Week 6 Flashcards
(80 cards)
1
Q
Primary adrenal insufficiency
patho, presentation, clinical features
gradual vereus rapid
A
- Pathophysiology: damage to the cortical cells (90% of cortex lost) that produce aldosterone and cortisol (adrenal medulla is preserved) → increased ACTH
- Presentation:
- Rapid (Waterhouse-Friderichsen): adrenal crisis due to hemorrhage → hypovolemic shock/coma → treat with glucocorticoids immediately
- Etiology: DIC secondary to N. meningitidis (children)
- Gradual (basal cortisol may be normal): Addison’s disease
- Rapid (Waterhouse-Friderichsen): adrenal crisis due to hemorrhage → hypovolemic shock/coma → treat with glucocorticoids immediately
- Clinical features: weakness, fatigue, loss of appetite, N/V, abdominal pain, weight loss, hyperpigmentation of skin (elevated ACTH → melanocyte production)
2
Q
Primary adrenal insufficiency
labs and etiology
A
- Labs: ACTH is elevated, hypoglycemia, hypotension, hyponatremia, hyperkalemia, eosinophilia (low cortisol effect), increased BUN/creatinine (volume depletion)
- Etiology: Autoimmune (majority), adrenal hemorrhage (due to anticoagulant therapy), infections, metastatic disease, adrenoleukodystrophy (X-linked, defect in fatty acid metabolism → very long chain fatty acids accumulate in organs), infiltrative diseases (i.e. amyloidosis), drugs (i.e. ketoconazole)
3
Q
Autoimmune polyglandular syndrome
1 versus 2
patho, etiology, Sx
A
- APS-1: Primary AI with hypoparathyroidism and mucocutaneous candidiasis
- Pathophysiology: autosomal recessive disease that is characterized by autoantibodies against cholesterol cleavage enzyme
- Etiology: mutation in autoimmune regulatory gene (AIRE)
- Sx: hepatitis, alopecia, vitiligo, hypogonadism, hypothyroidism
- APS-2: Primary AI with DM I and autoimmune thyroid disease
- Pathophysiology: anti-adrenal antibodies against 21-alpha-hydroxylase
- Associated with: genetic susceptibility linked to HLA-DR3/DR4
- Sx: less commonly alopecia, vitiligo, hypogonadism, celiac disease
4
Q
Secondary adrenal insufficiency
patho, etiology,
A
- Pathophysiology: deficient pituitary ACTH secretion → low ACTH → decreased cortisol and adrenal androgens, but NO aldosterone deficiency
- Early: basal cortisol is normal (decreased reserve or recent pituitary surgery)
- Late: further loss of ACTH secretion → atrophy of adrenal cortex → decreased basal cortisol
- Etiology: exogenous steroids (majority), hypothalamic/pituitary tumors (HA, vision changes, look for loss or hypersecretion of other pituitary hormones)
5
Q
Secondary adrenal insufficiency
sx, labs
A
- Sx: NO hyperpigmentation, NO hypotension, fatigue, loss of appetite, nausea, vomiting
- Labs: ACTH is low, hyponatremia (low cortisol → increased ADH → excessive water uptake), NO hyperkalemia, hypoglycemia, eosinophilia
6
Q
4 ways to diagnose AI
and how do they work
A
- AM cortisol (assesses basal cortisol): reasonable initial screening test, but may be normal in partial/early AI
- ACTH stimulation test (assesses adrenocortical reserve): normal peak cortisol >18 mcg/dL
- If abnormal cortisol response to test, check ACTH
- High ACTH → primary adrenal insufficiency
- Low ACTH → secondary adrenal insufficiency
- If abnormal cortisol response to test, check ACTH
- Metyrapone Test: evaluates HPA axis’ response to stress
- MOA: Metyrapone blocks the 11β-hydroxylase enzyme which converts 11-deoxycortisol to cortisol → decreased cortisol synthesis → stimulates ACTH → increases 11-deoxycortisol
- 11-deoxycortisol > 7 and ACTH > 100 → normal pituitary ACTH secretion and adrenal function
- MOA: Metyrapone blocks the 11β-hydroxylase enzyme which converts 11-deoxycortisol to cortisol → decreased cortisol synthesis → stimulates ACTH → increases 11-deoxycortisol
- Insulin-induced hypoglycemia test: evaluates entire HPA axis’ response to stress
- MOA: Hypoglycemia → increases CRH release → increases ACTH secretion → increases cortisol secretion
- Normal response is a peak cortisol > 18mcg/dL
- MOA: Hypoglycemia → increases CRH release → increases ACTH secretion → increases cortisol secretion
7
Q
Treatment of adrenal insufficiency
A
- Tx of acute adrenal crisis: IV glucocorticoids, IV fluids
- Tx of chronic AI: hormone replacement (glucocorticoids/hydrocortisone and/or mineralocorticoids/fludrocortisone)
8
Q
ACTH independent versus dependent Cushing syndrome
compare eitiologies
A
- ACTH-dependent Cushing syndrome:
- Cushing disease: due to ACTH secreting pituitary tumor → increased ACRH and bilateral adrenal hyperplasia (majority of syndrome)
- Ectopic ACTH or CRH secretion by non-pituitary tumors (small-cell carcinoma) → increased ACTH (hyperpigmentation) and bilateral adrenal hyperplasia
- ACTH-independent Cushing syndrome:
- Exogenous corticosteroid treatment → decreased ACTH and bilateral adrenal atrophy
- Primary adrenal adenoma, hyperplasia, carcinoma → produce cortisol → decreased ACTH → leads to atrophy of uninvolved adrenal gland
- Ectopic receptors in adrenal gland (respond to GIP/food dependent or HCG/pregnancy dependent) → Cushing syndrome
- Primary pigmented nodular adrenal disease (Carney complex)
9
Q
Cushing
sx, lab, path
A
- Symptoms: central obesity with thin extremities, moon facies, fat pad, thinning of skin → easy bruising and purple abdominal striae, osteoporosis, amenorrhea/hirsutism (women), proximal muscle weakness, immunosuppression, HTN, hypogonadism, decreased libido/impotence (men)
- Labs: low eosinophils (cortisol), possible hypokalemia, hyperglycemia (diabetes)
- Pathology: chronic high cortisol → pituitary cells accumulate cytokeratin filaments (hyaline material) → displacement of secretory granules to periphery (looks like rings)
10
Q
Diagnosis of Cushing Syndrome:
what is the intial screenign tests
what happens if those are positive
what is IPS
A
- Initial screening: increased 24 hour urine free cortisol, increased late night salivary cortisol, inadequate suppression of cortisol following 1mg dexamethasone overnight
- If initial screening is positive, proceed to measure ACTH
- Low ACTH → ACTH independent Cushing → perform CT of adrenal gland
- High ACTH → ACTH dependent Cushing
- High dose dexamethasone suppression test: no suppression (ectopic) or adequate suppression (Cushing)
- CRH stimulation test: increased ACTH and cortisol (Cushing) or no increase in ACTH and cortisol (ectopic)
- Inferior petrosal sinus (IPS) sampling: recommended if MRI does not reveal pituitary adenoma
- MOA: simultaneously measure IPS and peripheral ACTH before and after CRH
- IPS ACTH:peripheral ACTH > 2 before CRH, and >3 after CRH → pituitary ACTH-secreting tumor
- Drainage of blood: anterior pituitary → cavernous sinuses → IPS → jugular vein
- MOA: simultaneously measure IPS and peripheral ACTH before and after CRH
11
Q
Adrenal tumor-mediated hypertension
name 5 etiologies
explain each
A
- Cushing Syndrome
- Pheochromocytoma (functional chromaffin tumors from adrenal medulla → excess epi and norepi)
- Sx: episodic episodes of headaches, diaphoresis, and palpitations (classic triad)
- 5 P’s: pressure, pain, palpitations, pallor, and perspiration
- Etiology: germ line mutation (NF-1, VHL, RET)
- Epidemiology (rule of tens): 10% are malignant, bilateral, extra-adrenal, calcified, and in children
- Dx: increased serum metanepherines and increased 24 hour urine metanephrines and vanillylmandelic acid
- Tx: phenoxybenzamine
- Sx: episodic episodes of headaches, diaphoresis, and palpitations (classic triad)
- Primary hyperaldosteronism → excess aldosterone (zona glomerulosa)
- Etiology: aldosterone secreting adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia
- Sx/signs: HTN, hypokalemia, hypernatremia, metabolic alkalosis
- Labs: high aldosterone, low renin (high aldo:renin ratio)
- Secondary hyperaldosteronism: high aldosterone, high renin (aldo:renin ratio < 10)
- Etiology: cirrhosis, heart failure, nephrotic syndrome, renovascular HTN, renin secreting tumor
- Low aldo and low renin: CAH, exogenous mineralocorticoids, Cushing, Liddle syndrome (mutation in sodium channel → Na reabsorption), 11 beta hydroxysteroid dehydrogenase 2 deficiency (inactivation of cortisol to cortisone)
12
Q
Describe the gross anatomy, blood supply, and innervation of the adrenal glands
A
- Gross anatomy: left adrenal gland is bigger than right adrenal gland
- Blood supply:
- Adrenal glands are supplied by inferior phrenic aa, superior adrenal aa, and middle adrenal aa.
- Adrenal glands are drained by inferior phrenic vv, and adrenal vv.
- Innervation:
- The adrenal medulla is the only case in which the organ is directly innervated by preganglionic neurons (allows for quick fight and flight response)
13
Q
what are the layers of the adrenal gland
A
- Cortex (outer to inner): zona glomerulosa (G), fasiculata (F), reticularis (R),
- Medulla (M)
14
Q
Discuss the synthesis and regulation of catecholamines in the chromaffin cell
A
- Synthesis of catecholamines in chromaffin cells:
- Tyrosine (via tyrosine hydroxylase) → DOPA → dopamine → enter chromaffin granule → norepinephrine → exits chromaffin granule → epinephrine via PNMT → enters chromaffin granule
- Regulation of catecholamines:
- Ach driven sympathetic innervation (triggered by stress) → catecholamine synthesis
- Cortisol maintains PNMT gene expression
15
Q
Explain the action of catecholamines on different adrenergic receptors
A
- Catecholamine MOA: binds to GPCRs
- Norepinephrine: tends to be agonist for alpha receptors
- Epinephrine: tends to be agonist for beta receptors
- Catecholamine effect on receptors
- Alpha1 (Gq): vasoconstriction (systemic and to GI specifically)
- Alpha2 (Gi): glucagon release
- Beta1 (Gs): inotropic effect on heart
- Beta2 (Gs): vasodilation (muscles), bronchodilation, decreased insulin (pancreas), gluconeogenesis/glycogenolysis/ketogenesis (liver and muscles)
- Beta3 (Gs): lipolysis
16
Q
CAH: 11-beta-hydroxylase deficiency
A
- Leads to a deficiency of cortisol and aldosterone and an increased production of testosterone
- Sx: virilization (testosterone), HTN/hypokalemia (increased 11-DOC)
17
Q
21-hydroxylase deficiency
A
- Leads to deficiency of aldosterone and cortisol and increased testosterone
- Sx: virilization, salt wasting (salt is excreted w/o aldosterone)
18
Q
CAH: 17-alpha-hydroxylase deficiency:
A
- Leads to deficiency of cortisol, testosterone, DHEAS (lack of secondary sexual characteristics) and increased production of aldosterone (high-normal levels due to negative feedback)
- Sx: HTN/hypokalemia (both due to increased 11-deoxycorticosterone), abnormal sexual development (infertility), dysmenorrhea
19
Q
Describe the physiologic actions of cortisol, aldosterone, DHEAS,
A
- Cortisol
- Regulation: HPA axis (negative feedback), produced in paraventricular nucleus (follows circadian rhythm of release, highest right before waking up), released in response to stress/excitation
- Pathway: PVN releases CRH → anterior pituitary releases ACTH → cortisol is released by the adrenal glands (zona fasiculata)
- Effects: Acute/mins (mobilization of cholesterol and elevated pregnenolone), chronic, chronic/hrs (increased expression of genes for steroidogenic enzymes), trophic/months (hypertrophy of zona fasiculata/reticularis)
- DHEAS (bimodal elevations at birth and puberty)
- Pathway: ACTH → zona reticularis → DHEAS release
- No negative feedback on HPA axis, not associated with cortisol levels
- Pathway: ACTH → zona reticularis → DHEAS release
- Aldosterone
- Regulation: RAAS pathway (renin secreted by juxtaglomerular apparatus)
- Hyperkalemia → aldo increases, HTN → ANP increase → aldo decreases
- Effects: Na+ reabsorption, K+ excretion, pro-inflammatory effect on LV of heart
- Regulation: RAAS pathway (renin secreted by juxtaglomerular apparatus)
20
Q
what is the action on insulin
and structure
A
- Actions of insulin:
- Activate: glucose uptake, glycolysis, glycogen synthesis, protein synthesis, uptake of ions
- Inhibit: gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, and proteolysis
- Structure of pro-insulin from beta cells
- A-chain and B-chain make up pro-insulin (bound by disulfide bonds)
- C-peptide is cleaved from A-chain and B chain to activate insulin
- Due to long half-life, c-peptide can be used to determine amount of insulin
21
Q
what is whipples triad
A
- Whipple’s triad: presence of symptoms (TIRED: Tachycardia, Irritability, Restlessness, Excessive hunger, Diaphoresis), documented low blood glucose, and eventual resolution of symptoms with raising blood sugar
22
Q
Endogenous hyperinsulinemia
name some etiologies
A
- Endogenous hyperinsulinemia (i.e. insulinoma, nesidioblastosis/beta cell hyperplasia, Roux-en-Y gastric bypass)
- Roux-en-Y gastric bypass: due to excess GLP-1 secretion from bypassed duodenum
- Dx: fast patient to achieve low blood glucose → take labs (insulin, proinsulin, C-peptide, cortisol, free FA)
- Labs: look for decreased blood glucose and increased C-peptide (increased insulin:glucose ratio and increased proinsulin:insulin ratio)
- Tx: pancreatectomy (nesidoblastosis) or tumor resection (insulinoma)
23
Q
how does AI lead to hypoglycemia
A
- Adrenal insufficiency: low cortisol → low blood glucose without hyperinsulinemia
24
Q
what are non-endocrine causes of hypoglycemia
3 overarching ways
A
- Liver and renal disease
- Normal: These organs contain glucose-6-phosphatase → releases glucose into circulation (therefore decreased cell mass → hypoglycemia)
- Liver: ethanol shuts down gluconeogenesis → hypoglycemia
- Renal: disease → alters insulin clearance → hypoglycemia
- Tumor and malignancies
- Tumors → insulin growth factor (IGF) expressed → increased glucose uptake → hypoglycemia
- Dx: no detectable insulin levels (IGF ≠ insulin)
- Tumors → insulin growth factor (IGF) expressed → increased glucose uptake → hypoglycemia
- Antibodies/immunologic
- Etiology:
- Pathway 1: anti-insulin antibody binds to insulin → pancreas produces more insulin → antibodies release insulin → LOTS of insulin → hypoglycemia
- Pathway 2: anti-insulin receptor antibodies act as insulin agonist → acts as insulin → hypoglycemia
- Associated with: SLE, biliary cirrhosis, and myasthenia gravis
- Etiology:
25
* Drug-induced hypoglycemia
* Interference with metabolism, binding, or clearance of anti-diabetes drug:
* Adrenergic blocking drugs, heptotoxins, nephrotoxins, quinolones (i.e Cipro)
* Stimulation of K+ and/or Ca++ in beta cells:
* Anti-arrhythmic, macrolides, antihistamines
26
* Jamaican vomiting sickness
* Etiology: Unripe Ackee fruit produces hypoglycin A/B → hypoglycemia
27
* Factitious hypoglycemia
* Etiology: self-induce hypoglycemia caused by:
* Insulin injections, sulfonylureas, meglitinides
* Dx: mimics finings of endogenous hyperinsulinemia (NO elevated proinsulin:insulin ratio)
* Labs: high insulin, low c-peptide
28
Non-pathologic hypoglycemia
3 types
* Reactive hypoglycemia
* Mechanism: high carb meal → excess insulin release → hypoglycemia
* Types
* Alimentary: post GI surgery due to dysfunctional glucose absorption → longer insulin release
* Prediabetic: delayed first phase insulin release → build-up of insulin during non-fed states → hypoglycemia
* Idiopathic post-prandial syndrome (not hypoglycemia)
* Mechanism: exaggerated catecholamine release in response to insulin → hypoglycemic-like symptoms without low blood sugar
* Somatostatinoma
* Mechanism: somatostatin releasing tumor → inhibition of insulin, glucagon, gastrin, GIP, CCK, secretin, GH, TSH → hypo or hyper-glycemia
* Sx: gallstones, steatorrhea, achlorhydria
29
Glucagonoma
* Glucagonoma → hyperglycemia
* Mechanism: glucagon releasing tumor from alpha cells→ severe hyperglycemia
* Sx: depression, diarrhea, declining weight, dermatitis, DVT and anemia
* Necrolytic migratory erythema
* Description: erythematous blisters and swelling in areas of increased friction (present in majority of cases) – similar rash seen in zinc deficiency
30
what is obesity
how to measure and what are the different BMI categories
* Obesity: storage of excess calories as fat
* Possible measurement techniques: BMI (can be misleading based on muscle mass), hip-to-waist ratio, Edmonton Obesity Staging System (most accurate – assesses obesity based on medical, mental and functional co-morbidities)
* BMI categories
* Under 16.5 (severely underweight), 16.5-18.4 (underweight), 18.5-24.9 (normal), 25-29.9 (overweight), 30-34.9 (class 1 obesity), 35-39.9 (class 2 obesity), 40 and over (class 3 obesity)
31
thrifty gene versus set point theory
* Thrifty gene hypothesis: premise that humans evolve to store fat efficiently, burn energy slowly, spare muscle breakdown, and desire for calorically dense foods (i.e. ice cream)
* Set point theory: the body’s ability to restore to the physiological “setpoint” by changing intake, expenditure, and fat stores
32
what are peptides/hormones involved with body weight
* Leptin: hormone produced by adipocytes leading to satiety
* Ghrelin: neuropeptide produced by stomach epithelial cells in response to shrinking of stomach → hunger
* MCH (melanin concentrating hormone): direct stimulation of appetite
* AgRP (Agouti related peptide): normally causes loss of appetite suppression
* NPY (neuropeptide Y): potent stimulus for hunger
* POMC gene: gives rise to MSH (melanocyte stimulating hormone) → appetite suppression
* Mutations of POMC gene → early childhood onset obesity (sx: AI)
* FTO gene: discovery of gene that is associated with adiposity (decides to store fat vs burning) independent of caloric intake → BMI is partially inherited
33
**Explain the types of fat**
* White adipocytes: _store energy_ via triglycerides; release leptin, resistin, adiponectin, and other adipokines
* Brown adipocytes: no storage of energy, no release of adipokines, constitutive _thermogenesis_
* Beige (combination): adipocytes CAN store energy or CAN be induced for thermogenesis via beta-3 stimulation
34
**Assess the health consequences of obesity; compare the relative contributions of obesity to various health consequences.**
* Consequences of obesity: CAD/hypercholesterolemia, diabetes type 2, HTN, obstructive sleep apnea, NAFLD, gallbladder disease, gynecologic abnormalities, osteoarthritis, gout, stroke, severe pancreatitis, cancer
35
* Phentermine (Adipex/Fastin)
* MOA: inhibits reuptake of monoamines (i.e. HT, DA, NE) → satiety
* SE: tachycardia, palpitations, tremors, mood swings
36
* Orlistat (Xenical/Alli)
* MOA: lipase inhibitors → decreased fat absorption
* SE: diarrhea, steatorrhea
37
* Lorcaserin (Belviq)
* MOA: selective serotonin agonist → stimulates POMC production → appetite suppression
* SE: same as Phentermine (tachycardia, tremors, mood swings)
38
* Phentermine/Topiramate (Qysmia) – most effective
* MOA: diminishes appetite via unknown mechanism in hypothalamus
* SE: fatigue, cognitive decline
39
* Buproprion/Naltrexone (Contrave)
* MOA:
* Buproprion (anti-depressant): dopamine/norepinephrine reuptake inhibitor → stimulates POMC production → appetite suppression
* Naltrexone: opioid antagonist → suppresses POMC inhibition → appetite suppression
* SE: N/V, constipation
40
* Liraglutide (Saxenda) – same as Victoza (used to treat DM-2)
* MOA: injected GLP-1 (glucagon-like peptide) → increases insulin production and activates parts of brain involved in appetite suppression → weight loss
* SE: C-cell hyperplasia (thyroid), nausea, abdominal pain, bloating
41
DIABETES ACUTE COMPLICATIONS
## Footnote
**Cerebral edema**
* Epidemiology: pediatric patients
* Risk factors: severe baseline acidosis, too rapid correction of hyperglycemia, excessive fluid replacement
* Sx: new onset headache, AMS
* Tx: IV mannitol
42
DIABETES ACUTE COMPLICATIONS
**HHNS**
* Pathophysiology: hyperglycemia → excessive osmotic diuresis → dehydration
* Due to circulating insulin, no ketogenesis or lipolysis occurs
* Signs/symptoms: thirst, polyuria, lethargy, seizures/coma, death, absence of Kussmaul respirations/fruity breath
* Labs: hyperglycemia (\>600 mg/dL), increased serum osmolarity (\>320 mOsm/kg), hypernatremia, no acidosis, no ketones (small amounts of insulin present)
* Treatment: aggressive IV fluids, insulin therapy, potassium
43
DIABETES ACUTE COMPLICATIONS
## Footnote
**Cerebral edema**
* Epidemiology: pediatric patients
* Risk factors: severe baseline acidosis, too rapid correction of hyperglycemia, excessive fluid replacement
* Sx: new onset headache, AMS
* Tx: IV mannitol
44
DIABETES CHRONIC COMPLICATIONS
**Diabetic retinopathy**
* Pathophysiology:
* Non-proliferative retinopathy: increased vascular permeability → edema → hemorrhaging or microaneurysms → visual impairment (if in macula)
* Proliferative retinopathy: increased VEGF → neovascularization → vitreous hemorrhage/retinal detachment
* Tx: VEGF inhibitor
45
DIABETES CHRONIC COMPLICATIONS
**Due to osmotic diuresis**
* General pathophysiology: glucose enters cells → aldose reductase converts glucose to sorbitol → sorbitol accumulation in cells → osmotic damage via oxidative stress→
* Distal symmetric polyneuropathy
* Decreased sensation and proprioception in the distal limbs
* Charcot foot: loss of sensation → repetitive microtrauma of joint → bone deformity
* Peripheral neuropathy: isolated peripheral neuropathy (damage to nerves), painful diabetic neuropathy (burning, numbness)
* Autonomic neuropathy: gastroparesis, diabetic enteropathy (i.e. fecal incontinence due to nerve damage), neurogenic bladder (incomplete emptying), erectile dysfunction, dyspareunia (decreased vaginal lubrication)
46
DIABETES CHRONIC COMPLICATIONS
## Footnote
**Due to non-enzymatic glycosylation**
**in large versus small vessels**
* Large vessels
* Pathophysiology: glycosylation of basement membrane → atherosclerosis
* CAD → MI
* Peripheral vascular disease → gangrene + neuropathy → limb loss due to ulcers
* Cerebral vascular disease → stroke
* Small vessels
* Pathophysiology: glycosylation of small vessels → diffuse thickening of basement membrane →
* Renal arterioles → glomerulosclerosis → scarred kidneys
* Renal efferent arterioles → glomerular hyperfiltration injury → nephrotic syndrome (Kimmelstiel-Wilson nodules) → microalbuminuria/proteinuria
* Tx: optimize glucose/BP, ARBs/ACEi (dilate efferent arterioles)
* Systemic arteries → arteriosclerosis → HTN
47
DIABETES ACUTE COMPLICATIONS
## Footnote
**DKA**
* Pathophysiology: increased insulin requirement (stress, infection, insulin non-compliance) → increased energy demand → lack of insulin causes increased epinephrine release → glucagon release → lipolysis and ketogenesis → production of ketones
* Signs/symptoms (mnemonic: DKA): **_D**_ehydration, delirium/psychosis, _**K**_ussmaul respirations (deep), _**A_**bdominal pain/N/V, fruity breath
* Labs: hyperglycemia (\>300 mg/dL), anion gap metabolic acidosis, leukocytosis, ketonuria, hyperkalemia (insulin shifts K+ intracellularly), hyponatremia (hyperglycemia shifts water to interstitial space)
* Complications: death, cerebral edema, MI
* Tx: insulin (mainstay to treat acidosis), IV fluids, potassium
48
**Describe the physiology of insulin secretion**
* Insulin processing: pre-proinsulin → proinsulin → C-peptide (alpha and beta chains)
* C-peptide is used to measure endogenous insulin
* Physiology of insulin secretion
* Mechanism: Glucose enters beta cells via GLUT2 → increased ATP synthesis via glycolysis → negative inhibition of K-ATP channel → membrane depolarization → influx of Ca++ via L type channels → exocytosis of insulin
* Biphasic insulin release:
* 1st phase: insulin spikes within minutes after increase in glucose due to readily available insulin exocytosis
* 2nd phase: more prolonged spike in insulin due to transcription of insulin
49
what is insulin action
* Generalized function: glucose transport into cells, suppresses proteolysis and lipolysis → increases fat storage → OBESITY
* Liver: decreased gluconeogenesis and ketogenesis, increased glycogen synthesis and fatty acid synthesis
* Adipose tissue: decreased lipolysis, increased glycogen and fatty acid synthesis, and glucose uptake
* Muscle: increased glucose uptake (most glucose uptake post-meal), AA uptake → protein synthesis
* Other: growth factor, increases sympathetic NS, increases sodium absorption, vasodilator, ovarian steroidogenesis (PCOS?)
50
**Differentiate the actions of glucose counter-regulatory hormones.**
**glucagon, catecholamines, glucocorticoids, GH**
* Glucagon (minutes): opposes insulin action → glycogenolysis, gluconeogenesis → raises blood glucose and glucose production
* Catecholamine (minutes):
* Actions: increases hepatic glycogenolysis and gluconeogenesis, inhibits glucose uptake in muscle, increases lipolysis, stimulates glucagon, inhibits insulin
* Glucocorticoids (hours to days):
* Actions: increases proteolysis, inhibits glucose uptake, increases hepatic gluconeogenesis
* Growth hormone (hours to days):
Action: inhibits glucose uptake, stimulates lipolysis, stimulates protein synthesis
51
* Secondary causes of diabetes:
* Pancreatic issues: pancreatitis, trauma, neoplasia, CF, hemochromatosis
* Endocrinopathies: over-secretion of GH, cortisol, glucagon, or catecholamines OR hyperthyroidism
* Drugs: corticosteroids, high-dose thiazides, 2nd generation antipsychotics, pentamidine, beta agonists
52
* Maturity Onset Diabetes of the Young (MODY)
* Pathophysiology: autosomal dominant mutations of enzymes involved in the insulin secretion pathway
* Epidemiology: \< 25 y/o, normal weight
* Characteristics: no auto-antibodies, MODY3 (hepatic nuclear factor-1alpha) most common, low risk of DKA
53
* Latent Autoimmune Disease of Adults (LADA):
* Pathophysiology: slow autoimmune beta cell destruction
* Natural history: eventual insulin requirement (not needed in early stages)
* Epidemiology: \> 50 y/o
54
dawn phenomenon vs. somoygi effect
* Description: increased exogenous insulin intake at night → hypoglycemia overnight → glucagon release → hyperglycemia in morning
* Tx: decrease insulin dose
55
DM type 1 vs 2
patho, characterisitics of each
56
**Explain the multi-organ impairment in Type 2 Diabetes**
* Decreased insulin secretion: decline of beta cell function
* Increased hepatic glucose production: insulin resistance in liver → inability to detect insulin → continued gluconeogenesis
* Decreased glucose uptake: insulin resistance → decreased glucose uptake
* Increased lipolysis: insulin resistance → lipolysis in adipose tissue
* Decreased incretin (GLP-1) effect: decreased effect of GLP-1 in the gut
* GLP-1 normally stimulates beta cells to secrete insulin
* Increased glucagon secretion: inability to sense insulin → glucagon secretion
* Neurotransmitter dysfunction: insulin resistance in the brain → increased food uptake → obesity
* Increased renal glucose absorption: increased threshold for glucose reabsorption in kidneys → decreased urinary glucose excretion
57
what are some (6) **Glucose Monitoring and Insulin Delivery Systems**
* Insulin pen: injects insulin when needed (usually rapid acting)
* Capillary glucose meter (glucometer): determines the approximate glucose concentration in the blood
* Insulin pump: delivers rapid/short-acting insulin through a catheter placed under the skin (alternative to multiple injections)
* Dual hormone delivery system: acts as artificial pancreas by delivering insulin and glucagon to control glucose levels
* Continuous glucose sensor: measures glucose levels of interstitial fluid (very close to blood glucose) around the clock; can be used in conjunction with an insulin pump
* Pancreas transplant: last resort treatment (can do combined pancreas-renal transplant)
58
facts about
## Footnote
**Insulin administration**
* Rate of absorption: abdomen \> upper arm \> thighs \> buttocks (rate of absorption is greater with less subcutaneous tissue)
* If lipohypertrophy occurs, rotate areas of injection
59
what is first line treatment for DM1 and DM2
* First line: metformin (DM2), insulin (DMI, gestational diabetes, severe illness, poorly controlled DM2)
60
what tx are contradindicated in hypoglycemia, weight gain, renal disease, GI symptoms
* Frequent hypoglycemia:
* Contraindications: sulfonylurea, metglinides, insulin
* Weight gain:
* Indications: metformin, GLP-1 agonist, SGLT2 inhibitors, amylin analog
* Contraindications: sulfonylurea, metglinides, insulin, thazolidinediones
* Renal disease:
* Contraindications: metformin, GLP-1 agonist, SGLT2 inhibitors, sulfonylurea, metglinides, insulin, thazolidinediones
* GI symptoms
* Contraindications: metformin (diarrhea), GLP-1 agonists (nausea/bloating), alpha-glucosidase inhibitor (diarrhea), bromocriptine/dopamine agonist
61
what tx are contradindicated indelayed empyting, CHF, CVD, bone disease, UTI
* Delayed emptying
* Contraindications: amylin mimetic, GLP-1 analog, dipeptidyl Peptidase 4 inhibitors
* CHF
* Contraindications: thazolidinediones (moderate risk)
* CVD
* Contraindications: SGLT2 inhibitors, sulfonylureas, metglinides
* Bone issues
* Contraindications: thazolidinediones (moderate risk)
* UTI
* Contraindications: SGLT2 inhibitors
62
what are clinical presentations are type 1, 2 and LADA
* Type I DM
* Weight loss, thin, younger, possibly active
* Type II DM
* Acanthosis nigricans, older, obese, sedentary
* Latent Autoimmune Disease of Adults (LADA)
* Older, weight loss, possibly active
63
* Diagnosis of **diabetes** is established by _one_ of the following:
* Symptoms plus casual plasma glucose _\>_ 200 mg/dL
* Fasting plasma glucose _\>_ 126 mg/dL
* Plasma glucose _\>_ 200 mg/dL with 2 hours after 75 g oral glucose load
* HbA1C _\>_ 6.5
64
* Diagnosis of **prediabetes** is established by one of the following:
* Fasting plasma glucose 100-125 mg/dL (Impaired Fasting Glucose)
* Plasma glucose 140-190 mg/dL with 2 hours after 75 g oral glucose load (Impaired Glucose Tolerance)
* HbA1C: 5.7–6.4%
65
comapare DKA and HHS
66
* Hypoglycemia
* Symptoms (TIRED): tachycardia, irritability, restlessness, excessive hunger, diaphoresis
* Cold and clammy needs candy
* Treatment: IV dextrose, glucagon, oral glucose
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**DDx of PCOS**
**what are some pertient positives and negatives**
* Androgen producing tumor in ovary or adrenal (rapid onset of sx), exogenous sex steroids, hyperprolactinemia, simple obesity, severely insulin resistant states (diabetes)
* Congenital Adrenal Hyperplasia (CAH)
* Description: disorder of steroid biosynthesis due to various enzyme deficiencies
* Epidemiology: adult onset, Ashkenazi Jews
* Cushing Syndrome
* Description: disease due to excess circulating cortisol
* Pertinent positives: personality changes, ecchymoses, proximal myopathy
* Other sx: central obesity, fatigue, HTN, hirsutism, amenorrhea striae
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PCOS
SPEEDCT w/ no T
* Epidemiology: young, obese woman with masculine features
* Sx: central obesity, fatigue, HTN, amenorrhea/infertility
* PE: clitoromegaly, striae, hirsutism
* Hirsutism: hair loss on top of head, facial hair growth, hair on midline of body
* Labs: elevated testosterone, 17-OH-progesterone, prolactin, TSH; LH:FSH (2:1), increased sex-hormone binding globulin (SHBG)
* Diagnosis (need 2/3): oligo/anovulation, signs of hyperandrogenism, and polycystic ovarian
* Complications:
* Insulin resistance → diabetes → acanthosis nigricans
* Dyslipidemia → obesity → metabolic syndrome
* Endometrial cancer
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PCOS
treatment
talk about OCP, letrozole, clomiphene and metformin
* Overall treatment: metformin
* Treats insulin resistance, some benefit to infertility/hirsutism
* Letrozole (aromatase inhibitor) \> clomiphene (SERM) \> metformin
* MOA (treats infertility): aromatase inhibitor → interferes with estrogen feedback at the hypothalamus → increased release of FSH from pituitary
* Clomiphene
* MOA (treats infertility): SERM → decreases estrogen feedback at the hypothalamus → increased release of FSH from pituitary
* Risk: exacerbates metabolic dysfunction (increases BMI)
* OCP:
* Treats hirsutism and acne; prevents diabetes, CVD, and endometrial cancer
* Risk: can worsen insulin resistance
* Diet and exercise
* Decreases incidence of diabetes
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difference between insulins
* humulog/novolog
* novolin
* long acting
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Canaglifozin
MOA: Reduces absorption of glucose from kidney → increase in urinary glucose, SGLT2i
SE:UTI/yeast infection, dehydration, AKI, ketoacidosis
OTHER:
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Sitagliptin
MOA:Prevents degradation of GLP-1 → increases insulin secretion → slows gastric emptying, suppresses glucagon (effects of GLP-1)
SE:Nausea, bloating (delayed gastric emptying)
OTHER:
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Exena**_tide_**
Lirglu**_tide_**
MOA:GLP-1 receptor analog → increases insulin secretion → slows gastric emptying, suppresses glucagon (effects of GLP-1)
SE:Nausea, bloating (delayed gastric emptying)
OTHER:
Take 60min BEFORE meal
Risk of c-cell thyroid CA
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acarbose
MOA:Inhibit alpha glucosidase → decreased breakdown of complex carbs → decreased glucose absorption in gut
SE:Diarrhea (osmotic), abdominal pain
OTHER:
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Pramlintide
MOA:Synthetic analog of amylin (usually co-secreted with insulin) → enhances satiety, slows gastric emptying, suppresses glucagon (mirrors insulin effects)
SE: N/V (slowed gastric emptying), hypoglycemia
OTHER:
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Pioglitazone
MOA:Activates peroxisome proliferator-activator receptor gamma (PPAR-gamma) → activates insulin responsive genes → increase glucose uptake
SE: Edema, fractures (due to decreased aromatase)
OTHER:
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metformin
MOA:
1. Inhibits gluconeogenesis in liver (increased production of lactic acid instead of pyruvate)
2. Reduce insulin resistance via increased AMPK → increased GLUT4 expression
SE:Diarrhea, decreased absorption of B9/B12, lactic acidosis
OTHER: Contraindicated in renal dx due to lactic acidosis
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Repaglinide
MOA:Blocks ATP-sensitive K-channels → membrane depolarization → influx of Ca → insulin release
SE:Hyperinsulinemia, weight gain, hypoglycemia
OTHER: rapid acting
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Glipizide
MOA:Blocks ATP-sensitive K-channels → membrane depolarization → influx of Ca → insulin release
SE:Hyperinsulinemia, weight gain, hypoglycemia
OTHER: Long acting
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