LM 4.1: Insulin and Glucagon

Question 1

what hormones involved in glucose homeostasis does the pancreas release?

Answer 1

1. insulin from β cells

2. glucagon

Question 2

which organs are involved in glucose homeostasis?

Answer 2

1. pancreas
2. liver
3. muscles
4. muscles
5. fat cells
6. brain

Question 3

what is the general role that the liver plays in glucose homeostasis?

Answer 3

it takes up glucose when levels are high and releases glucose when levels are low

it also stores glucose in chains as glycogen

Question 4

what is the general role that the muscles plays in glucose homeostasis?

Answer 4

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

Question 5

what is the general role that the fat cells plays in glucose homeostasis?

Answer 5

fat cells take up glucose when insulin is present

fat cells use glucose to make more fat

Question 6

what is the general role that the brain plays in glucose homeostasis?

Answer 6

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

Question 7

what are the 2 functional portions of the pancreas?

Answer 7

1. exocrine

produces enzymes that get secreted into the pancreatic duct to help with food digestion

2. endocrine

islets of Langerhans (alpha, beta, delta) release hormones like insulin and glucagon into the blood stream

Question 8

what portion of the islets of Langerhans are alpha vs. beta vs. delta vs. F cells? what do each of them secrete?

Answer 8

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%)

Question 9

what is the anatomical orientation of all the cells in one islet of Langerhans?

Answer 9

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

Question 10

how do the islets of Langerhans communicate?

Answer 10

islet cells communicate via gap junctions or via paracrine secretion and signaling

Question 11

what is the function of alpha cells?

Answer 11

synthesize and secrete glucagon to elevate glucose levels in blood

Question 12

what is a glucagonoma?

Answer 12

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)

Question 13

which clinical condition is associated with alpha cells?

Answer 13

glucagonoma

Question 14

which clinical condition is associated with beta cells?

Answer 14

type I and II DM

Question 15

what is type I DM?

Answer 15

an absolute insulin deficient condition that follows T-cell mediated destruction of β cells

the diagnosis is suggested by presence of pancreatic autoantibodies

Question 16

what is type II DM?

Answer 16

characterized by hyperglycemia and insulin resistance, but also relative impairment in insulin secretion

Question 17

what is the function of somatostatin?

Answer 17

inhibits secretion of:

1. insulin
2. glucagon
3. gastrin
4. GH

Question 18

what is the clinical condition associated with delta cells?

Answer 18

somatostatinoma

Question 19

what is somatostatinoma?

Answer 19

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

Question 20

how do you diagnose a somatostatinoma?

Answer 20

presence of a fasting plasma somatostatin level exceeding 30 pg/mL

Question 21

what is the function of γ cells?

Answer 21

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

Question 22

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?

Answer 22

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

Question 23

what is the general function of insulin?

Answer 23

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

Question 24

what is the general function of glucagon?

Answer 24

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

Question 25

what is the structure of the insulin receptor?

Answer 25

the insulin receptor is composed of two extracellular α subunits and two transmembrane β subunits linked together by disulphide bonds

Question 26

what stimulates and inhibits insulin secretion?

Answer 26

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

Question 27

what is function of GLUT1 and where is it found?

Answer 27

1. brain 2. kidney 3. placenta 4. RBCs uptake of glucose

Question 28

what is function of GLUT2 and where is it found?

Answer 28

1. liver 2. pancreatic β cells 3. small intestine 4. kidney rapid uptake and release of glucose

Question 29

what is function of GLUT3 and where is it found?

Answer 29

1. brain 2. kidney 3. placenta uptake of glucose

Question 30

what is function of GLUT4 and where is it found?

Answer 30

1. heart 2. skeletal muscles 3. adipose tissue insulin stimulated uptake of glucose

Question 31

what is function of GLUT5 and where is it found?

Answer 31

small intestine absorption of glucose

Question 32

what is function of SGLT-1 and where is it found?

Answer 32

1. small intestine 2. kidney active uptake and reabsorption of glucose

Question 33

which glucose transporter does insulin regulate? how does it do it?

Answer 33

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

Question 34

what causes the release of insulin from β-cells?

Answer 34

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

Question 35

what type of receptor is the insulin receptor?

Answer 35

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

Question 36

what happens when insulin binds to the insulin receptor?

Answer 36

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

Question 37

what pathways does insulin activate once it binds to an insulin receptor?

Answer 37

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 1. 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. 2. 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

Question 38

what are the overall actions of insulin on the liver, skeletal muscle and adipose tissue?

Answer 38

1. striated muscle: promotes the uptake of glucose, glycogen synthesis and protein synthesis 2. adipose tissue: promotes glucose uptake, increases lipogenesis and inhibits lipoprotein lipase which decreases lipoplysis 3. liver: promotes lipogenesis and glycogen synthesis while suppressing gluconeogenesis

Question 39

what is the function of glucagon?

Answer 39

increases blood glucose by: 1. triggering glycogen breakdown in the live aka glycogenlysis 2. activates glucose production pathways through gluconeogeneisis 3. 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 4. AA are taken up by the liver and used in gluconeogenesis

Question 40

what activates glucagon secretion?

Answer 40

1. sympathetic activity/epinephrine 2. secretin 3. CCK 4. elevated AA 5. low glucose

Question 41

what inhibits glucagon secretion?

Answer 41

1. parasympathetic activity 2. insulin 3. high blood glucose

Question 42

what happens when glucagon binds to its receptor?

Answer 42

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 2. 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

Question 43

what is the major abnormality involved in the pathogenesis of type II DM?

Answer 43

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

Question 44

what are incretin hormones? what are the 2 primary incretin hormones?

Answer 44

1. GIP 2. 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

Question 45

what is the pathway through which GIP and GLP1 stimulate insulin secretion?

Answer 45

1. they bind to their specific GPCR receptors which leads to activation of adenylate cyclase and subsequent elevation of intracellular cAMP 2. increased cAMP then activates protein kinase A (PKA) and exchange protein activated by cAMP2 (EPAC2)/cAMP-guanine nucleotide exchange factor (GEF)II 3. 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 4. 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 5. 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

Question 46

what is the non-insulin involved effect of GIP and GLP1 on pancreatic β cells?

Answer 46

1. GIP stimulates glucagon secretion 2. 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 3. GIP and GLP1 promote promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass

Question 47

how are GIP and GLP1 broken down?

Answer 47

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

Question 48

what are GIP levels in T2DM patients?

Answer 48

GIP is involved in fat accumulation and fats strongly enhance GIP secretion GIP levels are high in obese type 2 diabetes patients

Question 49

what is the function of GIP?

Answer 49

1. increased bone formation 2. increased fat accumulation 3. increased memory 4. increased insulin 5. increased glucagon 6. decreased B cell apoptosis/increased B cell proliferation 7. decreased gastric acid secretion

Question 50

what is the function of GLP-1?

Answer 50

1. increased memory 2. decreased food intake 3. increased insulin 4. decreased glucagon 5. decreased B cell apoptosis/increased B cell proliferation 6. decreased gastric emptying 7. increased cardioprotection 8. increased CO

Question 51

how is GLP1 used medically for obesity?

Answer 51

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

Question 52

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

Answer 52

1. hepatic glucose output 2. 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.