Exam 1 Flashcards
(110 cards)
1
Q
Endocrine system function
A
- coordinate and integrate the activity of the cells and tissues of the body using signaling molecs (hormones) that are carried in circulation
- influences many organ systems
2
Q
Pancreas: Endocrine
A
- regulates energy balance and control of fuel mobilization by hormone production into blood (hepatic portal vein)
- 1% of pancreatic weight (islets)
- 10-15% arterial blood flow of pancreas
- richly vascularized
3
Q
Pancreas: Exocrine
A
- secretes bicarb and digestive enzymes
- 99% of pancreatic weight
- products go to SI (duodenum)
4
Q
Alpha cells (secrete 4)
A
- surround beta cells towards outside of islet
- secrete glucagon, proglucagon, GLP-1 and 2
5
Q
Beta Cells (secrete 5)
A
- concentrated in center of islet
- secrete insulin, amylin, proinsulin, C-peptide, GABA
6
Q
Delta Cells
A
- surround beta cells towards periphery of islet
- secrete somatostatin
7
Q
somatostatin
A
- inhibitory of glucagon and insulin
8
Q
PP cells (F cells)
A
- around beta cells towards periphery
- secrete pancreatic polypeptide (PP)
9
Q
Blood flow of endocrine pancreas
A
- from islet center TO periphery
- fenestrations help blood to get to capillaries from islet cells
10
Q
Fenestration
A
- holes in capillary walls
11
Q
Insulin inhibits:
A
- glucagon secretion
- somatostatin secretion
12
Q
glucose levels should be between:
A
- 70-120 mg/dL
13
Q
how much insulin is stored in pancreas vs how much secreted/day?
A
- 8 mg in pancreas
- 0.5-1mg secreted daily
14
Q
Production of insulin in B cells
A
- synthesized as preproinsulin
- cleaved to proinsulin and packaged into vesicles
- processed to insulin in vesicles
15
Q
What receptor does insulin and insulin-based drugs activate?
A
- tyrosine kinase receptor
16
Q
most insulin drugs are ______ based
A
- recombinant DNA based
17
Q
glucose metabolism increases the ______ (sensed by B cell)
A
- ATP/ADP ratio
18
Q
glc entry into B cells occurs via ______
- what happens once in B cell?
A
- GLUT2
- phosphorylated to G6P by hexokinase
- metabolized to generate ATP and increase ATP/ADP ratio
19
Q
High ATP/ADP ratio
A
- stims insulin secretion
- closes ATP-sensitive K channel
- activates voltage gated Ca channels
- leads to influx of Ca
- stims exocytosis of vesicles with insulin
- also cAMP generated which activates pathways which lead to release of intracellular Ca
20
Q
K/ATPase pump regulates _____
A
- insulin secretion
- target of diabetes drugs
- bind to SUR1 subunits to inhibit
21
Q
other activators of insulin secretion
A
- nonglc sugars
- AA
- FA
- parasymp activity
- GLP-1 and GIP (glc-dependent insulinotropic polypeptide
22
Q
where is insulin degraded and by what?
A
- insulinase in the liver and kidney
23
Q
half life of insulin
A
- 6 mins
24
Q
what happens at target tissues of insulin
A
- insulin binds to receptors on target cells
- all tissues express insulin receptors
- activates intracellular tyrosine kinase
- activates a GPCR to bring glc transporters (GLUT4) to cell surface
25
insulin receptor makeup
- glycoprotein
- 4 disulfide-linked subunits
- two extracellular a subunits
- two transmembrane b subunits
- intracellular tyrosine kinase domain
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Glycogenesis
- synth of glycogen in muscle and liver from glc
- insulin favors glycogenesis
- built by glycogen synthase
27
Glycogenolysis
- breakdown of glycogen in muscle and liver to glc
- insulin negative regulator of glycogen phosphorylase
- liver and kidney have G6-phosphatase which can export glc from these cells
- muscles does not have this enzyme so glc remains intracellular
28
hexokinase
- adds p to glc (glc import)
| - in most tissues
29
glucokinase
- adds p to glc (glc import)
| - in liver
30
insulin (Stims/inhibits) glycolysis
- STIMULATES
| - turns glc to energy
31
Gluconeogenesis
- antagonized by insulin
- converting noncarb precursors to glc or glycogen
- substrates are glucogenic AA, lactate, and glycerol
- mostly done in liver and kidneys
- done in states of starvation
- also occurs to clear metabolites
32
Glc made from gluconeogenesis pathway to out of cells:
- G6P converted to Glc by G6-phosphatase
- in liver and kidney but not in muscle and adipose
- need this to export Glc out of cells
33
Lipid storage in adipose
- stores triglycerides synthed from 3 FA and glycerol
- insulin favors net deposition of triglycerides by increasing translocation of GLUT4 transporters to cell membranes
- activates lipogenic enzymes
- FA synth also stimed in liver and other tissues and can be transported to adipose via circulation
34
Lipolysis
- hydrolysis of triglycerides by hormone-sensitive lipase to be exported from adipose and used by the body
- stimulated by glucagon and inhibited by insulin
35
Glucagon
- secreted by A cells
- proprotein is cleaved to make glucagon (among other hormones (GLP-1-2)
- stims mobilization of glucose, fats, and protein for energy
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other stimuli for glucagon secretion
- sympathetic nervous system, stress, exercise, high plasma levels of AA
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half life glucagon & what it is degraded by
- 6 mins
| - degraded by liver and kidneys
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what does glucagon activate on plasma membrane?
- GPCR which increases cAMP and PKA
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glucagon (catabolic or anabolic)
catabolic
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insulin (catabolic or anabolic)
anabolic
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PFK-1 does what
- Glycolysis (stimulated by insulin)
42
pyruvate kinase does what
- gluconeogenesis (by liver)
| - stimed by glucagon
43
somatostatin overview
- secreted by d cells in pancreas, hypothalamus, and GI tract
- decreases insulin AND glucagon secretion
- inhibits GI tract motility
- inhibits secretion of some non-pancreatic hormones
- stimuli are high plasma levels of glc, AA, and FA
44
half-life of somatostatin
- 2 mins
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GLP-1
- glucagon like peptide 1
- produced in enteroendocrine cells (L cells) of ileum
- different cleavage of proglucagon
- released from L cells during nutrient absorption in the GI tract
46
what does GLP-1 do? (pancreas, stomach, hypothalamus)
- pancreas: increases insulin secretion, suppress glucagon
- stomach: delay gastric emptying
- hypothalamus: decrease appetite
- appeal for type 2 diabetes drug target
47
half life of GLP-1, what degraded by
1-2 mins, degraded by dipeptidyl peptidase-IV (DPP-IV)
48
Leptin
- secreted from fat cells
- regulates long term energy balance
- signals to CNS the amount of energy stored (fat)
- decreases appetite
- allows endocrine system to spend energy on growth, reproduction, and maintenance of high metabolic rate
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Leptin acts on 2 centers
- orexigenic and anorexigenic centers
| - need balance between the two
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orexigenic
- eat more, metabolize less
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anorexigenic
- eat less, metabolize more
52
what organ sees highest concentration of insulin?
- liver
| - insulin dumped into hepatic portal vein by pancreatic b cells
53
What happens with continued fasting?
- catecholamine and glucocorticoid levels increase
- promote release of FA from adipose
- promote breakdown of protein to AA in muscle
- type 1 and 2 diabetes mimic fasting state in hormone response
54
FFA are precursors to what?
- ketone body production in liver
- high rate of fatty acid oxidation in diabetes
- can lead to ketoacidosis (potentially fatal)
55
Pathophys of Diabetes Mellitus
- disease state with hyperglycemia
- type 1: lack on insulin secretion b/c of autoimmune destruction of b cells
- type 2: insulin resistance of cells, response of insulin inadequate to take in glc from bloodstream
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type 1 diabetes
- autoimmune destruction of b cells
- 5-10% US cases
- starvation-like response when not treated
- typical onset in childhood but can occur any age
- onset of clinical disease sudden, but actual destruction of b cells occurs gradually
- onset when 85% of cells are destroyed
- brief honeymoon phase with intermittent periods of adequate insulin
57
Type 1 diabetes: Liver effects
- glycogenolysis and gluconeogenesis produce excess glc
- excess conversion of FA to ketone bodies, b-hydroxybutyrate, and acetoacetate
- high levels of these deplete bicarb and cause diabetic ketoacidosis (life threatening)
58
Type 1 diabetes: Muscle effects
- breaks down protein and releases AA
- AA substrate for liver gluconeogenesis
- lose muscle mass and contractile protein
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type 1 diabetes: adipose tissue
- breaks down triglycerides to release FA and glycerol
- glycerol substrate for liver gluconeogenesis
- FA substrate for ketone body production
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type 1 diabetes: kidneys
- blood glc levels exceed kidney's ability to reabsorb gluc
- glc excreted in urine, water follows glc
- causes osmotic diuresis and polyuria and polydipsia
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type 1 diabetes affect on appetite and weight
- appetite increased (excessive hunger/polyphagia)
| - weight loss b/c nutrients cannot be stored
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type 1 diabetes possible onset triggers-
- genetic predisposition
- flu-like syndrome may occur few weeks before onset
- may represent viral illness that is a trigger to the autoanitbodies to b cell proteins
- may also be increased levels of inflammatory mediators of autoimmune rxn
- enviro factors also influence development
63
all synthetic insulin drugs tend to do what?
- bind to insulin receptors on cells
64
administrations of insulin
- usually subcu
- IV used in hospital setting
- FDA approved inhaled forms as well
65
why is insulin usually injected subcu?
- can create a depot of insulin at injection site
66
factors affecting rate of insulin absorption
- solubility of insulin prep
- local circulation site-to-site variability
- person-to-person variability
- faster absorption gives faster onset of action and also shorter duration of action
67
hexamer vs monomer absorption
- hexamer: least absorbable, slow onset, long-acting
| - monomore: most absorbable, fast onset, short-acting
68
regular insulin
- short acting
- structurally identical to endogenous insulin
- aggregates into hexamers
- dissassociation of hexamers to monomers is rate-limiting step for absorption
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Insulin Lispro, Aspart, and Glulisine
- ultrarapid-acting insulins
- keeps molec in monomeric to speed absorption
- difference between the three (& regular insulin) is in AA substitutions
- can be injected minutes before a meal
- abministered subcu
- same mech of action as regular insulin (bind to tyrosine kinase receptor once in circulation)
70
in principle.. IV rate of absorption vs injection
- IV, everyone should have same rate of absorption b/c directly into blood stream
- injection, diff rate of absorption
71
NPH insulin
- neutral protamine Hagedorn insulin
- intermediate-acting
- insulin combined with protamine (fish sperm protein)
- prolongs absorption time of insulin
72
Insulin Glargine, Detemir, and Degludec
- long acting preparations
- steady absorption w/o peak
- mimics basal insulin secretion
- modifications of AA increase presence of hexamer form
73
acute vs chronic measurement of glc in diabetic
acute: measure blood glc with glc meter
chronic: measure glycohemoglobin (HbA1c)
74
Glycohemoglobin test (HbA1c)
- glc in blood non-enzymatically glycosylates blood proteins
- occurs at rate proportional to level of glc in blood
- RBC cannot make new Hb and cannot break down Hb
- gets rid of sampling bias wiht acute testing
75
lifespan of RBC
120 days
| - important for HbA1c test for chronic blood glc levels
76
Type II diabetes info
- 90% of US cases
- obesity most important risk factor (also genetics play role)
- commonly affects >40 yrs
- develops gradually, usually found in routine screening
- transporters are insulin resistant, need increased insulin to respond correctly to glc intake
- initially resistance is compensated with increased insulin secretion, but eventually b cells cannot keep up with demand
77
What % of type II diabetes cases are caused by rare variants?
- 1-2%
78
rare variants in type II diabetes
- Maturity onset diabetes of the young (MODY)
| - healthy, not obese children
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B cell failure in type II diabetes
- MODY: mutations impair B cell function
| - lean and insulin sensitive patients often reduced B cell function
80
Sudden onset of type II diabetes sometimes caused by (2)
- glucocorticoids
| - pregnancy (typically goes away after pregnancy)
81
Morbidity and Mortality with type I and type II diabetes
- type 1: progress rapidly to ketoacidosis, coma, and death if left untreated (rare for type II)
- type 2: if left untreated can lead to death in week to months, side effects typically kill
82
Diabetic Hyperosmolar Syndrome
- blood glc >600 mg/dL
- kidney cannot recover all glc from filtrate
- leads to excess urine and severe dehydration
- causes mental status changes, other complications, and death
- most commonly associated with other illnesses (like infections) in type II patients
83
Long-term Vascular Pathology (4)
- type 1 and type 2
- premature atherosclerosis
- retinopathy
- nephropathy
- neuropathy
84
Long-term vascular pathology... what happens
- sorbitol builds up causing osmotic problems in tissues that more readily take up glc than others
- damages the microvasculature
- buildup of sorbitol attracts water into the cells and causes damage
85
Patient Strategy for type II diabetes
- improve insulin sensitivity by reducing body weight, increasing exercise, and altering diet
- alone or in combo with pharm treatments
86
Pharm agent mechs for type II drugs
- increase insulin secretion by b cells
- sensitize target cells to actions of insulin
- inhibit glc recovery from kidneys
- use insulin therapy (not first choice in type II)
- slow absorption of sugars from the GI tract
87
Biguanides
- used to treat type II diabetes
- act by increasing insulin sensitivity
- available agent: metformin
- common choice for initial treatment
- other biguanides withdrawn from US market because of toxic side effects
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Metformin general info
- half life 1.5-3 hrs
- not bound to plasma proteins or metabolized in humans
- excreted unchanged by kidneys
- oral delivery
89
Metformin mechanism of action
- activate AMP-dependent protein kinase (AMPPK)
- increases AMP production
- blocks breakdown of FA
- inhibit hepatic gluconeogenesis and glycogenolysis
- increased activity of insulin receptor
- energy metabolism effects more indirect
90
Metformin therapeutic effects
- lowers blood glc and insulin levels
- beneficial in treating insulin resistance with polycystic ovarian syndrome (PCOS)
- does not induce hypoglycemia
- lowers serum lipids and decreases weight
91
Metformin adverse effects
- mild GI distress common
- usually transient and can be minimized by adjusting dose
- lactic acidosis (cause of nausea and weakness)
- patient to patient variability
92
Lactic Acidosis
- adverse effect of metformin
- causes nausea and weakness
- metformin decreases flux of metabolic acids through gluconeogenic pathway so lactic acid can accumulate
- incidence low and predictable (not huge concern for type II population as a whole)
- risk factors: hepatic disease, heart failure, resp disease, alcohol abuse
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Metformin caution and contraindications
- renal disease can reduce clearance b/c drug not metabolized in body
- patients over 65 may have renal impairment that reduces clearance as well
- reduced clearance means it remains in system longer
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Beneficial features of metformin
- high efficacy in type II diabetes
- low risk of hypoglycemia
- not associated with weight gain
- low cost
- can be combined with additional drugs that have diff mechs of action
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Sulfonylurea Drugs
- treat type II diabetes by stim insulin RELEASE from pancreatic b cells
- uses raising circulating insulin levels sufficiently to overcome insulin resistance
- inhibit b cell K/ATP channel
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Sulfonylurea mechanism of action
- bind to the SUR1 subunit of K/ATP channel
- thought to displace Mg-ADP that activates channel
- inhibiting channel leads to Ca influx and increased insulin secretion
97
Glyburide, Glipizide, and Glimepiride
- second-gen sulfonylureas (1st gen less potent)
- lower blood glc and cause metabolic improvements through increased insulin action
- oral delivery
- metabolized by liver
- vary in duration of action
98
which sulfonylurea has longest duration of action?
- Glyburide
| - use in patient with low risk of hypoglycemia
99
Sulfonylurea adverse effects
- hypoglycemia resulting from too much insulin secretion
- can be very problematic for patients with impaired clearance or reduced capacity to recognize signs of hypoglycemia (e.g. elderly, use short acting drugs)
- weight gain due to increased insulin action at adipose tissues
100
Tolbutamide, tolazamide, acetohexamide, chlorpropamide
- 1st gen sulfonylurea drugs
- same mech of action as second gen (bind to SUR1 subunit of K/ATP channel, causing Ca influx and increased insulin secretion)
- may be chosen for unique pharmokinetic properties, i.e. shorter duration of action, less chance of hypoglycemia (more freq dosing)
101
which of the 1st gen sulfonylurea drugs has short duration?
- tolbutamide
102
Meglitinides
- type II diabetes treatment
- similar to sulfonylureas in absorption, metabolism, and adverse effects
- stims insulin release by binding to SUR in b cell K/ATP channel
- bind at diff site on SUR1 than sulfonylureas
103
Repaglinide and Nateglinide
- meglitinide class
- rapidly absorbed from SI
- complete metabolism in liver in inactive metabolites (half life
104
Exogenous Insulin Drugs
- always used for type I diabetes
- sometimes used in type II if diet and other therapies not effective
- high efficacy at reducing blood glc levels
- high risk of hypoglycemia
- weight gain also adverse effect
105
Thiazolidineodines (TZDs)
- type II diabetes treatment.. also treats PCOS
- Rosiglitazone and Pioglitazone
- sensitize peripheral tissues to insulin
- act as antagonist for nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARy)
- changes in fat metabolism alter metabolic enviro and indirectly increase liver and muscle insulin sensitivity
- oral delivery
106
PPARy
- peroxisome proliferator activated receptor-y
- site of action for thiazolidinediones (TZDs)
- forms a heterodimer with retinoid X receptor (RXR)
- activates transcription of target genes in promoter regions involved in glucose and lipid metabolism
- mainly expressed in adipose tissue
- TZDs increase insulin sensitivity in adipose tissue
- inhibits hormone-sensitive lipase in adipose
107
TZD site of action
- PPARy is expressed at quite low levels in liver and muscle
- TZDs have little effect on insulin sensitivity in liver and muscle cells in vitro
- liver and muscle are primary sites of insulin resistance in type II diabetes
108
Thiazolidineodiones (TZD) adverse effects
- weight gain common
- edema
- heart failure
- hepatotoxicity
- do not increase insulin secretion or cause hypoglycemia
109
GLP-1 agonists and mimetics
actions mimic endogenous peptide hormones called incretins including GLP-1
- GLP-1 is of the enteroendocrine cell class
- released from SI following nutrient absorption
- cause increased insulin release, decreased glucagon release, slow gastric emptying, and decrease in appetite
110
GLP-1 agonists and mimetics differences between endogenous GLP-1
- GLP-1 endogenous has a very short half-life (1-2 mins)
- broken down by dipeptidyl-peptidase IV (DPP-IV)
- drugs have been developed to increase bioactivity
- these drugs are peptide based, cannot survive GI tract, given sub cu
- DPP-IV inhibitors developed to increase hormone half life
