patient exhibits **deep, rapid breathing** (Kussmaul). You note **fruity breat**h (exhalation of acetone; volatile ketoacid). You also note **decreased skin turgor** and **dry mucous membranes** (volume depletion). You suspect DKA. How is it managed?

1. _IV fluids (normal saline)_ * ---fluid deficit (due to osmotic diuresis) * --add glucose when blood glucose drops to ~250 mg/dL (switch to D5 half normal) 2. _IV insulin_ * --dec. hyperosmoalrity (dec. hyperglycemia) * --inc. peripheral use of glucose * --dec. glucose production 3. _Manage potassium_ * --close monitoring * --Total body = low (vomiting, urine loss) * \*correction of acidosis = K+ flows in = hypOkalemia

Pancreas path: A 75 year old patient presents with thirst, polyuria, lethargy, and focal neurologic deficits (seizures). Labs reveal: 1. Hyperglycemia (**\> 800mg/dL**) 2. Inc. serum osmolarity (**\>320 mOsm**) 3. NO acidosis (**pH \> 7.3**) 4. **NO** ketosis You suspect

Hyperosmolar hyperglycemic state \*elderly \*due to limited ability to drink \*excessive osmotic diuresis = dehydration = hyperosmolar **Tx**: IV fluids, Insulin therapy

Pancreas path: True/False - In hyperosmolar hyperglycemic state, there is enough insulin to prevent lipolysis and ketogenesis, however, still inadequate amounts to promote glucose uptake. True/False - Ultimately, excess glucose is lost in the urine leading to osmotic diuresis and marked dehydration. This results in decreased RPF and decreased renal function.

True \*still have hyperglycemia and hyperosmolality (CNS signs) \*\*preciptated by acute illness (infection, MI, stroke) \*mortality

Pancreas path: There is a strong association between the degree of chronic hyperglycemia and development/progression of microvascular complications. Tight glycemic control can reduce complications. Which of the following is a long term complication of diabetes mellitus? a. retinopathy b. nephropathy c. neuropathy d. peripheral vascular disease

all of the above 1. Microvascular: - retinopathy (blindness), neprhopathy, neuropathy 2. Macrovascular --CAD, cerebrovascular, peripheral vascular --mechanism: enhanced atherosclerosis

Pancreas path: True/False - patients with diabetes develop cardiovascular problems more frequently and at an earlier age than those without diabetes. Many of the same CV risks are present in type 2 diabetics. Chronic hyperglycemia may lead to endothelial injury (trigger atherosclerosis) and inflammation (atherosclerosis).

True

Pancreas path: True/False - HbA1c concentration is a predictor of mortality. Increased HbA1c levels correlate with increased mortality (especially CV mortality) even at levels less than those diagnostic for diabetes.

True

Pancreas path: In diabetes, proteins can become non-enzymatically glycated following exposure to sugars. These glycated proteins may have **altered structure and behavior** (e.g. collagen binding by albumin and IgG). They may also **exhibit cross-linking with collagen** (basement membrane) leading to increased vascular stiffness. Finally, these glycated proteins can **attach to specific receptors** _______ on inflammatory cells, endothelium and vascular SM. Activation of these receptors can inc. ROS, SM proliferation, monocyte influx, and endothelial permeability.

RAGE receptors \*binding of AGE to RAGE-r's contribute to microvascular/macrovascular complications (promote atherosclerosis) **NUTSHELL:** persistent glucose binds to and alters protein shape/function. Proteins then attach to RAGE on inflammatory cells, inc. endothelial damage and causing hardening of vessels.

Pancreas path: Non-enzymatic glycosylation of proteins is associated with 1. Small vessel disease (microvascular) 2. Large vessel disease \_\_\_\_\_\_ is associated with basement membrane thickening and presents as retinopathy, neprhopathy (nodular sclerosis), and arteriolosclerosis).

Small vessel disease NOTE: Large vessel - MI (thrombosis, plaque rupture), Stroke PVD (limb loss)

Pancreas path: Hyperglycemia is associated with an inc. production of ROS (free radical damage). In normal cells, aldose reductase reduces toxic aldehydes into inactive OH. However, in cases of elevated glucose, aldose reductase reduces glucose to sorbitol (later oxidized to fructose). What is the significance of this?

Blurry vision, cataracts, neuropathy \*\*Sorbitol causes cellular swelling (osmotic effect) -- edema in the lens of the eye

Pancreas path: Hyperglycemia is also associated with NADPH depletion. NADPH is essential for maintaining glutathione, an important anti-oxidant in its reduced state. Lack of NADPH lead to dec. glutathione and inc. oxidative stress. Why is this significant?

Dec. NADPH predisoposes to ox stress which contributes to diabetes-induced microvascular injury

Pancreas path: Diabetes is the leading cause of blindness in the developed world. Diabetic retinopathy is a disease of the vasculature of the retina. It contributes to retinal ischemia and associated damage. Retinopathy is strongly correlated with duration of diabetes and degree of glycemic control. There are two types: 1. NOn-proliferative retinopathy 2. Proliferative retinopathy \_\_\_\_\_ is thickening of the BM of retinal blood vessels leading to hemorrhage, microaneurysms and exudates

Non-proliferative retinopathy

Pancreas path: Diabetes is the leading cause of blindness in the developed world. Diabetic retinopathy is a disease of the vasculature of the retina. It contributes to retinal ischemia and associated damage. Retinopathy is strongly correlated with duration of diabetes and degree of glycemic control. There are two types: 1. NOn-proliferative retinopathy 2. Proliferative retinopathy \_\_\_\_ is growth of new blood vessels as a consequence of retinal hypoxia

Proliferative retinopathy

Pancreas path: Complications of diabetes can include cataracts (opacification of the lens). This is due to the accumulation of sorbitol within the lens forming an osmotic gradient. True/False - Glaucoma may be a risk factor, although association is not as clear as vasculopathy and reinopathy

True

Pancreas path: Diabetes is a leading cause of chronic renal failure (dialysis; transplants). Renal complications from diabetes are associated with glomerular **hypErfiltration** (osmolar load and intra-renal HTN) and **damage to the glomerular basement membrane** (proteinuria; leaked proteins). These ultimately lead to fibrosis and scarring (glomerulosclerosis). \_\_\_\_\_\_\_ is the earliest clinical evidence of diabetic nephropathy.

Microalbuminuria \*\*ACE inhibitors: protective in diabetes; dec. intraglomerular pressure and dec. proteinuria

Pancreas path: A diabetic patient presents with **sensory loss** that is **bilateral** and **symmetric**. It occurs in a "**stocking-glove**" pattern. He admits to **numbness** and **insensitivity** to pain and temperature, leading to development of **ulcers**. He also reports **tingling** and **burning sensations**. Admits to l**oss of balance and coordination**. You suspect

Peripheral neruopathy/Distal sensorimotor neuropathy \*damage to **nerves** and **Schwann cells** \*sensory loss first -- bilateral and symmetric \*caused by both metabolic and vascular changes

Pancreas path: A diabetic patient presents with complaints of **postural hypotension**. He admits to **sexual dysfunction**, and **bladder atony**. ROS reveals delayed **gastric emptying (gastroparesis)**, and **silent MI**. You suspect

Autonomic neuropathy \*bladder atony (acontractile) - difficulty urinating

Pancreas path: A diabetic patient presents with cognitive decline. You suspect Central neuropathy. What is role of Insulin in central neuropathies?

Persistently high insulin dec. activity of insulin degrading enzyme (elevating B-amyloid protein) -GABA and Glutamate receptors \*B-amyloid protein involved in neurotoxicity \*see slide 68

Pancreas path: Complications of diabetes include Increased susceptibility to infections including: 1. UTI 2. Candida 3. Malignant otitis externa (pseudomonas) 4. Rhnicerebral mucormycosis (Rhizopus, Abisdia, Mucor) True/False - Increased infections are associated with multi-factorial mechanisms that invovles impaired WBC function and vascular compromise

True \*NOTE: Mucor life threatening in DKA

Pancreas path: A patient presents with **hyperpigmented, velvety dermal plaques** located in the axillary region, groin, and posterior neck. This is NOT specific to diabetes, but is a common manifestation. You suspect

acanthosis nigricans \*intertiginous regions \*insulin resistance; hyperinsulinemia due to: **IGF** stimulation on epidermal cells

Pancreas path: Gestational diabetes is a form of diabetes that occurs during pregnancy. It is due to anti-insulin effects of human placental lactogen (hpl), progesterone and cortisol. It is associated with a high risk of developing diabetes at a later date and an increased risk for gestational diabetes in future pregnancies. How is it maintained/treated?

1. Strict control of glucose in mother 2. May need to give newborn glucose to prevent neural damage

Pancreas path: Gestational diabetes is a form of diabetes that occurs during pregnancy. It is due to anti-insulin effects of **human placental lactogen** (hpl), **progesterone** and **cortisol.** It is associated with a high risk of developing diabetes at a later date and an increased risk for gestational diabetes in future pregnancies. What are risks to the fetus?

1. ARDS * insulin = dec. surfactant 2. Seizures at birth * inc. insulin = hypoglycemia 3. Macrosomia * inc. aa uptake in muscle (anabolic) and fat in adipose

Pancreas path: A patient presents with **mental status changes**, **HA, inability to concentrate, and confusion**. He exhibits adrenergic symptoms including **sweating, tremors, anxiety** and **palpitations**. Labs reveal: 1. Blood glucose **\< 70mg/dL** * (clinical manifestations \< 60) 2. Dec. Insulin 3. Inc. glucagon 4. Inc. Cortisol, Epinephrine and Ach You suspect

Hypoglycemia \*seizures, loss of consciousness, death if prolonged/severe

Pancreas path: Hypoglycemic patients tend to present with mental status changes, HA, inability to concentrate (neuroglycopenic symptoms) and adrenergic symptoms. Common etiologies of hypoglycemia include: 1. Surreptitious/Excessive insulin/sulfonylurea (MC) 2. Chronic renal failure 3. Cirrhosis 4. Malnutrition 5. Insulinoma Explain the MOA of these

1. Chronic renal failure (dec. insulin clearance) 2. _Cirrhosis_ * decreased gluconeogenesis and glycogen 3. _Malnutrition_ * decreased gluconeogenic precursors 4. _Insulinoma_ * inborn errors of metabolism

Pancreas path: Fasting state hypoglycemia is associated with chronic alcohol use (ethanol binging). Malnutrition is often previously present and patients tend to present with signs of liver disease (e.g. glycogen depletion and defective gluconeogenesis). The mechanisms by which hypoglycemia occurs is increased NADH that converts pyruvate to \_\_\_\_\_\_. As a result, there is less pyruvate available for gluconeogenesis.

Lactate \*nutritional/vitamin deficiencies common OH users w/ acute hypoglycemia (DD withdrawal) \*Thiamine before glucose (memory, cerebellar, or confusion)

Pancreas tumors: Pancreatic neuroendocrine tumors are **uncommon, slow growing** pancreatic neoplasms most often seen in 50-60 year olds. They may be functional or non-functional, but are all considered **malignant** due to their potential (unless \< 5mm). Malignancy is often defined by behavior (e.g. presence of invasion or metastasis). They are associated with what syndromes?

1. hyperinsulinism 2. hypergastrinemia and ZE syndrome 3. MEN 1 (most cases) \*graded low, intermediate, high (mitotic figures and Ki-67 cell prolif. index)

Pancreas tumors: A patient presents with **mild hypoglycemia that is exacerbated by exercise**. You suspect her hypoglycemia is secondary to a neoplasm. Past imaging reveals a **benign tumor of the pancreas** (MC fxning endocrine pancreatic tumor). Labs reveal: 1. Inc. Insulin and C-peptide 2. Dec. Glucose (High insulin to glucose ratio) (Inc. circulating insulin) You suspect

Beta cell tumor (insulinoma) \*tumors = excessive insulin secretion (hypoglycemia) \*mild hypoglycemia (may nerver be symptomatic; episodic) Tx: Surgery

Pancreas tumors: What are important DD of hypoglycemia?

Insulin or sulfonylurea overdose Abnormal insulin sensitivity diffuse liver disease inherited glycogenoses ectopic production of insulin by certain retroperitoneal fibromas and fibrosarcomas

Pancreas tumors: Patients with Insulinoma may present with 1. Low blood glucose 2. Whipple triad 3. Resolution of symptoms after glucose levels are normalized What is the Whipple triad?

Symptoms of hypoglycemia (**lethargy, syncope, diplopia**) \*differentiate with C-peptide levels (only seen in endogenous insulin)

Pancreatic tumors: 1. Dec. Insulin and Dec. C-peptide are indicative of 2. Inc. Insulin and Dec. C-peptide are indicative of 3. Inc. Insulin and Inc. C-peptide are indicative of

1. 2. Exogenous insulin (no C-peptide) 3. Endogenous insulin (Insulinoma, Sulphonylureas)

Pancreatic tumors: A diabetic patient presents with complaints of **epigastric pain and diarrhea** (malabsorption). Scope reveals **multiple peptic ulcers** located **distal** to the stomach (duodenum and jejunum). In addition, **esophagitis** is noted. Histology reveals **hyperplasia** of gastrin-responsive fundic mucosa. Labs reveal **Inc. gastrin**. You suspect

Zollinger Ellison syndrome \*gastrin secreting tumor of pancreas or duodenum \*pancreatic islet lesions, peptic ulceration and hypersecretion of gastric acid \*present in 90-95% of patients

Pancreatic tumors: More than half of gastrin producing (Zollinger Ellison; ZE) tumors are locally invasive or have already metastasized by the time of diagnosis. These tumors may be seen in conjunction with other endocrine tumors, as part of MEN-1 syndrome. MEN-1 associated gastrinomas are frequently \_\_\_\_\_\_\_, while sporadic gastrinomas are usually single

Multifocal Histology: Bland \*Intractabale jejunal ulcers - suspect ZE

Pancreatic tumors: A post-menopausal female with mild diabetes mellitus presents with a skin rash (**necrolytic migratory erythema**) and **anemia**. You suspect

alpha cell tumor \*glucagonoma \*MC perimenopausal and post-menopausal

Pancreatic tumors: A patient with diabetes mellitus presents with cholelithiasis, steatorrhea and hypochlorhydria. Imaging reveals a tumor that is difficult to localize pre-operatively. Labs reveal: 1. High plasma somatostatin levels You suspect

Delta cell tumors (Somatostatinoma) \*high plasma somatostatin required for Dx

Pancreatic tumors: A patient with diabetes mellitus presents with watery diarrhea, hypokalemia, achlorhydria (a.k.a WDHA syndrome) for follow up after imaging of a suspected mass. Labs reveal a tumor that secretes VIP. You suspect VIP-oma. What is the next step?

VIP assay \*see slide 11 Other associations: neuroblastoma, ganglioneuroblastoma, ganglioneuroma, pheochromocytomas

Pancreatic tumors: Review neuroblastomas and Pheochromocytomas

Pancreas path: Review squamous cell carcinoma

Metabolic syndrome: A patient presents with 1. Abdominal waistline girth \> 40 inches (men) and \> 35 inches (women) 2. HDL \< 40mg/dL (men)/ \< 50mg/dL women 3. Fasting glucose \> 100mg/dL 4. Serum TG \> 150 mg/dL 5. BP \> 130/85 mmHg You suspect metabolic syndrome. What is the primary mediator?

insulin resistance Risk factor for type 2 diabetes, CVD Tx: underlying (weight, obesity); Tx CV risk factors

Pancreas tumors: Distinguish b/t MEN1 and MEN 2A

_MEN 1:_ * --tumor suppressor * encodes protein menin * pituitary, parathyroid, pancreas neoplasms _MEN2A:_ * RET protoncogene * Medullary carcinoma, pheochromocytoma, parathyroid hyperplasia or adenoma

Diabetes Pharm: ______ act to stimulate insulin release by binding to sites on B-cell K-ATP channels SUR inhibiting its activity (block K+ channels; inc. insulin and calcium release). K-ATP inhibition causes cell membrane depolarization and the cascade of events leading to insulin secretion

Sulfonylureas 1st gen: Chlorpropamide, Tolazamide, Acetohexamide, Tolbutamide 2nd gen: Glyburide, Glimepiride, Glipizide \*Chlorox, Tolbooth

Pancreas tumors: ________ are rare tumors that MC affect the **small intestine**. They are 5HT producing tumors and can metastasize to the pancreas. Patients present with **diarrhea, flushing, wheezing, R-sided heart valve disease.**

Carcinoid tumors Dx: Inc. urine 5-HIAA

Diabetes pharm: Sulfonylureas act by blocking K+ channels, increasing insulin, Ca2+ and C-peptide. Which of the following is a side effect of Sulfonylureas? a. hypoglycemia b. weight gain c. disulfiram-like reaction d. inc. risk hospitalization and mortality

All of the above \*anything that inc. endogenous insulin = **hypoglycemia** risk Cx: Renal failure (dialysis); Sulfur allergy

Diabetes pharm: Biguanides include Metformin and Metformin hydrochloride. These drugs act by **decreasing hepatic glucose production** (gluconeogenesis) and **increasing insulin-mediated peripheral glucose uptake**. Metformin is the 1st line therapy for patients needing an oral drug. What are adverse effects of metformin?

1. GI upset 2. Lactic acidosis 3. B12/Cobalamin deficiency Cx: GFR \< 30 NOT recommended: GFR 30-45

Diabetes pharm: ______ include **Pioglitazone, Rosiglitazone, Troglitazone**. These drugs act as ligand for **PPAR Y receptor,** a nuclear hormone that regulates gene related to glucose and lipid metabolism. They also dec. insulin resistance by making muscle and adipose more susceptible to insulin. 6 weeks onset.

Glitazones/Thazolidinediones

Diabetes pharm: The following are adverse effects of what drugs? 1. Heart failure w/ fluid retention 2. Edema 3. Weight gain 4. Inc. risk fractures 5. Inc. adiponectin

Glitazones/Thiazolidinediones Cx: abnormal liver function, CHF Pio Cx: bladder cancer Rosi Cx: CV disease To Cx: off market (liver tox)

Diabetes pharm: Meglitinides include **Repaglinide** and **Nateglinide**. These drugs act by: a. stimulating insulin release by closing K-ATP channels in B-cells b. blocking enzymes that digest starches c. inhibiting DPP-4 enzyme inactivation of GLP-1

A. Closing ATP-dependent potassium (K-ATP) channels (inc. insulin) \*similar to sulfonylureas

Diabetes pharm: Meglitinides have a short duration of action. They act by stimulating insulin release via closure of K-ATP channels in B-cells. What are adverse effects of these meds?

1. Hypoglycemia (less than sulfonylurea) 2. Weight gain \*safe at higher levels of serum Cr than sulfonylureas

Diabetes pharm: ______ are diabetic medications that block enzymes that digest starches (starch, dextrin, disaccharides) in the small intestine. They do so by inhibiting the action of alpha-glucosidase in the brush border.

Alpha glucosidase inhibitors \*Acarbose, Miglitol

Diabetes pharm: What are the adverse effects of Alpha glucosidase inhibitors, Acarbose and Miglitol?

Flatulence or abdominal discomfort \*no weight gain Cx: IBD, Cirrhosis

Diabetes pharm: Incretin (GLP-1) mimetics include: 1. Exanatide (Byetta 2x daily; post-prandial) 2. Albiglutide (weekly) 3. Dulaglutide (weekly) 4. Liraglutide (daily) These drugs act to increase insulin, decrease glucagon, and decrease gastric emptying. They are useful medications for weight loss. What are adverse effects of these drugs? Contraindications?

_Adverse:_ 1. N/V/HA 2. **NO** Hypoglycemia 3. Pancreatitis/Renal dysfunction \* (rare) 4. Rapid absorbing drugs * Dec. rate/extent of absorption (pain releivers, antibiotics, OCPs) - admin @ least 1 hr. _Contraindications:_ - Gastroparesis, Pancreatitis - Cr clearance \< 30 (**Exanetide**) - Medullary thyroid carcinoma (**Liraglutide**)

Diabetes pharm: DDP-IV inhibitors act by **inhibiting DDP-4 enzyme inactivation of GLP-1/GIP**. This enables glucose uptake by peripheral tissues and decreases hepatic glucose production. Which of the following is a DDP-IV inhibitor? a. Sitagliptin b. Exanatide c. Bromocriptine d. Colesevelam

Sitagliptin Adverse: **URI, Nasal pharyngitis** \*Low risk hypoglycemia

Diabetes pharm: **Pramlinitide** is an amyline analog that is used for Tx of both Type 1 and 2 DM. Amylin is normally co-secreted with insulin and acts to decrease glucagon, gastric emptying, while increasing satiety. What are adverse effects of pramlinitide?

Weight loss, hypoglycemia, nausea

Diabetes pharm: Bromocriptine and Colesvelam are Dopamine receptor agonists that may be used to help Tx type ______ DM. They usually reduce A1c to 0.5%.

Type 2 DM

Diabetes Pharm: SGLT-2 inhibitors include 1. Canaglifozin 2. Dapagliflozin 3. Empagliflozin These drugs act to inhibit renal tubular Na2+ -glucose co-transporter. What are the net effects?

-reversal of hyperglycemia and glucotoxicity ## Footnote - glycosuria and salt/water loss - inc. GLUT4 translocation in mm - dec. glu-6-phosphatase in liver Advantages: daily oral admin; **weight loss and b.p. lowering**

Diabetes Pharm: Which of the following is a side effect of SGLT2 inhibitors? a. weight loss b. hypoglycemia c. b.p. reduction (d/t osmotic diuresis) d. UTI

A, C, D -**weight loss, dec. b.p, UTI, polyuria, genital mycotic infections** Dapagliflozin (not recommended): GFR \< 60 All: not recommended GFR \< 45

Diabetes pharm: Insulins \*\*FINISH

## Footnote _Adverse:_ Hypoglycemia (MC) _Drug interactions:_ \*\*Don't use sulfonylureas or meglitinides w/ insulin

Diabetes pharm: See Stroup Table (ADA goals/targets)

Parathyroid pharm: Finish

Parathyroid pharm: Osteomalacia is bone softening due to abnormal mineralization of new bone matrix. It results in Vitamin D deficiency, dec. Vit. D metabolism, Phosphate deficiency, and osteoblast dysfunction. How does this present in kids?

Rickets (Vitamin D deficiency) NOTE: drug causes: phenytoin and other anti-convulsants (interfere w/ vit. D absorption/metab)

Parathyroid pharm: Calcium can be used as therapy for the prevention and treatment of **osteoporosis** and **hypocalcemia**. Normal calcium requirements in individuals older than 50 include: 1. Males 51-70 = 1000 2. Females 51-70 = 1200 mg/day 3. \> 70 years = 1200 mg/day What are adverse reactions of Ca2+?

- Constipation - Modest inc. risk of MI (limit to daily recommended) - Bloating, Kidney stones Max intake: 600mg/dose

Parathyroid pharm: Calcium formulations include: 1. Calcium carbonate 2. Calcium citrate 3. Calcium phosphate 4. Calcium gluconate 5. Calcium chloride \_\_\_\_\_\_ can be taken as tablets, chews or oral suspension. It is preferred for low cost and high calcium content. However, it requires an **acidic** environment for optimal absorption (**take with meals**)

Calcium carbonate

Parathyroid pharm: Calcium formulations include: 1. Calcium carbonate 2. Calcium citrate 3. Calcium phosphate 4. Calcium gluconate 5. Calcium chloride \_\_1\_\_ is good for patients with **high gastric pH** and can be taken with or without food. \_\_2\_\_\_ is preferred in patients who are **hypophosphatemic**. This requires an acidic environment for optimal absorption (**take with meals**).

1. Calcium Citrate --high gastric pH 2. Calcium phosphate --take with meals --hypophosphatemic

Parathyroid pharm: Calcium formulations include: 1. Calcium carbonate 2. Calcium citrate 3. Calcium phosphate 4. Calcium gluconate 5. Calcium chloride \_\_\_\_\_\_ is given IV and is less irritating to veins. ____ is given IV and is more irritating to veins, but more concentrated.

1. Ca gluconate (less irritating) 2. Ca chloride (more irritating)

Parathyroid pharm: Calcium formulations have which drug interactions? a. Fluoroquinolones b. Tetracyclines c. Bisphosphonates d. Levothyroxine

all of the above \*take 2 hours before or after these medications \*Ca2+ dec. absorption of these drugs

Parathyroid pharm: Vitamin D is a fat soluble vitamin obtained from the diet. It is synthesized in the skin via UV radiation to Vit. D3 (cholecalciferol), then double hydroxylated in the liver (at 1 and 25 position) to calcitriol (active form). PTH stimulates renal hydroxylation of Vitamin D. Indications for use include: Rickets, Osteoporosis, Vit. D deficiency and hypocalcemia. What are drugs MC used?

1. **_Doxercalciferol and Paracalcitol_** --analogs of calcitriol --2ndary hyperparathyroidism due to CKD **_2. Calcifediol_** --vit. D3 analog --extended release --stage 3/4 CKD

Parathyroid drugs: Adverse effects of Vitamin D2 (ergocalciferol) analogs include 1. Hypercalcemia 2. Hypercalciuria 3. Hyperphosphatemia What are Common Drug interactions?

_**Interactions**:_ 1. *_Cholestyramine_* --dec. GI absorption 2. *_Phenytoin, Barbs_* *_-_*inc. metabolism Cx: Obesity (deposits in adipose); Hypercalcemia

Parathyroid pharm: _______ are the **first line treatment of osteoporosis**. They act by integrating into the bone structure and inhibiting osteoclast activity. These include: 1. Alendronate (2nd gen) 2. Risedronate (2nd gen) 3. Ibandronate (3rd gen) 4. Zoledronic acid (3rd gen) These must be takien 1st thing in the morning on an **EMPTY** stomach with 8oz water. **No food/drink for 30 minutes** (*60* minutes ibandronate). **Sit upright for at least 30 minutes** (*60* minutes ibandronate).

Bisphosphonate \*take with calcium/Vitamin D regimen NOTE: further reduced by food or drugs

Parathyroid pharm: Bisphosphonates (Alendronate, Pamidronate, Risderonate, Zoledronic acid) are **Cx in renal insufficiency (CrCl \<35mL/min)**. Which of the following is an adverse reaction of bisphosphonates? a. esophageal erosion (oral formulations) b. atypical femur fractures c. osteonecrosis of the jaw d. confusion

A-C Drug Intx: **-Calcium** and **Antacids** (separate by 2 hours)

Parathyroid drugs: List the bisphosphonates that can be taken 1. Daily 2. WEekly 3. Monthly

_1. Daily_ --Alendronate, Risedronate (oral) _2. Weekly_ --Alendronate, Risedronate (oral) _3. Monthly_ --ALL except Alendronate --Pamidronate and Zoledronic (IV); Ibandronate (oral, IV)

Parathyroid pharm: PTH analogs include 1. Teriparatide 2. Cinacalcet. \_\_\_\_\_\_ is administered subcutaneously daily for up to 2 years. Long term exposure can lead to **bone resorption**, but cessation leads to **rapid bone loss**. Thus, follow with a *bisphosphonate* or other anti-resorptive agent.

Teriperatide \*Adverse: Hypercalcemia \*Cx: Inc. risk osteosarcoma (Paget's); Inc. Alk phos

Parathyroid pharm: PTH analogs include: 1. Teriparatide 2. Cinacalcet Cinacalcet is an agonist to the Ca2+ sensing receptor on principle cells (Inc. receptor binding = dec. PTH). Indications for use include **hypercalcemia in patients with parathyroid cancer**. It should be administered *with food or shortly after*. What are adverse effects?

Hypocalcemia, QTc prolongation, GI bleeding

Parathyroid pharm: Denosumab acts as an antibody to \_\_\_\_\_\_, preventing **osteoclast** formation and bone resorption (cortical and trabecular). It is used for the treatment of osteoporosis.

RANKL Adverse: Hypocalcemia (give supplement) Administer: subcutaneous injection (every 6 mos)

Calcitonin

Parathyroid pharm: Other pharmacological agents used to Tx osteoporosis, Paget disease and hypercalcemia. 1. Calcitonin 2. Estrogen and Raloxifene 3. Sodium flouride and strontium **Estrogen** increases risk of Breast cancer and VTE. **Raloxifene** is a SERM that acts as an *agonist in bone* and *antagonist in breast/uterine tissue*. It also hase anti-estrogen effects. What are effects of Raloxifene?

1. Worsen hot flashes --anti-E2 2. Dec. breast cancer risk --post-menopause 3. Inc. risk stroke, PE, DVT

Parathyroid pharm: Other pharmacological agents used to Tx osteoporosis, Paget disease and hypercalcemia. 1. Calcitonin 2. Estrogen and Raloxifene 3. Sodium flouride and strontium **Sodium fluoride** is often used to prevent tooth decay. It fails to reduce fractures and can lead to \_\_\_\_1\_\_\_\_. **Strontium** acts by integrating into the bone surface, decreasing bone resorption and increasing bone formation (via osteoblasts). However, it may increase risk for \_\_\_2\_\_\_\_

1. osteosclerosis 2. inc. risk DVT/PE/MI

Parathyroid pharm: Management of osteoporosis involves lifelong calcium and Vit. D intake along with weight-bearing exercise and endogenous E2 and testosterone to minimize bone resorption. 1. ____ is used to maintain bone mineral density 2. _____ is used after extended use of #1 3. _____ and _____ used for low or rapidly decreasing BMD, previous fracture, or chronic corticosteroid use

1. Bisphosphonates 2. Calcitonin 3. Teriparatide, Denosumab

Parthyroid drugs: ______ are used most often in treatment of Paget disease of bone. ________ are most often used in hypercalcemia associated with cancer.

1. Paget --calcitonin or bisphophonate (zoledronic) --control bone pain/prevent deformity 2. Hypercalcemia --bisphosphonate --maybe w/ calcitonin

Exam II Flashcards

(260 cards)