Diabetic Adaptation 1 Flashcards
What is a normal fasting glucose
4-5.9mM - maintained by glucagon
What is a normal feeding glucose
7.8mM - dropped by insulin
How does insulin lower blood glucose
Drops glucose production by liver
Increases glucose uptake in adipose (to make more fat) and skeletal muscle (for energy)
Give some positive actions of insulin
Glucose uptake
glycolysis
Glycogen synthesis
Protein synthesis
Ion uptake (K)
Give some negative actions of insulin
Gluconeogensis
Glucogenolysis
Lipolysis
Ketogenesis
Proteolysis
Define diabetes mellitus
Metabolic disease characterized by hyperglycemia resulting in defects in insulin secretion due to beta cell destruction (DM1) or insulin resistance (DM2) or both.
What is associated with diabetes type 2
Obesity
How was insulin discovered
Minkowski removed pancreas of dog in 1899 which caused symptoms of diabetes
1921 - banting, best and macleod made an extract of the pancreas and cured dog by injecting back into pancreas
Cured boy in 1922 with DM1
What causes ketoacidosis
Anti-lipolytic effect of insulin is lost resulting in increase of serum free fatty acids into ketones.
Why does diabetes cause CVD
- Chronic low grade inflammation due to dyslipidemia and hyperglycaemia
- Hypertension and endothelial dysfunction due to nitric oxide decrease
- Both causing –> Atherosclerosis
How is insulin found
Preformed granules in beta cells to allow insulin release at any time
What is PDX1 (pancreatic and duodenal homeo-box 1)
A transcription factor that is required for all stages of pancreatic B cell development and mature B cell function and survival
Required for all stages of B cell function and maturation.
What is FoxA2/HNF3-beta
Works with PDX1 and acts as a pioneer factor to regulate PDX1 gene expression
What is MafB
Required in late development after PDX1 and FoxA2 but is not present n the mature B cell.
Restricted to adult alpha cells - glucagon
What is MafA and its role
Found exclusively in developing and adult Beta cells. Required for -
- Structure of islets
- Ratio of B cells: A cells
- Glucose stimulated insulin secretion
Gene expression of - Glut2 - beta cell glucose transporter
Where does glucagon act
On liver for glycogenolysis (glycogen break down into glucose) and gluconeogenesis (make more glucose)
What regulates glucose release
Glucose-6-phosphate
How does glucose enter the beta cell
Glucose entering the beta cell via glut2 transporters (high Km - no matter how high glucose conc goes it can keep transporting).
What happens to glucose inside the cell
Converted to glucose-6-phosphate by glucokinase.
What happens to G-6-P
Glycolysis and mitochondrial metabolism causing an increase in ATP/ADP ratio.
What 2 things does a rise in this ATP/ADP ratio do
Depolarise cell –> which releases insulin
How does cell depolarisation release insulin
The ATP/ADP ratio leads to activation of the sulphonylurea receptor 1 (SUR1) protein
Lead to closure of the adjacent potassium ATP channel (potassium inward rectifier [KIR] 6·2 channel).
The closure of the potassium channels will alter the membrane potential and open calcium channels.
This triggers the release of preformed insulin-containing granules
What is the 2 roles of GLUT2
Glucose stimulated insulin secretion from beta cells of pancreas islets.
Controls entry and exit of glucose in liver.
What is the role of GLUT4
An insulin RESPONSIVE glucose transporter.
Found in heart, skeletal, muscle, adipose tissue and brain to uptake glucose.
On a molecular level, what causes type 2 diabetes
Results from impaired insulin secretion caused by failure of the beta-cell K ATP channel to close in response to increased intracellular ATP.
How do sulfonylureas treat type 2 diabetes
Close the K ATP channel by an ATP-independent route.
What SNP has been noted in DM2
In the KCNJ11 and ABCC8 genes which code for the sulfonlyurea protein and K ATP channel. this single nucleotide polymorphism limits insulin release
What happens with a KO of the KCNJ11 gene in mice
Koster 2000
Causes overactive K ATP channel and therefore develops severe hyperglycemia with hypoinsulinaemia and severe ketoacidosis.
What did pearson et al in 2006 discover about Kir6.2 mutaitons
Switched patients to sulfonlyureas for better response.
What is the role of incretin hormones
Released from gut during digestion and can enter bloodstream and regulate beta cell function
Give 2 examples of incretin hormones
GLP-1
GIP
What do DPP4 inhibitors do (sitagliptin)
Drug that can break down DPP4 and increase GLP-1 as DPP4 is a GLP-1 inhibtor.
What stimulates GLP 1
Glucose, fatty acids, amino acids
Vagus nerve, insulin
What inhibits GLP-1
Somatostatin
What is the main purpose of incretins
To increase intracellular calcium in beta cells which therefore triggers more insulin release
Where do incretins bind
G protein coupled receptors to act on adenylyl cyclase
This activates cAMP which increases PKA and Epac
Which increases intracellular calcium levels and in turn increase insulin release
Is GLP-1 secretion deficient in diabetics
No, not in any state - Baltimore longitudinal study of aging.
What is exenatides/liraglutide role
GLP-1R agonist/GLP-1 analogs.
How do tyrosine kinase receptors work
WIDER READING – Saltiel 2001
Have two alpha and two beta subunit which function as allosteric enzymes where the alpha subunits inhibit the activity of the beta subunits.
This inhibition of Beta subunits causes transphorylation of these subunits which lets the receptor undergo conformational change and increase activity.
How are GLUT4 vesicles excytosed when insulin binds
WIDER READING – Pessin 1999
Unknown but believed to be a microtubule network
What protein is important in GLUT4 docking
WIDER READING – Pessin 1999
v-SNARE protein – VAMP2 interacts with syntaxin 4 on GLUT4 vesicles during docking and allows fusion to the plasma membrane.
What happens with a cre-loxP conditional gene knockout of GLUT4 if the muscle of mice
WIDER READING – KIM et al 2000
Have normal glucose tolerance as a shift of the excess glucose is uptaken in the fat causing an increase in adipose tissue mass and circulating free fatty-acids and triglycerides.
What happened with V cells Specific insulin receptor knockout in pancreas and brain-specific insulin knockout in brain occurred
WIDER READING – Bruning et al 2000
Defect in glucose stimulated insulin release and an increased food intake ability with mild adiposity. Showing that insulin resistance in the B cell and other body tissues combine to produce the pathophhsiology of DM2
In those with diabetes that are insulin deficient, what was found to be their most common complication
WIDER READING – Ahlqwist 2018
Diabetic retinopathy – shows the vast complexity and varied presentation of those with diabetes.
In those with diabetes that are insulin resistant what was found to be their most common complication
WIDER READING – Ahlqwist 2018
Diabetic nephropathy – shows the vast complexity and varied presentation of those with diabetes.
How does excess fat cause insulin resistance
WIDER READING – Kamei et al 2006
Adipocytes secrete chemokine MCP-1 which drives macrophage accumulation into adipose tissues and this induces insulin resistance in them.
Confirmed with MCP-2 knockout in mice improves insulin sensitivity in mice – Kanda et al 2006
What role do toll-like receptors (TLR) have in insulin resistance
WIDER READING - shi et al 2006
TLR2 and TLR4 can be activated by saturated fatty acids which indicate that these receptors play a role in obesity driven inflammation. Confirmed with mice as knockout of these TLRs protected from obesity and obesity associated insulin resistance
What is the incretin effect
WIDER READING – Nauck 2017
A 2-3 fold increase in insulin secretion in response to oral glucose compared to IV glucose which is diminished in type 2 diabetics
What happens to the incretin effect in T2DM
WIDER READING – Nauck 2017
Diminished or no longer present because of substantially reduced effectiveness of GIP on the diabetic endocrine pancreas.
Why is GLP-1 so important in type 2 diabetic Rx
WIDER READING – Nauck 2017
GLP-1s insulinotropic and glucagonostatic effects are still present in diabetics and therefore can significantly lower plasma glucose and improves glycaemic control.
Other than the effects on blood glucose lowering, what other benefits do GLP-1 provide to diabetics
WIDER READING – Nauck 2017
Reduce appetite and food intake weight loss
Also further backed up by the fact – GLP-1 receptors are found in the hypothalamus
What is the role of GIP (incretin) in fat storage and how was it confirmed
WIDER READING – Miyawaki 2008
GIP receptor knockout mice don’t develop obesity with hypercaloric feeding
GIP also known to induce lipoprotein lipase – enzyme that releases fatty acids from chylomicron triglycerides in adipose tissue thus promotes the elimination of chylomicron triglycerides
E.g. – GIP believed to promote fat storage in subcutaneous tissue
What does GIP receptor knockout do to beta cells
WIDER READING – Campbell 2016
Increased apoptosis of them
What do mice overexpressing GLUT4 in adipocytes show
WIDER READING – Moraes-vieira 2016
Elevated adipose tissue lipogenesis and enhanced glucose tolerance despite being obese
What role does TNF-alpha play in obesity-related diabetes and how was this shown.
Wider reading – Gokhan 1994
TNF-alpha is a key mediator in insulin resistance – used a rat model for obesity and insulin resistance after neutralzing TNF-alpha and this resulted in a marked increase in insuline stimulated autophosphorylation of the insulin receptor as well as IRS-1 phosphorylation in muscle and fat of these rats restoring them to near lean levels. Also lowered plasma glucose and FFAs.
No effects seen on IRS-1 or IR in the liver.
Shows that – TNF-alpha inhibits the IR tyrosine kinase in muscle and fat which induces obesity-related diabetes.
