Energy Homeostasis and Type II Diabetes Mellitus (Week 12) Flashcards
Pancreatic islets compose what percentage of total pancreatic mass?
1%
In the pancreas, blood flows from the centre of the ______ to the periphery
islet
Alpha cells produce ________
glucagon
Beta cells produce _________
insulin
Delta cells produce __________
somatostatin
PP cells (aka F cells) produce __________
pancreatic polypeptide
Beta cells comprise what percent of an islet?
70%
Note: this is majority of the islet
Alpha cells comprise what percent of an islet?
20%
Delta cells comprise what percent of an islet?
5-10%
function of glucagon
acts on several tissues to make energy stored in glycogen and fat available for use via glycogenolysis and lipolysis
INCREASES blood glucose
function of insulin
acts on several tissues to cause entry of glucose into cells
DECREASES blood glucose
function of somatostatin
inhibits release of other islet cell hormones
True or False: Glucose homeostasis is part of a positive feedback loop
False
Negative feedback loop
If glucose drops below ______, then insulin secretion rapidly drops and epinephrine & glucagon secretion increase
3 mmol/L (50 mg/L)
True or False: Multiple hormones increase blood glucose, but only ONE hormone decreases blood glucose (i.e., insulin)
True
REVIEW: Where is insulin produced?
in the beta cells of the pancreas, within structures called the islets of Langerhans
Insulin synthesis begins with the transcription of _____________
the insulin gene (INS)
precursor to insulin
proinsulin
three domains that comprise proinsulin
A chain, B chain, and the connective C-peptide
Note: as the polypeptide chain is elongated, it folds into its three-dimensional structure
Where does proinsulin undergo post-translational modification, where it is cleaved into mature insulin and C-peptide?
the endoplasmic reticulum (ER) and Golgi apparatus
After processing, mature insulin is packaged into secretory vesicles along with enzymes and other regulatory proteins inside the vesicle. Insulin is then secreted into the bloodstream when ____________
blood glucose levels rise
While circulating the body, insulin can bind to insulin receptors on target cells such as?
muscle, fat, and liver cells
Insulin is a protein hormone, comprised of alpha and beta chains, connected by __________
disulfide bonds
Insulin is degraded by __________ in the liver, kidney, and other tissues
insulinase
Although not active, __________ is released alongside insulin, therefore is a good measure to determine how much endogenous insulin is secreted by diabetics
C-peptide
What is the mechanism that triggers the release of insulin?
- low blood glucose concentrations change the intracellular ratio of ADP:ATP (more ADP than ATP)
- this changes the membrane potential (via changing the potassium conductance) which leads to an influx of Calcium and insulin release
Ex: low glucose –> increased ADP:ATP ratio detected –> K+ channels stay closed –> leads to depolarization –> Ca 2+ channels open and Ca 2+ enters –> signals exocytosis of insulin-containing vesicles
REVIEW: What does the PI3K pathway activate?
Akt and mTOR activation
Binding of insulin to the insulin receptor leads to dimerization of the receptor and the activation of _________
protein tyrosine kinase
Note: following this is a cascade of phosphorylation events
Activated protein/receptor tyrosine kinase in response to insulin binding, leads to activation of IRS-1 and IRS-2. What does IRS further activate?
IRS activates Ras –> activates Raf –> activates MAPK and MEK –> protein synthesis
What can happen when cells are chronically exposed to high levels of insulin?
insulin receptor desensitization
(reduce # of insulin receptors expressed and down-regulation of some signalling pathways distal to receptor activation)
What inhibits insulin secretion?
hormones:
- somatostatin
- epinephrine
- leptin
sympathetic nervous system:
- both epinephrine and norepinephrine
What stimulates insulin secretion?
nutrients in bloodstream:
- glucose (major)
- amino acids (arg, lys)
- FFAs
hormonal signals:
- incretins (CCK, GIP, GLP-1; released in response to food)
- parasympathetic innervation (from cephalic phase of digestion)
- growth hormone
True or False: Activation of the sympathetic nervous system (SNS) results in net inhibition of insulin secretion
True
True or False: IV glucose will not cause incretin release
True
This is because incretin is released from the intestines in response to nutrients in the GI tract, but IV glucose bypasses this = thus no incretin release and much lower insulin spike (less insulin released)
What metabolic processes in the liver increase after a 24 hr fast?
- glycogenolysis
- gluconeogenesis
What metabolic processes in the liver increase a couple hours after a meal?
- glycogen synthesis
What metabolic processes in the liver decrease a couple hours after a meal?
- glycogenolysis
- gluconeogenesis
After a fast, lipids are _________ (mobilized/synthesized)
mobilized
After a meal, lipids are _________ (mobilized/synthesized)
synthesized
Glucose transport occurs _______ (up/down) its concentration gradient
down
(from high concentration after meals in the bloodstream, into cells where its concentration is lower)
True or False: Glucose can diffuse freely across the cell membrane
False
Due to its hydrophilic nature (vs. lipid-based structure of cell membranes), glucose requires specialized transport proteins embedded within the membrane to facilitate their movement across the membrane
family of proteins that facilitate glucose transport
glucose transporter proteins (GLUTs)
Note: There are several types, each with different tissue distributions and kinetic properties
Where is GLUT1 predominantly found?
brain, RBCs, placenta
(ensures basal glucose uptake)
Where is GLUT2 predominantly found?
liver, pancreas, kidneys
(participates in glucose sensing and hepatic glucose uptake)
Where is GLUT3 predominantly found?
neurons
(crucial role for glucose uptake in the brain)
Where is GLUT4 predominantly found?
skeletal muscle and adipose tissue
(GLUT4 is insulin-sensitive and plays a major role in post-prandial glucose uptake)
How does insulin regulate GLUT4?
insulin promotes translocation of GLUT4 transporters from intracellular vesicles to the cell membrane (thereby increasing glucose uptake into insulin-sensitive tissues)
True or False: Glucose transport via GLUTs usually involves facilitated diffusion, whereby glucose binds to the transporter and induces a conformational change, allowing it to be released on the other side
True
Which GLUT is important during exercise?
GLUT4
Which glucose transporters are insulin-independent?
SGLT-1 and SGLT-2 (intestine and kidneys); aka sodium-dependent glucose transporters
GLUT-1 and GLUT-3 (wide distribution)
GLUT-2 (liver and pancreas)
major insulin-dependent glucose transporter
GLUT-4 (skeletal muscle, cardiac muscle, adipose tissue)
How does insulin affect the liver?
- increase glucose uptake from bloodstream –> glucokinase activation (conversion of glucose into G6P)
- increased glucose storage (increased glycogenesis; decreased glycogenolysis) and glucose use (increased glycolysis for energy)
- increased fatty acid synthesis and VLDL formation
- decreased ketogenesis (gluconeogenesis and beta-oxidation is inhibited)
- increased protein synthesis and decreased urea cycle activity
How does insulin affect muscle?
- increased glucose uptake (via increased GLUT-4 availability)
- increased glucose use (glycolysis) and storage (increased glycogenesis; decreased glycogenolysis)
- increased amino acid uptake
- increased protein synthesis, decreased proteolysis
- increased Na-K ATPase activity
How does insulin affect adipose tissue?
- increased glucose uptake (via increased GLUT-4 availability)
- increased glucose use (glycolysis)
- increased TG production (esterification of fats)
- decreased lipolysis (inhibition of hormone-sensitive lipase)
- increases removal of lipids from VLDL and chylomicrons –> into the adipocyte
Depending on how the peptide chain is cleaved, proglucagon may yield what?
- glucagon-related polypeptide (GRPP)
- glucagon
- IP-1
- GLP-1
- IP-2
- GLP-2
Proteases in the __________ cells cleave proglucagon at points that yield GRPP, glucagon, and C-terminal fragment
pancreatic alpha cells
Proteases in __________ cleave proglucagon at points that yield GLP-1 and GLP-2 (aka incretins)
neuroendocrine cells in the intestine
What stimulates glucagon secretion?
- drop in blood glucose
- rise in serum amino acids (arg, ala)
- cortisol
- sympathetic nervous system stimulation
- exercise, stress
What inhibits glucagon secretion?
- rise in blood glucose
- somatostatin
How does glucagon affect the liver?
1) increased glucose output to other tissues:
- increased glycogenolysis, decreased glycogenesis
- increased gluconeogenesis, decreased glycolysis
- increased uptake of gluconeogenic precursors (ala, glu, pyruvate, lactate)
2) increased beta-oxidation
3) increased ketogenesis
4) increased urea cycle activity
How does glucagon affect muscle?
no direct affects; glucose uptake and use decreased
How does glucagon affect adipose tissue?
stimulation of hormone-sensitive lipase (HSL); promotes lipolysis and release of free fatty acids
a high insulin/glucagon ratio indicates a ___________ (anabolic/catabolic) state
anabolic state
(nutrient incorporation into tissue)
a low insulin/glucagon ratio indicates a __________ (anabolic/catabolic) state
catabolic state
(nutrient mobilization)
True or False: Insulin fluctuates much more than glucagon
True
a polypeptide hormone produced in pancreatic delta cells and GI tract, that acts predominantly in a paracrine fashion in the pancreas
somatostatin
Somatostatin tends to _______ (increase/decrease) the secretion of BOTH insulin and glucagon
decrease
What stimulates the release of somatostatin?
- stimulators of insulin release (increase in serum glucose, increase in serum amino acids, increase in serum fatty acids)
- secretin
- CCK
How many islets of Langerhans do we have?
~ 1 million
Why is urine “sweet” in diabetes mellitus?
because the body is having trouble regulating sugar; we shouldn’t be excreting sugar but because there is so much, they kidneys cannot reabsorb all of it and we have to get rid of the excess –> leading to frequent urination and sweet urine
How is diabetes diagnosed?
- random blood glucose (RBG) > 11.1mmol w/ classic signs and symptoms (only has to be observed once)
- fasting blood glucose (FBG) > 7.0mmol on more than one occasion
- abnormal oral glucose tolerance test (OGTT) > 11.1 mmol, 1 hour after ingestion of glucose on more than one occasion
- hemoglobin A1c (HbA1c) > 6.5%
What is a normal fasting blood glucose (FBG) concentration?
< 5.6 mmol
Which races are at higher risk (1.5-2x) of developing diabetes?
- Aboriginal people (especially Pima aboriginals)
- Hispanics
- African ancestry
What type of diabetes is an autoimmune disease characterized by pancreatic cell destruction with an onset usually in childhood (but sometimes early adulthood)?
type 1 diabetes
What type of diabetes is characterized by a combination of peripheral resistance to insulin action and an inadequate secretory response by beta cells?
type 2 diabetes
What percentage of diabetes is type 1?
5-10%
What percentage of diabetes is type 2?
90-95%
When is type 2 diabetes usually diagnosed?
> 30 yrs
True or False: Type II diabetes is characterized by initial inadequate insulin secretion response followed by insulin resistance
False
It’s characterized by initial insulin resistance, followed by inadequate or almost absent insulin secretion
What percentage of people with diabetes are obese?
80%
True or False: There is a significant genetic component in type 2 diabetes mellitus, although “proper diet and adequate activity” can reduce the progression of the disease
True
What are some notable genes that are associated with an increased risk for type 2 diabetes?
- TCF7L2 gene
- PPAR receptor
- IRS genes
most important environmental risk factor for type 2 diabetes
obesity
Note: central obesity = more crucial
True or False: Progression to overt T2DM appears to require impaired insulin secretion, which seems to arise after a long history of insulin resistance, thought to be related to “islet cell burnout” after years of increased insulin secretion
True
Lack of insulin secretion results in excessive activity of lipoprotein lipase, which leads to increased ________
free fatty acids
When energy demand is high (e.g., fasting or during exercise), ____________ are released from adipose tissue via lipolysis and when intracellular concentrations build up, this causes serine phosphorylation of insulin receptors, inactivating the receptors, which leads to insulin resistance
non-esterified fatty acids (NEFA or FFA)
Note: same as free fatty acids
protein hormones from fat cells that can modify sensitivity of insulin receptor (i.e., increase insulin resistance)
adipokines
examples of anti-hyperglycemic adipokines
leptin, adiponectin
examples of hyperglycemic adipokines
resistin, retinol-binding protein 4
inflammation and reduction in the number and size of islets
type 1 or type 2 diabetes?
type 1 diabetes
Recall: type 1 diabetes = autoimmune, therefore makes sense for there to be inflammation
reduction in islet cell mass as well as amyloid deposition around beta cells, + no inflammation
type 1 or type 2 diabetes?
type 2 diabetes
What does persistent hyperglycemia lead to?
advanced glycation end products (AGEs)
AGEs can bind to R-AGE on macrophages, T cells, smooth muscle cells, and endothelial cells
leads to release of pro-inflammatory cytokines and growth factors, generation of ROS in endothelial cells, increased procoagulant activity, and enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
all of this can lead to decreased artery elasticity, narrowing of smaller arteries, deposition of atherosclerotic plaques, and increased susceptibility to coagulation (clots)
metabolic products of glucose non-enzymatically linked to amino groups of intra and extracellular proteins
advanced glycation end products (AGEs)
True or False: A hallmark of diabetic macrovascular disease is accelerated atherosclerosis
True
True or False: Diabetic atherosclerosis looks a lot different than non-diabetic atherosclerosis and is about the same in severity of symptoms and age of onset
False
Diabetic atherosclerosis looks the SAME as non-diabetic atherosclerosis, but MORE SEVERE and with an EARLIER onset
most common cause of death in diabetics
myocardial infarction (MI)
(caused by atherosclerosis of the coronary arteries)
vascular lesion associated with hypertension more prevalent and severe in diabetics than in non-diabetics
hyaline arteriolosclerosis
diffuse thickening of basement membranes, prominent in capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla
(aka damage to small blood vessels)
diabetic microangiopathy
loss of small and large axons, myelinated and unmyelinated
(diabetic) neuropathy
What are the clinical features of type 2 diabetes?
- insidious onset
- usually asymptomatic initially
- 80% obese
- diabetic ketoacidosis (DKA) is rare; but may lead to severe dehydration and impaired level of consciousness
- slowly developing peripheral neuropathy, impaired wound healing, impaired vision
- atherosclerosis usually asymptomatic until angina or heart attack occurs
- renal failure usually aymptomatic
- acanthosis nigricans (hyper-pigmented velvety patches of skin in axillary regions and neck)
