lectures - regulation of insulin secretion and endocrine control of glucose homeostasis

what is the only source of insulin in the body

pancreas

where does the pancreatic duct exit to

duodenum

what are the main functions of pancreas

role in food digestion

regulation of glycemic levels

what are the 2 types of glands in the pancreas

exocrine with acinar cells (~98%)

endocrine with islets of Langerhans (~2%)

describe the exocrine function of pancreas

secretion of digestive enzymes in duodenum

describe the endocrine function of pancreas

production of insulin and glucagon to regulate blood glucose

production of somatostatin to regulate insulin and glucagon

what are the parts of the exocrine pancreas

acinus

ductal cells

main pancreatic duct

what is the acinus of the exocrine pancreas

cells that produce lipase, amylase, and trypsin

what are the ductal cells of the exocrine pancreas

product bicarbonate to neutralize stomach acid

what does the pancreatic duct join into

bile duct

what is the PDX-1 gene

necessary for diff of endocrine pancreas during development and for renewal of islet cells throughout life

remains active in ß and δ cells

with only 1 working chromosome for PDX-1 what happens

genetic diabetes - MODY - maturity onset diabetes of youth

pancreatic ß cells secrete what

insulin, C peptide, proinsulin, etc

pancreatic α cells secrete what

glucagon, proglucagon

pancreatic δ cells secrete what

somatostatin

islet has neurons for

sympath (adrenergic to ↑ α and ↓ß) and parasympath (ACh to ↑α and ↑ß) and sensory

hormones secreted by endocrine pancreas go to

hepatic portal vein and reach the liver

describe the process of insulin creation

nucleus (preproinsulin) -- signal peptide cut--> ribosome on ER (proinsulin) --> golgi--prohormone convertase--> C peptide cut and insulin formed and added to Zn and crystallized

why is insulin crystallized with Zn

allows for 6 to bind to one allowing for super concentrated insulin to be ready on demand

what is released in diabetes 2

proinsulin instead of insulin

whats the goal of insulin

to decrease blood glucose

whats the difference between human insulin and pig insulin

only 1 aa difference, a THR → ALA difference

what is the goal of glucagon

to increase blood glucose

glucagon is the product of

cleavage of proglucagon

tissue specific post-translational cleavage

where is proglucagon produced

in cells like pancreatic α cells and intestinal L-cells

cleavage of proglucagon in pancreatic α cells causes release of

glucagon via prohormone convertase II

cleavage of proglucagon in intestinal L-cells causes release of

GLP-1 via prohormone convertase I and III

what is GLP-1

incretin to help produce more insulin

what is the goal of somatostatin

to regulate release of glucagon and insulin

what is somatostatin-28

in pancreatic δ cells, potent at inhibiting glucagon and insulin

what is somatostatin-14

in CNS and hypothala, potent at inhibiting GH secretion

what is the most potent stimulator of insulin release

glucose

insulin levels rise how fast, peak around when, and return to basal by when after a meal

rise after 10-15 mins

peak around 30-45 mins

return 90-120 mins after

what is the hyperglycemic clamp

infusion with glucose to a certain level to keep a response going (artificial)

what are the 2 phases of insulin releases

1st immediate phase from exocytotically ready vesicles

2nd slower phase with insulin moving from further distances

what happens the the phases of insulin release in type 2 diabetes

ß cells secreting more insulin overcome the resistance, so there is no longer a readily available pool insulin, so the 1st phase is severely blunted

describe GLUT 1/3

found in all tissues

very high affinity for glucose

responsible for basal glucose uptake

describe GLUT 2

found in hepatic, intestinal, and renal tubular cells

medium affinity for glucose

responsible for glucose uptake when glycemic levels are high

describe GLUT 4

found in skeletal muscle and adipose tissue

dependent on insulin signaling to become active and transport glucose

also activated by exercise in skeletal muscle, mediated by AMPK

when levels of glucose are low, which GLUT channels are more liekly to be active

GLUT 1/3

what is GSIS

glucose stimulate insulin release, ß cells respond to glucose with insulin release

describe the process of insulin exocytosis

glucose enters cell and becomes pyruvate → enters mito and goes through TCA cycle → ↑ ATP/ADP ratio closes K channels → mem depolarization opens Ca channels → Ca triggers insulin release

how does ↑ ATP/ADP ratio lead to new insulin vesicle movement

moves new insulin vesicles to mem using protein powered by ATP

form of amplification

in ß cells, what is swapped in glycolysis

Hexokinase instead of glucokinase

what is the rate limiting step of glycolysis in ß cells

hexokinase

what is the rate limit step in most cells for glycolysis

PFK-1

deletion of 1 copy of hexokinase causes what

MODY II

describe incretins

gut-derived peptide hormones that promote:

insulin release from ß cells

slow gastic emptying

reduce hunger feeling via brain

what does GLP-1 do

triggers Gs subunit leading to PKA/Epac2 which in turn leads to reorganization of cytoskeleton promotes vesicle transport

biggest boost to 2nd phase

what do catecholamines (sympath NS) inhibit

cAMP

what does DAG do in insulin release and such

activates cAMP and Ca

acetylcholine does what

works through Gq GPCR to get more Ca

aas with (+) charge do what

can help depolarize mem

what are the targets of insulin

liver, muscle, adipose tissue

describe the insulin receptor

receptor tyrosine kinase (RTK)

dimer

has 2 pathways for effects

describe the MAPK pathway

GRB2 + SOS → RAS → MAPK path → mitogenic effects

what are the mitogenic effects of the MAPK pathway

cell prolif

gene expression

describe the PKB/AKT pathway

IRS1/2+PI3K → PIP2 → PIP3 → PKB/AKT → metabolic effects

what are the effects of PKB/AKT in skeletal muscle

↑ protein synth

↑ glycogen synth

inhibits of autophagy

↑ glucose metabolism (glycolysis)

promotes GLUT 4 mediated glucose transport

what are the effects of PKB/AKT in adipose tissue

↑ lipogenesis

inhibits lipolysis

promotes GLUT 4 mediated glucose transport

promotes GLUT 4 mediated glucose transport in liver

↑ glycogen synth

↑ protein synth

inhibits glycogen breakdown

inhibits gluconeo

what are the effects of glucagon in liver

↑ glycogen breakdown

↑ gluconeogenesis

↑ ketogenesis

inhibits glycogen synth

high carbo content meals stimulates what

insulin but not glucagon release

high protein content meals stimulates what

glucagon and insulin release