Pancreas Flashcards
which cells of the pancreas elicit endocrine functions
Islets of Langerhans
- alpha: glucagon
- beta: insulin
- delta: somatostatin
- epsilon: ghrelin
- F-cells (PP cells): pancreatic poylpetide
why is the blood supply of the pancreas so unique
there is hepatic artery branching from aortic artery and splenic and mesenteric veins to portal vein meaning there is a quick communication between pancreas and liver
glucagon, somatostatin, pancreatic polypeptide and ghrelin are produced by _____ and _____
islets of pancreases and cells of the gastrointestinal mucosa
glucagon stimulates _____ and ____ inhibits insulin, glucagon and pancreatic polypeptide and
somatostatin
somatostatin
structure of insulin
51 amino acids - 2 peptide chains connected by 2 disulphide bridges
_____ is a better measure of insulin secretion from the islets as it is metabolized in the _____
C-peptide
metabolized in kidney
steps of glucagon synthesis
preproglucagon processed to proglucagon to glucagon
composition of beta cells
made up of 5000-8000 granules of which the younger ones are found deeper in cytoplasm but more mobile than older granules. older granules are degraded intracellularly -> intracellular degradation of insulin
insulin is found in free form in beta cells. true or false
false, they are stored in granules
how is insulin released from beta-cells
- hexokinase serves as a glucose sensor
- uptake of glucose by type 2 facilitative glucose transporter GLUT2
- aerobic glycolysis and increase in ATP/ADP ration
- inhibition of ATP-sensitive K+ channels -> reduction of K+ efflux -> membrane depolarization
- opening of voltage gated Ca2+ channels
- increase in intracellular Ca2+ triggers exocytosis of insulin containing granules
- opening of Ca2+ activated potassium channels leads to the repolarization of the membrane
- metabolic coupling factors generated during glucose metabolism facilitates exocytosis and/or proinsulin synthesis [FFA, succinate]
- GLP-1 from intestine binds to GLP-1 receptors and trigger cAMP production -> potentiates amplification pathway, ion channels, and exocytosis
how is insulin secretion regulated neurally
the vagus nerve is the main neuronal coordinator of appetite control, digestion and metabolism -> it releases acetylcholine in the pancreases and stimulates insulin release
which are the major factors that stimulate the release of insulin from beta cells
- nutrients: glucose and amino acids [TG/FA]
- gastrointestinal hormones: gastrin, CCK, GIP, GLP-1, Secretin
- hormones: GH, glucagon
- autonomic nerves: cholinergic and beta adrenergic
which are the major factors that inhibit the release of insulin from beta cells
- hormones: adrenaline, cortisol, somatostatin
- autonomic nerves: alpha adrenergic
which are the major factors that stimulate the release of glucagon from alpha cells
- nutrients: hypoglycemia, amino acids arginine/alanine
- gastrointestinal hormones: gastrin, CCK, GIP
- hormones: growth hormone, adrenaline
- autonomic nerves: cholinergic and adrenergic
which are the major factors that inhibit the release of glucagon from alpha cells
- nutrients: free fatty acids
- gastrointestinal hormones: GLP-1, secretin
- hormones: insulin, somatostatin
what are the three sources of glucose throughout the day
dietary, gluconeogenesis, glycogenolysis
glucose levels are regulated by hormones that affect ____ and _____
appetite and cell metabolism
what kind of receptor is the glucagon receptor and which singling pathways are activated upon binding
GPCR -> PLC-IP3 pathway and cAMP-PKA pathway
what are the effects of glucagon upon binding
decreased glycolysis decreased glycogenesis increased gluconeogenesis increased glycogenolysis => increased glucose in circulation
how is glycogenesis regulated
- insulin binds to insulin receptor which has intrinsic tyrosine kinase activity
- phosphorylation of IRS-1
- Binding of IRS-1-P to PI3K
- PIP2 -> PIP3
- PKB phosphorylates GSK3 rendering it inactive
- glycogen synthase remains active
inactive glycogen synthase is activated by ____ and remains inactive with
insulin - activates
glucagon and epinephrine - inactive
____ acts on myocytes and ____ acts on hepatocytes in glycogenolysis regulation
epinephrine - myocytes
glucagon - hepatocytes
glycogenolysis is carried out using ____ receptor and ____ patwhay
GPCR
cAMP-PKA pathway
what are the outcomes of glycogenolysis stimulation in myocytes? in hepatocytes?
- myocytes: Glycogen -> glucose 1-phosphate -> glycolysis -> muscle contraction
- hepatocyte: glycogen -> glucose 1-phosphate -> GLUT2 -> glucose in blood
which are the major hormones that control blood glucose
insulin and glucagon
which are other important hormones, other than insulin and glucagon, which control blood glucose
- epineprhine
- cortisol
- GH
- thyroid hormone
- secretin
- cholecystokinin
____ is the only hormone that lowers blood glucose
insulin
what are the mechanisms involved in terms of regulation of blood glucose in the fasted state
low blood glucose -> restore blood glucose with glucagon, adrenaline or glucocorticoids
in the muscle: protein -> amino acids
in the liver: amino acids converted to glucose, glycogen -> glucose => increase in blood glucose
in adipose tissue: TG -> FA -> liver -> FA converted to keotone bodies in liver
post meal, what are the mechanisms involved in lowering BG
insulin
Gut -> increased BG:
glucose goes to: muscle [glu -> gly], liver [glu -> gly and TG], adipose [glu -> TG]
how does insulin have an anabolic effect
synthesis of protein in muscle, lipids in adipose tissue, glycogen in muscle
what are the 3 target tissues of insulin
liver, muscle, adipose tissue
glucagon increased many catabolic processes particularly in the ____
liver [production of glucose]
insulin is only released post-meal. true or false
false, it is continuously secreted to enable peripheral tissues to uptake glucose
insulin increases _____, _____ and ____ but decreases _____ and _____ in the liver
increases glycolysis, lipid accumulation and glycogen synthesis but decreases glycogenolysis and gluconeogenesis
glucagon increases _____ but decreases _____ and _____ in the liver
increases glycogenolysis but decreases glycogen synthesis and glycolysis
muscles lacks ____ receptor
glucagon
why does glycolysis increases in muscle tissue in effect to epinephrine [low blood glucose]
the muscle isoform pyruvate kinase is not phosphorylate by PKA therefore it remains active, increasing glycolysis
insulin increases _____ and _____ but decreases ______ in adipocytes
increases glycolysis and lipogenesis but decreases lipolysis
insulin increases _____ and _____ in muscle tissue
glycogenesis and glycolysis
usually, insulin has an anabolic effect. however, in the liver, muscle and adipose tissue there is an increase in _____ and _____ due to an increased activity in the enzymes ______ and _____
glycolysis and acetyl-CoA production due to an increased activity in the enzyme pyruvate dehydrogenase complex and PFK-1
glucose is taken up by _____ in muscle and adipose tissue which is stimulated by insulin
GLUT4
insulin promotes glucose uptake in the liver by stimulating ______ and this promotes phosphorylation of glucose to form glucose 6-phosphate. what are the consequences of this
glucokinase/hexokinase -> unphosphorylated Glucose concentration inside cell goes down and is lower compared to extracellular concentration of unphosphorylated glucose
Hepatocytes have GLUT 2 -> glucose transported down concentration gradient => facilitated transport of glucose into hepatocyte
what are the 9 steps in fuel metabolism in prolonged fasting
- protein degradation from muscle yield glycogenic AA
- urea [from amino group of AA] is exported to the kidney and excreted in urine
- citric acid cycle intermediate (oxaloacetate) is diverted to gluconeogenesis
- glucose is exported via the blood stream to the brain
- FA (from adipose tissue) are oxidized as fuel, producing acetyl-coA
- lack of oxaloacetate prevents acetyl-coA entry into the citric acid cycle; acetyl-coA accumulates
- acetyl-coA accumulation favours ketone body synthesis
- ketone bodies are exported via the bloodstream to the brain which uses them as duel
- excess ketone bodies end up in urine
alpha-MSH neurons regulate neurons that stimulate ____
anorexia and catabolism
NPY neurons stimulate ____
orexin and anabolism
NPY neurons are stimulated by ____ and inhibited by _____
stimulated by ghrelin (hunger signal) an inhibited by insulin, PYY and GLP-1 (satiety signals)
alpha-MSH neurons are stimulated by ____
leptin (satiety hormone)
what are the normal, prediabetes, diabetes values of blood glucose
normal: 4-6.1 mmol/L
prediabetes: 6.1-7.8 mol/L
diabetes: 7.8-11.1 mmol/L
what are the normal and prediabetic levels of glycated hemoglobin HbA1c
<5.7% and 5.7-6.4%
what are the two forms of diabetes and their characteristics
Type 1: insufficient production of insulin usually due to autoimmune destruction of beta cells [usually develops early in life and used to be called insulin-dependent or juvenile diabetes]
Type 2: insulin resistance when cells don’t respond appropriately to insulin, usually develops in late adulthood and is usually associated with obesity
what are some endocrinopathies that could cause diabetes
- Cushing’s syndrome
- acromegaly
- glucagonoma
- hyperthyroidism
- somatostatinoma
what are the pre-receptor causes of insulin resistance
- antibodies against insulin
- mutant insulin (A-C and B-C insulin)
what are the receptor causes of insulin resistance
- reduced INSR expression
- reduced affinity for insulin
- impaired tyrosine-kinase activity
- INSR antibodies
what are the common symptoms of type 1 and type 2 diabetes
elevated blood glucose which triggers excessive urination and thirst to dilute the glucose
what are type 1 diabetes symptoms
fat breakdown is accelerated leading to high production of ketone bodies and ketoacidosis
what are the consequences of ketoacidosis caused by high ketone bodies in type 1 diabetes
the raise in [H+] activates the bicarbonate buffering system which causes altered breathing and the breakdown of ketone body acetoacetate produces acetone -> expelled via the breath
untreated diabetes leads to dramatic ______
weight loss
what are the long-term effects of elevated blood sugar
proteins can be glycosylated [enzyme regulated] and excessive glucose causes glycation [non-enzymatic] + increased risk of cardiovascular disease, renal failure and damage to small blood vessels and nerves
what are the consequences of glycated hemoglobin
it compromises O2 delivery especially in extremities + impaired injury repair
what are symptoms associated with type 2 diabetes along with insulin resistance
- abdominal obesity
- high triglycerides
- low HDL
- high BP
- elevated blood glucose
what is the first line treatment for diabetes
weight loss 5-10% [highly effective for T2DM]
what are the effects of weight loss to treating diabetes
it reduces insulin resistance, hepatic glucose production and fasting hyperinsulinemia
which medications can be given to treat diabetes
- Metformin
- Thiazolidinediones
- Sulfonylureas
- Meglitinides
- GLP-1 receptor agonist
- alpha-glucosidase inhibitors
what is the mode of action of metformin and thiazolidinediones
increase insulin sensitivity and decrease glucose output by the liver
what is the mode of action of Sulfonylureas, Meglitinides and GLP-1 receptor agonist
promote insulin secretion from the pancreas
what is the mode of action of alpha-glucosidase inhibitors
decrease absorption of carbohydrates from the intestine
why is fatty liver disorder a consequence of diabetes
due to insulin resistance or deficiency, there is increased lipolysis in the adipose tissue. The FFA enter the liver causing increased triglyceride synthesis and decreased TG secretion therefore causing fatty liver
what is the “lipid burden” hypothesis
path from obesity to T2D
adipocytes become packed and unable to accommodate more TG leading to FA in the blood which enters muscle and liver creating lipid droplets.
there is a pro-inflammatory stage when the enlarged adipocytes produce monocyte chemotaxis protein MCP-1 which causes macrophages to infiltrate the adipose tissue and produce TNF-alpha, favouring export of FA to muscle forming ectopic lipid.
Ectopic lipid interferes with GLUT4 movement to the myocyte surface producing insulin resistance -> diabetes
