Endocrine Flashcards
1
Q
A defect in the endocrine gland is a ___ defect; a defect in another related organ is a ___ defect.
A
Primary; secondary or tertiary
2
Q
Hormone binding proteins are mostly for what type of proteins? There are 3 additional hormones that have binding proteins that do not fit this category. What are they?
A
Steroid hormones (lipophilic) IGF-1, GH, T4/T3
3
Q
What is the difference between a free hormone and a bioavailable hormone?
A
A free hormone is unbound; a bioavailable hormone is bound to albumin only.
4
Q
Kd = ?
A
Ligand (hormone) concentration that occupies 50% of binding sites (receptors)
5
Q
Ki = ?
A
Ability to displace ligand (hormone) at 50% of maximum activity
6
Q
Small Kd = ? (affinity)
A
Higher affinity
7
Q
Smaller Ki = ? (specificity)
A
Higher specificity
8
Q
True or false - the ligand concentration for maximal physiological response correlates with the Kd.
A
False - not necessarily
9
Q
Hormones are transcribed as ___, which contain a signal peptide sequence. The signal peptide is cleaved to form a ___, which is the hormone plus any copeptides. Subsequent processing and packaging into ___ cleaves the hormone from its associated copeptides.
A
Preprohormones; Prohormone; Vesicles
10
Q
What are the 4 examples of positive feedback in the human body?
A
- Parturition
- Lactation
- Ovulation
- Blood clotting
11
Q
High basal TSH but normal pituitary response to TRH indicates a ___ defect.
A
Primary
12
Q
Undetectable basal TSH and a lack of pituitary response to TRH indicates a ___ defect.
A
Secondary
13
Q
Low basal levels of TRH and a delayed returned to baseline following TRH stimulation indicates a ___ defect.
A
Tertiary
14
Q
The hypothalamus forms the floor of the ___.
A
Third ventricle
15
Q
What hypothalamic nucleus regulates sleep?
A
SCN
16
Q
What hypothalamic nucleus regulates feeding behavior/satiety?
A
ARC
17
Q
What hypothalamic nucleus regulates thirst?
A
PVN
18
Q
What hypothalamic nucleus regulates reproduction?
A
POA
19
Q
What hypothalamic nucleus regulates circadian rhythms?
A
SCN
20
Q
What hypothalamic nuclei regulate mood/motion/stress?
A
PVN/ARC
21
Q
What hypothalamic nucleus regulates body temperature?
A
POA
22
Q
What hypothalamic nucleus regulates blood pressure?
A
PVN
23
Q
What is regulated by the PVN?
A
Thirst, mood/emotion/stress, blood pressure
24
Q
What is regulated by the POA?
A
Reproduction, body temperature
25
What is regulated by the ARC?
Feeding behavior/satiety, mood/emotion/stress
26
What is regulated by SCN?
Sleep, Circadian rhythms
27
From which nuclei are GnRH/GnIH released?
POA
28
From which nuclei is CRH released?
PVN
29
From which nuclei is TRH released?
PVN
30
From which nuclei is GHRH released?
ARC
31
From which nuclei is Somatostatin released?
PeVN
32
From which nuclei is Dopamine released?
ARC
33
What is Kallman Syndrome?
Rare genetic disease in which the GnRH neurons fail to enter the CNS; results in reproductive failure and anosmia
34
Activation of IP3 by GnRH leads to hormone ___ (release or synthesis). Activation of DAG and PKC by GnRH leads to hormone ___ (release or synthesis).
Release; synthesis
35
High GnRH pulse frequency favors transcription of ___ (LH or FSH); low GnRH pulse frequency favors transcription of ___ (LH or FSH)
LH; FSH
36
What three hormones share a common alpha subunit?
TSH, FSH, LH
37
What is the tuberoinfundibular system?
Comprises all neurons that send axonal projections to the median eminence; hormones target the anterior pituitary through the capillary system
38
What is the neurohypophysial tract?
Comprises all neurons whose axons terminate in the posterior pituitary.
39
What are the three parts of the anterior pituitary?
```
Pars distalis (90%)
Pars tuberalis
Pars intermedia
```
40
What are the two parts of the posterior pituitary?
Pars nervosa
| Infundibulum (stalk)
41
Describe the tissue differences between the anterior and posterior pituitary.
Anterior: glandular
Posterior: neural
42
From what are the anterior the posterior pituitary derived, respectively?
Anterior: embryonic foregut
Posterior: neuroectoderm
43
Describe the components of the neurohypophysis.
Axons from the magnocellular neurons of hypothalamus terminate in the posterior pituitary. Hormones are released from here into systemic circulation.
44
What are dilations of unmyelinated axons near the terminals in the posterior pituitary from which hormones are released?
Herring bodies
45
What are glial-like cells of the posterior pituitary?
Pituicytes
46
What is neurophysin?
The binding protein to which AVP or OXY are bound at release from the posterior pituitary
47
What are the two types of acidophils in the anterior pituitary?
Somatotropes
| Lactotropes
48
What are the three types of basophils in the anterior pituitary?
Corticotropes
Gonadotropes
Thyrotropes
49
What is the most abundant category of cells in the anterior pituitary?
Acidophils
50
What is released from somatotropes?
GH
51
What is released from lactotropes?
Prolactin
52
What is released from corticotropes?
ACTH
53
What is released from gonadotropes?
LH/FSH
54
What is released from thyrotropes?
TSH
55
Describe how hormones are released from the anterior pituitary.
Axons from the parvicellular neurons of hypothalamus terminate at the median eminence. Hormones are released from here into long portal veins which travel to the anterior pituitary, which releases hormones into systemic circulation.
56
Most pituitary hormones are released in what fashion?
Circadian
57
Neurophysin I is bound to ___ as a prohormone; neurophysin II is bound to ___ as a prohormone.
OXY
| AVP
58
What stimulates AVP release?
Increased plasma osmolality
| Decreased blood volume
59
What is diabetes insipidus?
Excessive urine production caused by a defect in AVP
60
What are the two main causes of diabetes insipidus?
1. Decreased AVP release (secondary or tertiary defect due to trauma, cancer, or infection)
2. Decreased renal responsiveness to AVP (genetic or acquired via lithium treatment, hypokalemia)
61
What is SIADH?
Syndrome of Inappropriate Vasopressin Secretion - hyponatremia in the absence of edema
62
GH is structurally similar to ___.
Prolactin
63
What is gigantism?
GH excess that occurs before the closing of the epiphyseal plate; increases long bone growth resulting in extreme hight
64
What is acromegaly?
Gradual enlargement of hands and feet (arthritis), changes in facial features (protruding lower jaw, enlarged lips, tongue, nose), increased organ size
65
What are the two types of dwarfism?
Laron syndrome and African pgymy
66
What is Laron syndrome?
Genetic defect in GH receptor, no production of IGF-I (plasma GH levels are normal to high)
67
What is African pygmy?
Partial defect in GH receptor, some IGF-1 response, plasma GH levels normal
68
Why can high levels of GH cause galactorrhea?
GH is similar to Prolactin and can bind to its receptor
69
What is Sheehan's Syndrome?
Partial pituitary destruction resulting from excessive blood loss/shock during childbirth; affects other pituitary cell types leading to loss of axillary and pubic hair
70
What two hormones act synergistically to increase the amplitude of ACTH release from the anterior pituitary?
AVP and CRH
71
Under the control of CRH, what products are formed from the preprohormone for ACTH?
ACTH, beta-lipotropin
72
Under the control of norpeinpehrine, what products are formed from the preprohormone for ACTH?
Beta-endorphin, melanocortin stimulating hormone, enkephalin
73
What happens when there are supraphysiolgoical ACTH levels?
ACTH binds to low-affinity MC1R receptors in the melanocytes in the skin, melanin synthesis increases and skin darkens. Note this is different than what happens vi UV light (affects keratinocytes, increases POMC expression, produces alpha-MSH which binds to the MC1R receptor)
74
The adrenal cortex is derived from the ___; the adrenal medulla is derived from the ___.
Mesoderm; neural crest
75
The ___ artery gives rise to arterioles that peruse the cortex to the adrenal medulla.
Capsular
76
What is produced in the 4 distinct areas of the adrenal gland?
1. Cortex:
- Glomerulosa: mineralocorticoids
- Fasciculata: glucocorticoids
- Reticularis: androgens
2. Medulla: catecholamines
77
Where are glucocorticoids made?
Zona fasciculata
78
To what is cortisol bound in circulation?
CBG (90%)
Albumin (7%)
Free (3-4%)
79
CBG has a thirty-fold higher affinity for cortisol than ___.
Aldosterone
80
What two things decrease CBG, leading to an increase in free cortisol?
Estrogen and shock/severe infection
81
How is cortisone activated to cortisol?
11-beta-HSD1
82
What are the metabolic effects of cortisol action?
Mobilize energy stores, increase plasma glucose (counter-regulatory hormone to insulin) via increased gluconeogenesis, decreased glucose uptake, inhibits calcium absorption
83
How does cortisol increase gluconeogenesis?
Increases key hormones: tyrosine aminotransferase, PEP carboxykinase, and glucose 6-phosphatase
84
Cortisol decreases ___ insertion in the membrane of muscle cells.
GLUT 4
85
What are the effects of cortisol on muscle?
Decreased protein synthesis and increased protein degradation, leading to atrophy
86
How does cortisol lead to muscle breakdown?
Cortisol increases transcription of the E3 ubiquitin ligase MuRF-1 while simultaneously inhibiting amino acid uptake and AKT-phosphorylation.
NFkappaB is needed to activate MuRF-1.
Normally, phosphorylated AKT increases protein synthesis.
87
What are the effects of cortisol on adipose tissue?
Increased lipolysis; redistributes fat from the limbs to the abdomen
88
How does cortisol increase lipolysis in adipose tissue?
Increases transcription of:
1. Mg11 gene (codes for MAG lipase)
2. Lipe gene (codes for hormone sensitive lipase)
3. Angpt14 gene (increases cAMP, activates hormone sensitive lipase)
89
What are the effects of cortisol on the immune system?
Decreases inflammation
90
How does cortisol decrease inflammation?
Normally, NFkappaB is unbound from IkappaB (stops inhibition) by cytokines. NFkappaB moves to the nucleus, where it increases the expression of genes for cytokines, enzymes, and adhesion molecules. Cortisol interrupts this process by binding to activated NFkappaB directly to prevent its nuclear binding and by increasing transcription of IkappaB
91
What are the 4 ways in which cortisol inhibits immune function?
1. Stimulates anti-inflammatory cytokines
2. Inhibits prostaglandins
3. Suppresses antibody production by inhibiting T cell function
4. Increases neutrophils, platelets, and RBCs (inhibits neutrophil function)
92
What are the effects of cortisol on bone?
1. Inhibits intestinal calcium absorption
2. Inhibits bone formation
3. Increases bone resorption
(increases plasma Ca2+)
93
How does cortisol affect the bone?
1. Inhibits intestinal calcium absorption via decreased active transport (?)
2. Inhibits bone formation by decreasing IGF-1 receptors
3. Increases bone resorption by activating osteoclasts
94
How does cortisol affect the cardiovascular system?
1. Stimulates RBC production
2. Maintains responsiveness to catecholamine pressor effects (constrict peripheral vessels via alpha-adrenergic receptors. dilate coronary arteries via beta-adrenergic)
3. Maintains vascular integrity and reactivity
95
How does cortisol affect the CNS?
Emotional responses, increased perception, negative feedback on CRH and ACTH
96
What disease is caused specifically by excessive cortisol secretion due to pituitary adenoma? What disease is caused by excessive cortisol for other reasons?
Cushing disease; Cushing syndrome
97
What are the symptoms of Cushing's?
1. Change in body fat distribution (moon face, buffalo hump, abdominal obesity, thin skin, bruising)
2. Osteoporosis due to inhibition of intestinal calcium absorption
3. Hypertension (excess glucocorticoids activate MR)
4. Glucose intolerance (antagonism of insulin action)
5. Purple striae (fragile thin skin stretches over increased abdominal fat, vessels hemorrhage into striae)
98
What happens to the HPA axis due to chronic glucocorticoid therapy or primary adrenal excessive cortisol production?
Exert negative feedback on CRH and ACTH; prolonged shutdown of HPA axis leads to atrophy of the zona fasciculata and inability to synthesize endogenous glucocortioicds
99
What is the glucocorticoid:mineralocorticoid effect ratio of cortisol?
1:1
100
What is the glucocorticoid:mineralocorticoid effect ratio of prednisone?
3-4:0.5
101
What is the glucocorticoid:mineralocorticoid effect ratio of methylprednisone?
10:0.5
102
What is the glucocorticoid:mineralocorticoid effect ratio of dexamethasone?
20:0
103
What is the glucocorticoid:mineralocorticoid effect ratio of fludrocortisone?
12:125
104
What is adrenal insufficiency?
Failure of adrenal gland to secrete glucocorticoids, mineralocorticoids, or both
105
What is a primary adrenal insufficiency?
Failure at the adrenal gland
106
What is Addison's disease?
Type of primary AI involving autoimmune destruction of adrenals; cause of 70% of primary AI cases
107
What is a secondary adrenal insufficiency?
Failure to secrete CRH or ACTH
108
What is the most common cause of secondary AI?
Sudden cessation of glucocorticoid therapy
109
Contrast Aldosterone and AVP/ADH.
Aldosterone is a primary regulator of extracellular volume. It stimulates sodium primarily, as well as water reabsorption secondarily in the kidney.
AVP/ADH is a primary regulator of free water balance. It stimulates water retention, decreases plasma osmolality (secondarily affects sodium)
110
Despite the fact that it binds glucocorticoids with higher affinity than mineralocorticoids, MR is the primary mineralocorticoid receptor. Why?
95% of glucocorticoids are bound to CBG and aldosterone does not have a specific binding protein.
111
How is cortisol inactivated to cortisone?
11-beta-HSD type 2
112
What are the three causes of congenital adrenal hyperplasia?
1. 21 hydroxylase deficiency
2. 11 hydroxylase deficiency (CYP11B1 gene)
3. 17 hydroxylase deficiency
113
What is the major cell type in the adrenal medulla?
Chromaffin cells (pheochromocytes)
114
What are the arousal effects of EPI?
Pupil dilation, sweating, GI and bronchial muscle relaxation
115
What are the metabolic effects of EPI?
Glucose release, increased metabolic rate
116
What are the cardiovascular effects of EPI?
Vasoconstriction, increased heart rate
117
What are the metabolic effects of EPI on muscle, liver, and fat?
Muscle: block glucose uptake, release glycogen
Liver: synthesize;release glucose
Fat: release fatty acids
118
NE stimulates ___ to initiate a response to long-term stress.
CRH neurons (HPA axis)
119
What are pheochromocytomas?
Tumors originating from chromaffin cells
120
What are symptoms of pheochromocytomas?
Hypertension that does not respond to medication, headaches, tachycardia
121
How are pheochromocytomas diagnosed?
Measure urinary metanephrines
122
How are pheochromocytomas treated?
Surgery and alpha/beta blockers prior to surger
123
Why are pheochromocytomas called the 10% tumor?
10% are:
1. Malignant
2. Bilateral
3. In children
4. Familial
5. Recur
6. Associated with MEN syndromes
7. Present w/stroke
8. Extra-adrenal
124
What are the 4 major extra-adrenal sites of pheochromocytomas?
1. Sympathetic nerve chain along spinal cord
2. Overlying distal aorta
3. Within ureter
4. Within urinary bladder
125
What innervates the thyroid gland?
Middle and inferior cervical ganglion of the sympathetic nervous system
126
What is the functional unit of the thyroid gland?
Follicle
127
From what is the thyroid gland derived?
Branchial pouch of the endoderm
128
Parafollicular (C) cells produce ___.
Calcitonin
129
The lumen of follicles are filled with ___, which is the extracellular storage site of what three things?
Colloid
T3, T4, thyroglobulin
130
What are the two precursors of thyroid hormones?
Thyroglobulin (TG) and iodide
131
Less than ___ micrograms/day of iodide results in TH deficiency.
20
132
Describe the autoregulation of iodide uptake.
Wolf-Chaikoff effect: increased iodide intake decreases gland transport and hormone synthesis.
133
What happens when a very high iodide dose is given?
Rapidly shuts down TH production
134
What is the most preventable cause of mental retardation?
TH deficiency
135
Describe the 7 steps in TH synthesis.
1. Iodide trapping: TSH stimulates iodide trapping by increasing activity of the NIS co-transporter in the basal membrane of the follicular epithelial cell.
2. Transport: iodide is transported to the lumen and oxidized by thyroid peroxidase to form iodine; thyroglobulin is transported to the lumen.
3. Iodination of tyrosyl residues on thyroglobulin
4. Conjugation of iodinated tyrosines to form T4 and T3-linked TG
5. Endocytosis of conjugated complex into follicular epithelial cell
6. Proteolysis releases TG, MIT, DIT, T4, and T3
7. Secretion of T4 and T3 into circulation
136
___ inhibits NIS co-transporter.
Lithium
137
What events occur at the apical surface of the thyroid follicle?
1. TH synthesis
| 2. Iodination of TG
138
What events occur at the basolateral surface of the thyroid follicle?
1. Iodine uptake (trap)
| 2. TH release
139
Which TH binds to the receptor with low affinity?
T4
140
Describe the formation of T3.
Tyrosine is converted to MIT by TPO. 1 MIT and 1 DIT form T3.
141
Describe the formation of T4.
Tyrosine is converted to MIT by TPO. MIT is converted to DIT. 2 DIT form T4.
142
How are T3 and rT3 distinguished from one another?
T3: 2 iodinated residues on inner ring
rT3: 2 iodinated residues on outer ring
143
What drug inhibits thyroid peroxidase?
Carbimazole
144
Normal uptake of iodide is ___% after 24 hours. Describe the definitions of hyperthyroidism and hypothyroidism.
25
Hyper: >60%
Hypo: <5%
145
___ is seen in hyperstimulated thyroid glands (Graves disease).
Accelerated turnover
146
What is an organification defect?
Inability to incorporate iodide into tyrosine
147
How can an organification defect be tested?
Block NIS with inhibitor (perchlorate)
148
Which deiodinases can convert T4 to active T3?
Type I, Type II
149
Which deiodinases can convert T4 to rT3?
Type I and Type III
150
What is the primary source of T3 in circulation?
Type I deiodinase
151
What is the thyroid hormone sensor in the pituitary?
Type II deiodinase
152
Describe the distribution of TH binding proteins.
TBG: 70% bound
TTR: 10% bound
Albumin: 15-25% bound
153
What two things increase TBG?
Estrogen and hepatitis
154
What two things decrease TBG?
Nephrotic syndrome, steroids
155
When TH binds, thyroid hormone receptors form heterodimers with ___.
Retinoic acid receptor (RXR)
156
TH receptors have a high affinity for ___.
T3
157
Describe what an increase in TH does to BMR, carbohydrate/protein/lipid metabolism, and thermogenesis.
1. Increased BMR
2. Increased gluconeogenesis, glycogenolysis (normal serum glucose)
3. Increased protein synthesis, proteolysis
(muscle wasting)
4. Increased lipogenesis, lipolysis, decreased serum cholesterol
5. Heat intolerance
158
What are the physiological effects of T3 on the brain?
1. Neuronal cell migration/differentiation
2. Myelination
3. Synaptic transmission
159
What is cretinism?
Iodine deficiency during development
160
What are the symptoms of cretinism?
Short stature/impaired bone formation, mental retardation, delayed motor development
161
What are the physiological effects of T3 on the heart?
Increased CO, increased resting heart rate and SV, increased beta-adrenergic receptors
162
What is the main form of hyperthyroidism?
Grave's Disease
163
What is Grave's Disease?
Autoimmune disorder in which antibodies (long-acting thyroid stimulators) stimulate the TSH receptor, leading to elevated TH
164
What are the symptoms of Grave's Disease?
Diffuse symmetrical goiters, tachycardia, opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting
165
What are the two types of hypothyroidism?
Hashimoto's thyroiditis, iodine deficiency
166
What is Hashimoto's thyroiditis?
Autoimmune destruction of thyroid follicles due to antibodies against TPO and TG
167
What are the symptoms of Hashimoto's?
Diffuse goiter, lethargy, fatigue, hair loss, cold intolerance, brittle nails, decreased appetite, weight gain
168
___ levels are good indicators of free calcium availability.
Albumin
169
What are the two primary regulators of calcium?
PTH and Vitamin D/Calcitrol
170
___ cells of the parathyroid gland synthesize PTH.
Chief
171
Describe the synthesis of PTH.
1. Signal peptide of preprohormone directs processing to the ER.
2. Pro PTH is made of the N-terminal fragment (1-34) and the C-terminal fragment (35-84).
172
Describe the differences between the 1-84, 1-34, and 35-84 fragments of PTH.
1-84: clinically important measurement
1-34: binds to PTH receptor
35-84: longest half-life, inactive
173
What is PTHrP?
PTH related peptide; mimics action of PTH in bone and kidney; normally found at very low concentrations and thus does not regulate plasma Ca2+
174
What is the primary PTH receptor?
PTH 1R
175
What binds to the PTH 1R? The 2R?
PTH 1R: 1-34, 1-84, PTHrP
| PTH 2R: 1-34
176
What are the net effects of PTH?
Increase plasma calcium, decrease plasma phosphorus
177
What do osteoblasts do?
Bone formation and mineralization
178
What do osteoclasts do?
Bone resorption
179
Which bone cells have PTH receptors?
Osteoblasts
180
From what are osteoblasts derived?
Mesenchymal stem cells
181
From what are osteoclasts derived?
HSCs
182
Describe the effects of PTH.
1. PTH binds to osteoblasts and stimulates M-CSF production.
2. M-CSF stimulates differentiation of osteoclast precursors.
3. PTH also stimulates RANK ligand, which leads to maturation of osteoclasts.
4. Osteoclasts absorb bone by secreting H+ and acid proteases which dissolve bone.
183
True or false - PTH stimulates osteoclasts directly.
False - PTH stimulates osteoclasts indirectly
184
What antagonizes RANK ligand?
Osteoprotegerin (OPG)
185
What stimulates OPG? What inhibits it?
Estrogens stimulate; glucocorticoids inhibit
186
Describe the effects of PTH on the kidney.
1. Stimulates CYP1-alpha, which encodes 1-alpha-hydroxylase, which converts the inactive form of Vitamin D to the active form.
2. Stimulates calcium channel insertion in the apical membrane of the DT, increasing calcium reabsorption
3. Reduces phosphate reabsorption in the kidney
187
How do CaSR (calcium-sensing receptors) regulate PTH?
Binds ionized calcium, inhibits PTH synthesis at the promotor level, stimulates degradation of preformed PTH
188
How does Vitamin D regulate PTH?
Binds its receptor, inhibits PTH synthesis at promoter level, stimulates CaSR gene transcription
189
What is the general term for vitamin D and other natural structural analogs?
Calciferol
190
What is the term for vitamin D3 from animal tissues?
Cholecalciferol
191
What is the term for vitamin D2 from vegetables?
Ergocalciferol
192
What is another name for 25-hydroxy-vitamin D, the immediate precursor to active vitamin D?
Calcidiol (calcifidiol)
193
What is another name for 1-25, dhydroxy-vitamin D, the active form of vitamin D?
Calcitriol (calcifitriol)
194
Broadly, what drives conversion of inactive vitamin D to active vitamin D?
Vitamin D deficiency
Hypocalcemia
Hypophosphatemia
195
Broadly, what drives conversion of active vitamin D to inactive vitamin D?
Vitamin D sufficiency
Normo/hypercalcemia
Normo/hyperphosphatemia
196
What does Vitamin D do in the bone?
Mobilize Ca2+, stimulate osteoclast proliferation/differentiation, increase plasma Ca2+ (which promotes bone mineralization)
197
What does Vitamin D do in the intestine?
Increase transcellular calcium absorption in the duodenum, stimulates phosphorus reabsorption
198
How does Vitamin D increase calcium absorption in the duodenum?
Increases TRPV5/6, calbindin, calcium-ATPase pump
199
How does Vitamin D increase intestinal phosphate absorption?
Increase expression of Na+-Pi cotransporter
200
What is the normal serum Ca2+ range?
2.2-2.6 mM (8.8-10.3 mg/100 mL)
201
What is the normal serum phosphate range?
0.8-1.45 mM (2.4-4.1 mg/100 mL)
202
What is osteoporosis?
Reduced bone density (mainly in trabecular bone)
203
What causes osteoporosis?
Genetics
Menopause (low estrogen)
Glucocorticoid therapy/chronic stress
Low dietary Ca2+
204
How is osteoporosis treated?
Estrogens
Calcitonin
Bisphosphonates (inhibit bone resorption)
Vitamin D
205
What causes primary hyperparathyroidism and what are symptoms?
Hyperplasia, carcinoma of parathyroid gland
| Symptoms: hypercalcemia, kidney stones
206
What causes secondary hyperparathyroidism and what are the symptoms?
Chronic renal failure, reduced Vitamin D leads to excess PTH synthesis
207
What are the symptoms of hypoparathyroidism and who can it be tested?
Hypocalcemic tetany
| Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
208
What causes rickets in children and osteomalacia in adults and what are the symptoms?
Unmineralized bone due to Vitamin D deficiency
Bowing of long bones (children)
Decreased bone strength
209
What causes pseudohypoparathyroidism?
Congenital defect in G protein that associates with PTH R1; leads to generalized resistance to PTH, TSH, LH, FSH
210
What are the clinical signs of pseudohypoparathyroidism?
Low Calcium
High Phosphorus
High PTH
Short stature
211
How can calcitonin be used in the clinic?
Inhibits osteoclast resorption and slows bone turnover, leading to reduction of plasma calcium; used to treat Paget disease (high bone turnover)
212
What is the escape phenomenon of calcitonin?
Rapid downregulation of calcitonin receptors; causes the antiosteoclastic actions of calcitonin to diminish within a few hours
213
What bond is cleaved by renin to convert angiotensinogen to angiotensin 1?
Leu-Val
214
ANP and BNP are potent ___ and they increase ___.
Vasodilators; natriuresis
215
What does PCB (polychlorinated biphenyl) do?
Competes with TH for binding to its transport protein in the blood; circulating TH is degraded faster, compensatory increase TH production
216
What does DES do?
Associated with increased cervical/vaginal cancer in DES daughters
217
What does BPA (bisphenol A) do?
Estrogenic, antagonizes TH receptor
218
The endocrine pancreas consists of 3 major cell types clustered in groups known as ___.
Islets of Langerhans
219
What do the beta cells of the pancreas secrete?
Insulin
220
What do the alpha cells of the pancreas secrete?
Glucagon
221
What do the delta cells of the pancreas secrete?
Somatostatin (SS14)
222
What do the PP cells of the pancreas secrete?
Pancreatic polypeptide (inhibit acinar cells)
223
What do the epsilon cells of the pancreas secrete?
Ghrelin
224
Describe the blood flow of the pancreas.
Blood flows from the center of the islet outward.
225
Describe the arrangement of alpha and beta cells in the pancreas.
Beta cells cluster in the core; alpha cells surround the beta cells as a sandwhich
226
What is the primary role of insulin?
Energy storage (anabolism)
227
What is the primary role of glucagon?
Energy mobilization (catabolism)
228
Describe the synthesis of insulin.
Proinsulin has an amino terminal beta chain and a carboxy terminal alpha chain linked by a C-chain. The C-chain is critical for proper folding and formation of disulfide bonds between the alpha and beta chains. Cleavage of the C-chain exposes the part of insulin that interacts with its receptor. Insulin and C-peptide are packaged together in vesicles.
229
Describe the process of insulin release from a pancreatic beta cell.
1. Glucose enters the beta cell via GLUT-2
2. Glucose is phosphorylated by glucokinase to G6P
3. Glucose is metabolized and ATP is produced
4. Increased ATP closes K+ channels, which depolarizes the cell.
5. Depolarization opens calcium channels
6. Calcium influx causes exocytosis of insulin-containing vesicles
230
Describe GLUT-2's affinity for glucose.
Low
231
How do sulfonylurea drugs work?
They close the K+ channel of beta cells (the channel has an SUR subunit) and bypass glucose binding step.
232
What else can increase ATP in beta cells through oxidation?
FFAs and amino acids
233
What do incretins (GLP-1) do to insulin release?
Potentiate insulin release
234
What do catecholamines do to insulin release?
Inhibit insulin release
235
Describe insulin binding to its receptors.
Insulin binds receptor tyrosine kinase at alpha subunit, which causes autophosphorylation of the beta subunit
236
True or false - glucose cannot enter a muscle cell without insulin.
True
237
How does glucose enter a muscle cell?
Insulin binds to its receptor. Autophosphorylation recruits insulin receptor substrates (IRSs), which activate intracellular signaling cascades. GLUT4 is inserted into the membrane.
238
Which GLUT transporter is insulin-dependent?
GLUT-4
239
What are the physiological effects of insulin in the liver?
Promote glycogen and TG production, reduce glucose production/output, increase glucose uptake
240
What are the physiological effects of insulin in the muscle?
Promote glycogen and TG production, protein synthesis, increase glucose uptake
241
What are the physiological effects of insulin in adipose tissue?
Promote TG production, release of FFAs from chylomicrons, inhibit lipolysis, increase glucose uptake
242
Describe the biosynthetic processing of glucagon.
Proglucagon: GRPP, glucagon, GLP-1, GLP-2
In pancreatic alpha cell: GRPP cleaved, glucagon secreted as active peptide, GLP-1 and GLP-2 remain bound and inactive
In intestinal L cell: GRPP and glucagon remain bound and inactive, GLPO-1 and GLP-2 are cleaved and activated
243
___ stimulate GLP release in intestines.
Carbohydrates
244
How are the relative rates of gluconeogenesis and glycolysis regulated?
By the actions of glucagon and insulin on a single bifunctional enzyme:
Insulin dephosphorylates the enzyme, conferring kinase activity; phosphorylation of downstream enzymes promotes glycolysis
Glucagon phosphorylates the enzyme, conferring phosphatase activity; dephosphorylation of downstream enzymes promotes gluconeogenesis
245
What is the primary role of glucagon?
Energy mobilization
246
What are the targets of glucagon?
Liver and adipose tissue (no receptors in skeletal muscle)
247
What stimulates somatostatin release? What inhibits it? What does it inhibit?
Stimulated by high fat, high carb meals
Inhibited by insulin
Inhibits insulin release
248
___ is released with insulin from vesicles in beta cells; it acts synergistically with insulin.
Amylin
249
What is the function of ghrelin?
Stimulates food intake at level of hypothalamus
| Stimulates GH release
250
What is the relationship between circulating ghrelin and obesity?
Decreased ghrelin leads to increased obesity
251
What does ghrelin inhibit?
Insulin release
252
How do GH and cortisol counter-regulate insulin?
Permissive effects on gluconeogenesis and lipolysis; defends against prolonged hypoglycemia
253
Wasting leads to what three effects?
1. Release of pro-inflammatory cytokines
2. Activation of HPA axis
3. Dysregulation of GH and IGF-I
254
What are the 4 characteristics of metabolic syndrome?
1. Visceral obesity (waist >40" in men, >35" in women)
2. Insulin resistance (fasting glucose > 100 mg/dL)
3. Dyslipidemia (TG >150 mg/dL, HDL <40 mg/dL
4. Hypertension (BP >135/80)
255
What hormone is produced by white adipose tissue?
Leptin
256
Describe the relationship between total fat and plasma leptin.
Higher body fat correlates with increased plasma levels.
257
What are two important transcription factors produced in adipose tissue?
SREBP-1C (promotes TG synthesis)
| PPAR-gamma (regulates TG storage and adipocyte differentiation)
258
How are PPAR-gamma agonists used in clinic (Thiazolidinediones - TZD)?
Treat insulin resistance and T2DM --> induces differentiation of adipocytes to make more fat cells and increase fat storage
259
What are 2 stimulators of appetite?
Neuropeptide Y and AGRP
260
What are 2 inhibitors of appetite?
alpha-MSH, CART
261
How does Leptin inhibit appetite?
Inhibits release of Neuropeptide Y and AGRP, activates release of alpha-MSH and CART
262
What occurs in insulin resistance?
Insulin does not efficiently transport glucose into cells, leading to high levels of glucose and insulin; high insulin leads to downregulation of insulin receptors; pancreas reduces insulin output
263
What causes conversion of T2DM to T1DM?
Beta cell depletion
264
What characterizes T2DM?
Impaired beta cell function and insulin resistance
265
How is T2DM diagnosed?
1. Elevated HbA1C >48 mMol/1
2. Fasting blood glucose >125 mg/dL
3. Oral glucose tolerance test >200 mg/dL
266
What are the 3 symptoms of T2DM?
1. Polyphagia (excessive hunger)
2. Polyuria (excess glucose in blood leads to increased plasma osmolality and excessive water and sodium loss)
3. Polydipsia (excessive thirst due to severe dehydration)
267
How is T2DM treated?
1. Sulfonylureas: close ATP-dependent K+ channels in beta cells causing insulin release
2. Metformin: inhibits hepatic gluconeogenesis, increases insulin receptor activity making cells more sensitive to insulin
3. Alpha-glucosidase inhibitors: delays intestinal absorption of carbohydrates
268
What is T1DM characterized by?
Development of ketoacidosis in the absence of insulin therapy and destruction of pancreatic beta cells (insulin dependent)
269
How is T1DM treated?
Insulin injections, close monitoring of blood glucose levels, diet
270
Describe the formation of diabetic ketoacidosis.
Decreased insulin and increased couterregulatory hormones leads to increased FFA release; metabolism of ketone bodies for energy results in increased blood acidity
271
Mental acuity is a function of ___.
Osmolality (gets worse as osmolality increases)
272
What are the genetic risk factors for T2DM?
Genes that affect beta cells, insulin signaling, glucose transport, obesity; most high associated with genetic polymorphism in TCF72 (Wnt signaling, coactivator of beta-catenin)
273
What are environmental risk factors of T2DM?
Impaired beta cell proliferation during childhood (malnutrition, maternal factors), increased propensity for insulin resistance (high caloric diet, lack of activity, acquired organ dysfunction for glucose homeostasis)
274
What is a key early characteristic of T2DM?
First phase insulin secretion is impaired
275
Islet neogenesis occurs during embryonic development and beta cell replication continues during childhood/adolescence. ___ is important for both islet neogenesis and beta cell proliferation. ___ targets regulate beta cell proliferation. ___ is key for endocrine cell development.
PDX-1; TCF72; Neurogenin 3
