LM 4.1: Insulin and Glucagon Flashcards
what hormones involved in glucose homeostasis does the pancreas release?
- insulin from β cells
2. glucagon
which organs are involved in glucose homeostasis?
- pancreas
- liver
- muscles
- muscles
- fat cells
- brain
what is the general role that the liver plays in glucose homeostasis?
it takes up glucose when levels are high and releases glucose when levels are low
it also stores glucose in chains as glycogen
what is the general role that the muscles plays in glucose homeostasis?
they are able to take up and store lots of glucose when insulin is present
more muscles mass means more of a reservoir for glucose
what is the general role that the fat cells plays in glucose homeostasis?
fat cells take up glucose when insulin is present
fat cells use glucose to make more fat
what is the general role that the brain plays in glucose homeostasis?
it takes up glucose whenever it needs energy and it doesn’t require insulin to do so
glucose is the fuel the brain normally uses
what are the 2 functional portions of the pancreas?
- exocrine
produces enzymes that get secreted into the pancreatic duct to help with food digestion
- endocrine
islets of Langerhans (alpha, beta, delta) release hormones like insulin and glucagon into the blood stream
what portion of the islets of Langerhans are alpha vs. beta vs. delta vs. F cells? what do each of them secrete?
α cells secrete glucagon and proglucagon (20%)
β cells secrete insulin, C-peptide, proinsulin and amylin (75%)
δ cells secrete somatostatin (3-5%)
γ/F/PP cells secrete pancreatic polypeptide (PP) (<2%)
what is the anatomical orientation of all the cells in one islet of Langerhans?
β cells are in the center closest to the systemic blood supply from the pancreatic arterioles
β cells are surrounded by α cells
on the outside at the peripheral are the δ and PP cells
periportal blood flow within the islets is from beta to alpha to delta cells
how do the islets of Langerhans communicate?
islet cells communicate via gap junctions or via paracrine secretion and signaling
what is the function of alpha cells?
synthesize and secrete glucagon to elevate glucose levels in blood
what is a glucagonoma?
a rare neuroendocrine tumor derived from multipotential stem cells of endodermal origin that can cause up to 1000-fold overproduction of glucagon
blood glucose rises through gluconeogenesis and lipolysis
clinical features includes glucose intolerance/diabetes mellitus, necrolytic migratory erythema, weight loss, diarrhea, venous thrombosis
most are sporadic, but up to 20% are associated with MEN1 (multiple endocrine neoplasia type 1)
which clinical condition is associated with alpha cells?
glucagonoma
which clinical condition is associated with beta cells?
type I and II DM
what is type I DM?
an absolute insulin deficient condition that follows T-cell mediated destruction of β cells
the diagnosis is suggested by presence of pancreatic autoantibodies
what is type II DM?
characterized by hyperglycemia and insulin resistance, but also relative impairment in insulin secretion
what is the function of somatostatin?
inhibits secretion of:
- insulin
- glucagon
- gastrin
- GH
what is the clinical condition associated with delta cells?
somatostatinoma
what is somatostatinoma?
tare neuroendocrine tumor that secrete excessive amounts of somatostatin resulting in an extreme reduction in secretion of insulin and causes diabetes
classic triad: diabetes/glucose intolerance, cholelithiasis, diarrhea/steatorrhea (abdominal pain and weight loss)
cholelithiasis may result from inhibition of cholecystokinin release, which reduces gallbladder contractility and diarrhea/steatorrhea result from inhibition of pancreatic enzyme and bicarbonate secretion and intestinal absorption of lipids
45% occur in association with MEN1
how do you diagnose a somatostatinoma?
presence of a fasting plasma somatostatin level exceeding 30 pg/mL
what is the function of γ cells?
they make and release pancreatic polypeptide (PP) in response to ingestion of food
PP exerts inhibitory function including inhibiting release of somatostatin
γ cells predominantly reside in the head of the pancreas
A 56 y/o male with h/o HTN presents with a painful lower extremity and found to have a DVT. He c/o 25 lb weight loss, polyuria, polydipsia and has a blood glucose level of 280 mg/dl. New-onset diabetes is diagnosed. On exam, he is thin and has an annular rash pattern of erythema with central crusting and bullae across his feet and ankles. What is the most likely etiology of his diabetes?
glucagonoma syndrome
development of diabetes type 2 in an abrupt fashion should prompt consideration for secondary diabetes – the presence of new-onset diabetes and necrotizing migratory erythema accompanied by weight loss suggests glucagonoma syndrome, which has a mean age of presentation of 55 years
other clinical features can include anemia, stomatitis, thromboembolism, GI and neuropsychiatric disturbances.
necrolytic migratory erythema is the typical rash associated with glucagonoma and is present in 80% of cases – it can be itchy, painful and often affects genital/anal region, groin, buttocks, and lower legs – it’s nontender with irregular borders, sometimes associated with scaling/crusting, and progresses through an initial ring-shaped area that blisters, erodes, then crusts over and leaves behind a brown mark
what is the general function of insulin?
released by β cells and it helps get glucose into cells for utilization/storage
glucose is the primary fuel for cellular energy and can be stored in liver and muscles as glycogen
what is the general function of glucagon?
it’s released by α cells and stimulates breakdown of stored energy into glucose
glycogen breakdown can quickly supply glucose but also lipids and proteins can be converted to glucose
what is the structure of the insulin receptor?
the insulin receptor is composed of two extracellular α subunits and two transmembrane β subunits linked together by disulphide bonds
what stimulates and inhibits insulin secretion?
insulin secretion is stimulated by high blood glucose levels, amino acid ingestion, and gastrointestinal hormones (including cholecystokinin)
insulin secretion is inhibited by scarcity of dietary fuel and epinephrine
what is function of GLUT1 and where is it found?
- brain
- kidney
- placenta
- RBCs
uptake of glucose
what is function of GLUT2 and where is it found?
- liver
- pancreatic β cells
- small intestine
- kidney
rapid uptake and release of glucose
what is function of GLUT3 and where is it found?
- brain
- kidney
- placenta
uptake of glucose
what is function of GLUT4 and where is it found?
- heart
- skeletal muscles
- adipose tissue
insulin stimulated uptake of glucose
what is function of GLUT5 and where is it found?
small intestine
absorption of glucose
what is function of SGLT-1 and where is it found?
- small intestine
- kidney
active uptake and reabsorption of glucose
which glucose transporter does insulin regulate? how does it do it?
GLUT 4
in the basal state, a dynamic trafficking process ensures that the bulk of GLUT4 is sequestered into intracellular vesicles resulting in a low level of GLUT4 at the cell surface
insulin stimulates GLUT4 translation to the plasma membrane predominately by releasing GLUT4 from this specialized intracellular pool resulting in a pronounced increase in glucose uptake
what causes the release of insulin from β-cells?
glucose enters β-cells via GLUT2 transporters
the metabolism of glucose in the mitochondria via the Krebs cycle generates an increase in the intracellular ATP/ADP ratio
the increased ATP ratio inactivates the K+ channel that depolarises the membrane so that K+ can no longer leave the cell and instead, the Ca2+ channels open up and allow Ca2+ ions to flow inward into the cell
the ensuing increase in levels of Ca2+ ions inside the cell leads to the exocytotic release of pre-synthesised insulin stored in vesicles
what type of receptor is the insulin receptor?
the insulin receptor belongs to a family of receptor-tyrosine kinases (RTKs), which phosphorylate their substrate proteins on tyrosine residues
insulin receptor comprises of two subunits: the extracellular α-subunit and the transmembrane β-subunit –> the functional receptor exists as a dimer/heterotetrameric complex: α2β2
the α-subunit contains the ligand binding site while the β subunit is involved in intracellular signaling
what happens when insulin binds to the insulin receptor?
when blood glucose levels rise, insulin binds to the insulin receptor on muscle cells and/or adipocytes and facilitated dimerisation of the receptor
as a result of this dimerisation, the receptor is autophosphorylated at specific residues
what pathways does insulin activate once it binds to an insulin receptor?
insulin’s interaction with its cell surface receptor triggers both metabolic and mitogenic cellular responses and in order to do this, insulin employs two kinds of pathways: Ras-dependant and Ras-independent
- Ras-dependant Pathway: Upon insulin binding, the Ras protein is phosphorylated leading to activation of Mitogen Activated Protein Kinase (MAPK) pathway which is involved in cellular growth and proliferation.
- Ras-independent Pathway: on this case, another pathway known as the PI-3/AKT signaling pathway [phosphatidylinositol-3-kinase (PI 3-kinase)/protein kinase B(AKT)] is activated by a series of events facilitating glucose uptake by the cell
so when the insulin receptor binds insulin, the activate receptor phosphorylates the IRS-1 protein which can then lead to recruitment of GRB2, activating the Ras-MAPK pathway!
IRS-1 also activates PI3-kinase which catalyzes the addition of a phosphate group the membrane lipid PIP2, thereby converting it to PIP3 –> PIP3 binds a protein kinase called Akt which is activated by other protein kinases – Akt catalyzes phosphorylation of key proteins leading to an increase in glycogen synthase activity and recruitment of the glucose transporter, GLUT4 to the membrane
what are the overall actions of insulin on the liver, skeletal muscle and adipose tissue?
- striated muscle: promotes the uptake of glucose, glycogen synthesis and protein synthesis
- adipose tissue: promotes glucose uptake, increases lipogenesis and inhibits lipoprotein lipase which decreases lipoplysis
- liver: promotes lipogenesis and glycogen synthesis while suppressing gluconeogenesis
what is the function of glucagon?
increases blood glucose by:
1. triggering glycogen breakdown in the live aka glycogenlysis
- activates glucose production pathways through gluconeogeneisis
- elicits breakdown of stored lipids into glycerol and free FA through lipolysis –> glycerol is used in gluconeogenesis while free fatty acids can be made into ketone bodies
- AA are taken up by the liver and used in gluconeogenesis
what activates glucagon secretion?
- sympathetic activity/epinephrine
- secretin
- CCK
- elevated AA
- low glucose
what inhibits glucagon secretion?
- parasympathetic activity
- insulin
- high blood glucose
what happens when glucagon binds to its receptor?
it results in activation of adenylyl cyclase
the increase in cAMP results in activation of cAMP-dependent kinase with activation of glycogen phosphorylase (leading to breakdown of glycogen to glucose) and inhibition of glycogen synthase
this happens when cAMP activates protein kinase and PKA will do 2 things:
1. phosphorylate the active form of glycogen synthase, converting it to the inactive glycogen synthase b which prevents glucagon formation
- phosphorylation of phosphorylase kinase, leads to its conversion of inactive glycogen phosphorylase b to active glycogen phosphorylase a
sidenote: glucagon receptors do not affect adenylate kinase directly. Instead they activate a G-protein complex that interacts with the adenylate cyclase
what is the major abnormality involved in the pathogenesis of type II DM?
decreased peripheral glucose disposal
early in the disease course, the primary defects in type 2 diabetes are evident in skeletal muscle and adipocytes, where decreased insulin action (referred to as “insulin resistance”) is demonstrated and results in decreased glucose disposal
initially, the pancreatic beta cell compensates for this insulin resistance by increasing its insulin secretion, resulting in maintenance of normal blood glucose but on patients who develop diabetes, pancreatic compensation falters, and insulin secretion is no longer able to surmount the decreased insulin action in peripheral tissues
what are incretin hormones? what are the 2 primary incretin hormones?
- GIP
- GLP-1
incretin hormones are gut-derived hormones secreted from the intestine on ingestion of glucose or nutrients and they lead to stimulation of insulin secretion
they both bind to their respective receptors which are both G-protein coupled receptors and their binding activates and increases level of intracellular cAMP in the pancreatic β cells, stimulating glucose-dependent insulin secretion
what is the pathway through which GIP and GLP1 stimulate insulin secretion?
- they bind to their specific GPCR receptors which leads to activation of adenylate cyclase and subsequent elevation of intracellular cAMP
- increased cAMP then activates protein kinase A (PKA) and exchange protein activated by cAMP2 (EPAC2)/cAMP-guanine nucleotide exchange factor (GEF)II
- activation of PKA promotes closure of Katp channels and facilitates membrane depolarization.
PKA also leads to inhibition of the delayed rectifying K channel, a negative regulator of insulin secretion in pancreatic β cells, resulting in prolongation of action potentials
- depolarization opens voltage-gated Ca channels, allowing an increase of intracellular Ca concentration that mobilizes Ca from intracellular stores through PKA- and EPAC2-dependent mechanisms
- increased Ca concentration triggers fusion of insulin-containing granules with the plasma membrane and insulin secretion from the β cells
increased Ca level also promote transcription of the proinsulin gene, thereby increasing the insulin content of the β cell
activation of EPAC2 increase the density of insulin-containing granules near the plasma membrane to potentiate insulin secretion from the β cell
what is the non-insulin involved effect of GIP and GLP1 on pancreatic β cells?
- GIP stimulates glucagon secretion
- GLP-1 suppresses glucagon secretion when plasma glucose levels are above fasting level
GLP-1 loses its inhibitory effect on glucagon secretion at hypoglycemic levels and does NOT attenuate the counter-regulatory response to hypoglycemia
- GIP and GLP1 promote promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass
how are GIP and GLP1 broken down?
they undergo proteolytic processing by dipeptidyl peptidase (DPP-4), and are thereby inactivated and excreted from the kidney
DPP-4 processed incretins lose their insulinotrpic effects
what are GIP levels in T2DM patients?
GIP is involved in fat accumulation and fats strongly enhance GIP secretion
GIP levels are high in obese type 2 diabetes patients
what is the function of GIP?
- increased bone formation
- increased fat accumulation
- increased memory
- increased insulin
- increased glucagon
- decreased B cell apoptosis/increased B cell proliferation
- decreased gastric acid secretion
what is the function of GLP-1?
- increased memory
- decreased food intake
- increased insulin
- decreased glucagon
- decreased B cell apoptosis/increased B cell proliferation
- decreased gastric emptying
- increased cardioprotection
- increased CO
how is GLP1 used medically for obesity?
because of GLP-1’s effect on appetite suppression and decreasing stomach emptying, the GLP-1 receptor agonists are unique among the most commonly used anti-hyperglycemic drugs in that they promote weight loss
additionally, they have cardioprotective effects
A 50 y/o male, taking metformin for 3 years, presents for advice on treatment of his diabetes. He is obese (BMI 35), with h/o dyslipidemia and HTN. You decide to start him on a DPP-4 inhibitor. You explain to him that this drug, by increase GLP-1 levels, will target the following pathogenetic defects
- hepatic glucose output
- B cell dysfunction
incretin-based therapies include DPP-4 inhibitors and GLP-1 receptor agonists
DPP-4 inhibitors, through increasing endogenous GLP-1, can stimulate glucose-dependent insulin secretion from the β cell and can lower glucagon secretion, thereby lowering hepatic glucose output
GLP-1 receptor agonists exert the same effects as DPP4 inhibitors and, in addition, SLOW gastric emptying and DECREASE food intake, which can promote weight loss
GLP-1 is deficient in patients with type 2 diabetes.
