Endocrine Diabetes and Metabolism UWorld Flashcards
Thyroid nodule aspirated to show large overlapping nuclei with finely dispersed chromatin, numerous intracellular inclusions and grooves and psammoma bodies.
Papillary thyroid carcinoma demonstrates cells with a ground-glass appearance and Orphan Annie nuclei
Thyroid nodule aspirated to show marked pleomorphism, irregular giant cells and basophilic spindle cells.
Anaplastic thyroid carcinoma.
Thyroid nodule aspirated to show polygonal spindle-shaped cells with a slightly granular cytoplasm and adjacent amyloid deposits
Medullary thyroid carcinoma
Levels of anti-androgen therapy
GnRH agonist - leuprolide
Inhibition of testosterone synthesis by Leydig cells - spironolactone
Inhibition of 5-alpha reductase: finasteride
Antagonism of androgen-binding receptor: flutamide, cyproterone and spironolactone.
PTH and Ca in primary and secondary hyperparathyroidism
Primary: both elevated
Secondary: PTH elevated, Ca low
Note that diuretics, vitamin D intoxication, granulomatous disease and lymphoma will cause an elevated Ca with low PTH.
How does thyroid hormone get synthesized?
I- is transported via the Na/I symporter against its gradient
Inside the follicular cells, I- undergoes organification to I2 by the enzyme thyroid peroxidase.
It then binds tyrosine residues on thyroglobulin to form MIT. 2 MITs can join together to form one DIT. 2 DITs can join to form T4 and a DIT + MIT can join to form T3.
In the thyroid cytoplasm, thyroglobulin is separated from the iodinated tyrosine residues that get secreted as T3 and T4. Inactive MIT and DIT residues are then recycled.
How do glucocorticoids cause adrenal atrophy?
They suppress CRH release from the hypothalamus and reduce the effect CRH has on the anterior pituitary. This causes atrophy of the CRH-secreting neurons in the hypothalamus, atrophy of corticotrophs in the anterior pituitary and atrophy of the adrenal gland.
Pioglitazone mechanism of action
It is a thiozoladinedione that binds PPAR-gamma which causes it to form a heterodimer with the retinoid X receptor. This results in increased GLUT-4 production (increasing insulin sensitivity), increased adiponectin (increases the number of insulin responsive adipocytes and up regulates beta-oxidation) and decreased production of TNF-alpha and leptin.
Delayed puberty + anosmia
Kallman syndrome: failure of the GnRH secreting neurons to migrate from their olfactory placode due to mutation in KAL-1 or FGFR-1 genes.
How does insulin affect glycolysis
It increases the activity of PFK-2, which converts Fru-6-P to Fru-2,6-BP. In turn Fru-2,6-BP activates PFK-1 and inactivates Fru-1,6-bisophosphatase, promoting glycolysis and inhibiting gluconeogenesis.
Note that glucagon activates Fru-2,6-bisphosophatase, reducing the amount of Fru-2,6-BP and promoting gluconeogenesis.
Inhibitors of thyroid hormone synthesis
PTU + Methimazole: inhibit thyroid peroxidase and prevent the organification of iodine and its coupling to tyrosine
Excess iodide: Wolff-Chaikoff effect, temporarily inhibits TPO and I- uptake…this is why you give KI if people are exposed to radioactive I131
Perchlorate and pertechnetate: inhibits I- transport through Na/I symporter
PTU, beta-blockers, ipodate: inhibit peripheral conversion of T4 -> T3 by inhibiting 5’ deiodinase
Hormones that signal through G-protein coupled receptor that activates adenylate cyclase.
"FLAT ChAMP" FSH LH ACTH TSH CRH hCG ADH (V2) MSH PTH
Hormones that signal through G-protein coupled receptor that activates guanylate cyclase
ANP, BNP, NO
Hormones that signal through intrinsic tyrosine kinase activation
Insulin + growth factors
Hormones that signal through JAK/STAT tyrosine kinase activation
"PIGGLET" Prolactin Immunomodulators GH G-CSF EPO Thrombopoietin
Hormones that signal by binding an intracellular receptor
"VETT CAP" Vitamin D Estrogen Testosterone T3/T4 Cortisol Aldosterone Progesterone
Hormones that signal through G-protein coupled receptor that activates phospholipase C -> DAG + IP3 formation
"GOAT HAG" GnRH Oxytocin ADH (V1) TRH Histamine AT II Gastrin
Muscles innervated by the superior laryngeal nerve and recurrent laryngeal nerve
Superior laryngeal has two branches: external and internal
- External: only innervates the cricopharyngeus and is prone to injury as it lies directly beneath the superior thyroid artery
- Internal: sensation to mucosa above vocal cords
Recurrent laryngeal: posterior and lateral crycoarytenoids, oblique and transverse arytenoids and thyroarytenoid
Effects of insulin on the cell after binding to its transmembrane surface receptor
Activation of cytosolic tyrosine kinase -> protein phosphatase activation -> glycogen synthase and fructose-1,6-bisphosphatase, dephosphorylation leading to activation of glycogenesis and deactivation of gluconeogenesis, respectively.
Disorganized lamellar bone structure in a mosaic pattern
Paget’s disease
Excessive osteoid matrix accumulation around trabeculae
Vitamin D deficiency
Persistence of primary spongiosa in medullary cavity without mature trabeculae
Osteopetrosis
3 presentations seen in 21-hydroxylase deficiency
Classic, salt-wasting: girls with ambiguous genitalia and hypo-aldosteronism at birth
Classic non-salt wasting: girls with ambiguous genitalia at birth, boys with virilization around 2-4
Non-classic: precocious puberty, acne, hirsutism
Treatment of CAH
Low exogenous doses of corticosteroids to suppress ACTH release
Location of genes that code for rRNA and tRNA needed in mitochondrial protein synthesis
Mitochondrial DNA
Compound that gets converted into vitamin D3 (cholecalciferol) in the skin
7-dehydrocholesterol
Patient has diabetes and erythematous plaques and papules on his legs, arms, face and perineum. As time goes on they enlarge and coalesce to have a central bronze-colored area with peripheral blistering and scaling.
This patient has necrolytic migratory erythema and diabetes suggestive of a glucagonoma.
Infant with marked cardiomegaly, hypotonia, macroglossia and hepatomegaly with normal glucose levels and muscle biopsy showing glycogen within lysosomes
Acid alpha-glucosidase, resulting in Pompe disease. The glycogen inside lysosomes is particularly specific for this disease.
Biologically active form of pantothenic acid
Coenzyme A
How do catecholamines, glucocorticoids, TNF-alpha and glucagon induce insulin resistance?
They activate serine kinases that phosphorylate serine residues on an the beta subunits of the insulin receptor and insulin receptor substrate 1 (IRS-1). This prevents Tyrosine phosphorylation of IRS-1 and downstream signaling, ultimately reducing translocation of GLUT-4 receptors to the cell surface.
Pathophysiology of von Hippel Lindau disorder
VHL gene regulates HIF-1. Mutation in VHL results in dysregulation of HIF-1 and increased production of VEGF and EPO. This results in formation of capillary hemangiomas. Renal cell and pheochromocytomas are also associated with this condition.
How do you treat nephrogenic DI?
Thiazides: induce mild hypovolemia that increases PCT Na and H2O reabsorption.
Indomethacin: decreases synthesis of ADH-inhibiting prostaglandins
Big differentiating factors between 17alpha-hydroxylase, 21-hydroxylase and 11beta-hydroxylase deficiencies.
17alpha-hydroxylase: no androgen + excess mineralocorticoids
21-hydroxylase: excess androgen + no mineralocorticoids
11beta-hydroxylase: excess androgen + excess mineralocorticoid from 11-deoxycorticosterone accumulation
Cinacalcet
Calcimimetic that allosterically activates the Ca-sensing receptor in the parathyroid glands to decrease PTH release
Sevalemer
Phosphate binder
Treatment and prevention of post-operative hypocalcemia after parathyroidectomy
Ca + Vitamin D
3 characteristic components of craniopharyngiomas
Solid, cystic and calcified regions
What contributes most significantly to fetal lung development
Increased maternal and fetal cortisol levels. Note that early on, the fetus lacks 3beta-hydroxysteroid dehydrogenase, preventing it from converting pregnenolone to cortisol on its own. Later in gestation, CRH stimulates cortisol release from the adult zone of the fetal adrenal gland and cortisol potentiates CRH release from the fetal pituitary.
Function of Herring bodies found in the posterior pituitary
Store hormones produced by magnocellular neurons in the hypothalamus (ACH, oxytocin) attached to neurophysin that are awaiting secretion into circulation.
Rb gene
Regulates the G1 - S phase transition. Mutation results in retinoblastoma and osteosarcoma.
Bcl-2
Anti-apoptotic gene activated in many cancers
Symptoms of VIPoma
Watery
Diarrhea
Hypokalemia
Achlorhydria
Key function of the pentose phosphate pathway
It reduces Glc-6-P to ribulose-5-P to generate NADPH and is the main generator of NADPH for cholesterol/fatty acid synthesis and glutathione oxidation.
Then the ribulose-5-P can be converted to ribose-5-P for nucleotide synthesis or fructose-6-P for glycolysis.
Metformin mechanism of action
Inhibition of mitochondrial glycerol-3-P dehydrogenase, prohibiting gluconeogensis
Mechanism of pretibial myxedema and exophthalmos in patients with Grave’s disease
TSH receptors are present on these tissues and when stimulated they activate T-cell secretion of cytokines that cause fibroblast proliferation and increased secretion of glycosaminoglycans in these tissues
How does anorexia cause amenorrhea?
Decreased fat stores = decreased circulating leptin = decreased pulsatile GnRH release = decreased LH/FSH secretion = amenorrhea
Why is carvedilol preferred in diabetic patients with hypertension
It is a selective beta-blocker that does not decrease gluconeogenesis or glycogenolysis by inhibiting beta-2 receptors. This is important because non-selective beta-blockers can prevent the metabolic response to hypoglycemia and mask the symptoms of hypoglycemia.
Meglitinides
Same mechanism of action as sulfonylureas, just shorter acting
DPP4 inhibitor side effect
Nasopharyngitis
GLP-1 agonist side effect
Pancreatitis
Thiazolidinedione side effects
Fluid retention and weight gain
Fructose transporter in small bowel
GLUT-5
Why do patients with aldolase B deficiency become hypoglycemic soon after ingesting fructose?
Fructose is converted to Fru-1-P by fructokinase upon absorption. In aldolase B deficiency, Fru-1-P accumulates because it cannot be converted to DHAP and glyceraldehyde. Phosphate reserves are used up by fructokinase and Fru-1-P directly inhibits glycolysis and glycogenolysis, causing hypoglycemia.
Glycolysis enzymes that are unidirectional and must be bypasses in gluconeogenesis
Hexokinase: this is bypassed by the enzyme glucose-6-phosphatase
Phosphofructokinase: this is bypassed by the enzyme fructose-1,6-bisphosphatase
Pyruvate kinase (PEP -> pyruvate): this is bypasses by biotin dependent carboxylation of pyruvate to oxaloacetate by mitochondrial pyruvate carboxylase. Oxaloacetate is converted to malate by malate dehydrogenase so it can exit the mitochondrial membrane to the cytosol. In the cytosol, malate is converted back to oxaloacetate by cytosolic malate dehydrogenase. Finally, PEPCK converts oxaloacetate to PEP.
Acetyl CoA allosterically inhibits and activates what enzymes?
Inhibits: pyruvate dehydrogenase, preventing formation of more acetyl CoA for the TCA cycle
Activates: pyruvate carboxylase, promoting gluconeogenesis
Alanine allosterically inhibits what enzyme?
Pyruvate kinase, this prevents formation of pyruvate from PEP, promoting gluconeogenesis in the presence of gluconeogenic amino acids like alanine that can be converted to pyruvate by transamination.
Citrate allosterically activates what enzymes?
Fructose-1,6-bisophosphatase: promoting gluconeogenesis
AcetylCoA carboxylase: promoting fatty acid synthesis
Amiodarone side effects
Hypothyroidism (drug is 40% I- by weight) Blue-grey skin discoloration Corneal micro-deposits Hepatitis Pulmonary fibrosis
Where in the cell is insulin cleaved prior to excretion?
N-terminal signalling peptide on preproinsulin is cleaved after ribosomal translocation to rER
Endopeptidases cleave proinsulin to C-peptide and insulin in secretory granules.
Electrolyte disturbances in primary adrenal insufficiency
Hyponatremic, hyperkalemic, hyperchloremic metabolic acidosis.
How does elevation of free fatty acids in the serum of diabetic patients contribute to insulin resistance?
They impair insulin-dependent glucose uptake in muscle and liver. They also increase gluconeogenesis, insulin release and release of pro-inflammatory cytokines.
Consequence of type 2 5-alpha reductase deficiency
Testosterone causes normal development of the internal genitalia (testes). However, lack of DHT causes poor development of male external genitalia and pseudohermaphroditism. In severe deficiencies, children are raised female due to external genitalia; however, high levels of testosterone converted to DHT by 5-alpha reductase in the skin during puberty cause deepening of the voice, scrotal enlargement. phallus enlargement and testicular descent that reveals the underlying deficiency.
What causes insulin release from beta-cells?
Glucose entry and ATP generation from glycolysis and oxidative phosphorylation results in closure of K+ channels, depolarization, Ca2+ influx and insulin release. Also, binding of GLP-1 receptor increases cAMP levels and causes insulin release.
Why do patients with diabetes accumulate sorbitol in their lenses and get cataracts?
Sorbitol dehydrogenase in the lens normally converts sorbitol to fructose, which can diffuse out of the lens and does not cause toxicity. However, the enzyme has a low Vmax and become fully saturated in periods of hyperglycemia, causing sorbitol to accumulate in the lens.
Why should you inject medially to the ischial spines, but not too medial when giving a pudendal nerve block?
The internal pudendal and inferior gluteal arteries lie directly medial to the nerve
Why do patients who binge drink for days on end become hypoglycemic?
Metabolism of alcohol by alcohol dehydrogenase and aldehyde dehydrogenase reduces NAD+ to NADH and increases the NADH:NAD+ ratio. This results in inability to convert lactate to pyruvate and malate to oxaloacetate. Since pyruvate and oxaloacetate are both needed for gluconeogenesis, this process is inhibited and patients become hypoglycemic once glycogen stores are depleted.
Thiamine dependent reactions
Pyruvate dehydrogenase’s conversion of pyruvate to acetyl CoA
alpha-ketoglutarate dehydrogenase’s conversion of alpha-ketoglutarate to succinyl-CoA
POMC cleavage products
MSH and ACTH, this is why people with Addison’s get bronze skin
Alterations to insulin seen in aspart, lispro and glulisine
Altered amino acid sequence at the C terminus of the B chain of insulin to prevent polymerization of insulin and expedite absorption of subcutaneous injection. Glargine and detemer have the opposite modifications that result in aggregation and extended release from the injection site.
Sulfonylureas with higher risk of hypoglycemia
Glyburide and glimepiride are longer-acting and have higher incidence of hypoglycemia. In contrast, glipizide is much shorter acting.
Enzymes that are affected by riboflavin deficiency
ETC complex I (needs FMN), complex II (needs FAD) and conversion of succinate to fumarate by succinate dehydrogenase (also needs FAD).
How are ketone bodies used for energy in peripheral tissue?
Beta-hydroxybutyrate is converted to acetoacetate. Thiophorase uses succinyl CoA to convert acetoacetate to Acetoacetyl CoA, which is converted to 2 acetyl CoA molecules in the mitochondria. Note that RBCs do not have mitochondria and cannot perform this and hepatocytes do not have the enzyme thiophorase, and cannot use ketones for energy.
Tissues that use ketones for energy
Muscle, heart, kidneys and brain
How can a prolactinoma cause osteoporosis
GnRH suppression -> reduced estrogen -> increased NF-kB ligand expression (RANK-L) -> osteoclast activation
Cascade of events after glucagon binds to its receptor
Gs activation -> adenylate cyclase activation -> cAMP increases -> PKA activation -> PKA phosphorylates Ser and Thr residues, resulting in enzymatic activation or deactivation, depending on the enzyme. Specifically, glycogen phosphorylase (glycogenolysis), pyruvate carboxylase (gluconeogenesis) and PEPCK (gluconeogenesis) are activated by PKA phosphorylation. TSH, PTH and beta-receptors have this same cascade.
Origin of rT3
Inactivation of peripheral T4
Growth hormone signal cascade
JAK-STAT
HLA genes associated with type I DM
DR 3/4 and DQ
Content of pancreatic islet cell amyloid in type II DM
Amylin
Why give PTU to a patient with thyroid storm instead of methimizole
It inhibits TPO AND peripheral conversion of T4 -> T3
Why would a patient have low EPI levels after a pituitary resection?
PMNT is the last enzyme in the catecholamine synthesis pathway that converts NE to EPI. It is upregulated in the medulla as cortisol passes through the venous drainage. Decreased cortisol from pituitary resection results in decreased PMNT activity and decreased NE -> EPI.
What happens to T4 levels when a post-menopausal woman is placed on HRT?
Increased estrogen causes upregulation of liver synthesis of TBG. This results in a transient decrease in fT4, a transient increase in TSH, an increase in total T4, but fT4 returns to homeostatic levels
Enzyme that converts sugars to molecules that can damage the lens
Aldose reductase converts glucose to sorbitol and galactose to galactitol, both which can cause cataracts when they build up in the lens.
Fibrate mechanism of action
They activate PPAR-alpha, which decreases hepatic production of VLDL and increases lipoprotein lipase (LPL) activity. Lipoprotein lipase hydrolyzes TGs in chylomicrons and VLDL to FAs that can be used to make HDL or stored in adipocytes, decreasing TG concentration in the circulation.
Fish oil supplement mechanism of action
They have omega-3-fatty acid that decrease VLDL and apolipoprotein B synthesis in the liver.
Molecules that use the JAK/STAT signaling pathway
GH, prolactin, cytokine receptors and IL-2
Molecules that use the MAP-kinase Ras pathway
EGF, PDGF, FGF growth factor receptors
Recommended treatment for patients with pyruvate dehydrogenase deficiency
PDH is needed to convert pyruvate to acetyl CoA. In its absence pyruvate is converted to lactate and patients become acidotic. In order to avoid this, patients are recommended a ketogenic diet. This means eating more AAs like lysine and leucine that are solely ketogenic and less amino acids like alanine, serine, phenylalanine, isoleucine and tryptophan that are glucogenic.
GLUT transporter found in…
A) Placenta and neurons
B) Spermatocytes and GI tract with fructose transport
C) Erythrocytes and blood-brain barrier with a basal rate of glucose transport
D) Hepatocytes, pancreatic beta-cells, renal tubular cells and small intestine involved in regulation of insulin release
E) Skeletal muscle and adipocytes with insulin-dependent glucose uptake
A) GLUT-3 B) GLUT-5 C) GLUT-1 D) GLUT-2 E) GLUT-4
G-protein coupled receptors present on pancreatic beta-islet cells
M3 -> Gq activation -> increased insulin release
Glucagon -> Gs/Gq activation -> increased insulin release
Beta-2 adrenergic and GLP-1 -> Gs activation -> increased insulin release
Alpha-2 adrenergic and somatostatin -> Gi activation -> decreased insulin release
EPI effects on blood glucose
It increases hepatic gluconeogenesis and glycogenolysis.
It decreases skeletal muscle uptake of glucose.
It increases Ala release from muscle for gluconeogenesis.
It increases TG breakdown from fat to FFAs and glycerol for gluconeogenesis.
Tissues on which glucagon has minimal effect
Adipose tissue, muscle and kidney
Why do patients with primary carnitine deficiency get muscle weakness and cardiomyopathy?
They are unable to metabolize fatty acids to acetyl CoA and ketone bodies for fuel.
