Diabetes and Insulin Flashcards
What is the main function of insulin and what metabolic activities does it suppress?
stimulates the uptake of glucose into cells and out of systemic circulation
suppresses:
- hepatic gluconeogenesis
(generation of glucose from non-carbohydrate sources)
- gylcogenolysis
(breakdown of glycogen to glucose in muscle and liver)
Islets of langerhans contain which cells and what do each cell secrete
Beta cells
- insulin
alpha cells
- glucagon
gamma cells
- somatostatin (regulates alpha and beta cells)
Epsilon cells
- grehlin (induced hunger)
PP or y cells
- pancreatic polypeptide (self-regulate pancreas secretions)
Beta cells produce crystallised insulin stored in granules and what else?
islet amyloid proteins
e.g. amylin
- secreted with insulin
- produce amyloid fibrils
What chromosome is the insulin gene on and what are the parts of the gene?
Chromosome 11
segments:
- insulin coding sequence for A and B chain
- sequence for C peptide
- untranslated regions (U)
- intervening sequence (I)
- signal peptide sequence (L)
What does the functional insulin molecule consist of
A chain (21 amino acids)
B chain (30 amino acids)
these are linked by disulphide bridges
What is the process of the insulin gene to its functional molecule?
- mRNA transcription
- excision of intervening sequence (I)
- Translation of mRNA (L,B,C,A) = pre-proinsulin
- transport of pre-proinsulin to lumen of ER
- U does not get translated
- signal peptide (L) removed = proinsulin
- only ABC chains left
- disulphide bonds and amino acid links hold the chain
together
- Proinsulin goes through golgi compartments
- endopeptidases cleave Lys-Arg and Arg-Arg bonds
- carboxypeptidases cleave off terminal Lys and Arg
amino acids
- C chain removed = final insulin molecule
- A and B chains held together by disulphide bonds
What regulates insulin transcription and translation
glucose and cAMP
How is insulin secreted by cells
- insulin co-precipitates with zinc ions and microcrystals in
secretory granules - microtubules transport granules to plasma membrane
- granules released by exocytosis
what type of peptide is insulin and what is its structure
peptide hormone
structure:
- 51 amino acids
- contains zinc ions
What is the primary stimulus for insulin secretion?
increase in blood glucose concentration which stimulates autonomic NS to secrete insulin
What is the pathway of glucose stimulated insulin secretion
- increase in blood glucose results in the uptake by pancreatic B cells through the GLUT2 transporter
- glucose is oxidised to pyruvate through glycolysis
- Pyruvate is oxidised in mito which increases ATP
- increased ATP closes the K+ ATP channel
- K+ remains in the cell = membrane depolarisation
- depolarisation opens the voltage sensitive Ca2+ channels which leads to an influx of Ca2+ ions
- rise in Ca2+ = migration of insulin-containing vesicles to plasma membrane
- insulin released into blood by exocytosis
What type of receptor is the insulin receptor and what is it’s structure
tyrosine kinase receptor
4 subunits
- two alpha
- two beta
When insulin binds to the insulin receptor what happens to the intracellular portion of the receptor?
autophosphorylation of tyrosine residues
this leads to the binding of insulin receptor substrate (IRS) phosphorylising IRS
What is the structure of IRS and what happens when it becomes phosphorylated?
Structure:
- PTB domain (binds to phosphorylated insulin receptor)
- pleckstrin homology (PH) domain (this can be phosphorylated)
When it becomes phosphorylated:
- docking site for other proteins (PI3K and Grb2)
Once IRS becomes phosphorylates what is the rest of the intracellular pathway
- PI3K converts PIP2 to PIP3
- PIP3 activates protein kinase B (PKB or Akt) and PDK1 through the PH domain
- PDK1 then phosphorylates PKB/Akt
- PKB/Akt gets released into cytosol and nucleus which activates other pathways
PKB/Akt activates other pathways? What do these pathways lead to?
- glucose uptake by glucose transporters (GLUT4)
- translocation of glucose transporters to
plasma membrane
- translocation of glucose transporters to
- protein synthesis
- stimulation of glycogen synthase (conversion of
glucose to glycogen for glucose storage)
Overview of insulin receptor pathway after insulin has bound
- phosphorylation of insulin receptor
- IRS-1 becomes phosphorylated
- IRS-1 binds to PI3K which phosphorylates
phospholipids from PIP2 to PIP3 - PIP3 recruits PDK1 and PKB/Akt to PM
- PKB/Akt release to activate signalling pathways
What is the pathway for glucose transport into cells once PKB/Akt releases into cytosol
- PKB/Akt phosphorylates AS160 (GTPase
activating protein) - phosphorylates AS160 binds to Rab proteins on
the outside of the GLUT4 vesicles - This removes the inhibition function of Rab
proteins - GLUT 4 vesicles transport to PM allowing
passive/facilitated diffusion of glucose
What are the effects of insulin?
- transmembrane transport of glucose and amino
acids - glycogen formation in liver and skeletal
muscles - conversion of glucose to triglycerides
- protein synthesis
What is diabetes mellitus Type 1
lack of insulin production due to auto-antibodies attacking pancreas beta cells
- insulin injections are usually required
When does diabetes type 1 usually develop
under 20 years old
If left untreated what occurs in a Type 1 Diabetic
insulin is not present to aid entry of glucose into cells
1. stores of triglycerides in adipose tissue get broken down to fatty acids and glycerol
2.a. cells use fatty acids to produce ATP
2.b. liver converts FA to ketone bodies which can lead to diabetic keto-acidosis
What is Diabetes Mellitus Type 2
normal or elevated insulin secretion but target cells have reduced sensitivity to insulin
When does Diabetes type 2 develop and how can it be controlled
obese individuals over 35
controlled by:
- diet and exercise
- eventually may need antidiabetic drugs
How do you diagnose diabetes
- fasting blood glucose test
- oral glucose tolerance test
(2 hours after a load of 75g glucose is given)
What is the range to diagnose diabetes in a fasting blood glucose test
normal range = 4-6 mmol/l
impaired fasting glycemia = 6.1-7 mmol/l
diabetes = 7 mmol +
What is the range to diagnose diabetes in the oral glucose tolerance test
normal = less than 7.8 mmol/l
impaired glucose tolerance = 7.8 - 11.1 mmol/L
diabetes = 11.1 mmol/L +
What are common treatments for diabetes
insulin injection = mostly type 1 and sometimes type 2 in later stages
controlling diet to regulate blood glucose levels = type 1 and 2
In type 1 diabetes when do autoantibodies produce? what do these autoantibodies specifically attack?
autoantibodies present for years before disease
(usually triggered by other infections to start attacking)
attack:
-glutamate decarboxylase (GAD)
- protein tyrosine phosphatase (I-A2)
- part of insulin secretory granule membrane
In type 1 diabetes due to lack of insulin uptake what organ takes the load to remove the excess glucose?
the kidneys attempt to wash out glucose leads to:
- increase in urine production (polyuria)
- increase of thirst (polydipsia)
In type 1 Diabetes because there is no energy source for cells what happens?
excessive appetite (polyphagia)
breakdown of fatty acids as an alternative
If Diabetes type 1 is not treated what are the long term effects to cells with glucose channels always present in the membrane
cell types:
- capillary endothelial cells of retina
- mesangial cells of kidney
- neurons and Schwann cells of peripheral nerves
leads to damage to blood vessels, kidneys, eyes and nerves
What are the main factors of Diabetes Type 1
genetic and environmental factors
What is the genetic predisposition involved in Type 1 diabetes
30 genetic susceptibility regions in the genes encoding for major histocompatibility complex (MHC) and Human leukocyte antigens (HLA)
- several loci on chromosome 6
- can lead to skewed functions in APC (presenting parts of beta cells instead of antigens)
Also genetic mutations in the insulin gene region (INS)
What are the environmental factors which contribute to the development of diabetes type 1
- viruses
- may trigger an autoimmune response which can cause pancreatitis and B cell death - chemicals
- other factors
- substances which alter antigens on pancreatic B cells causing APC to not recognise as self cells
What happens to the pancreas in type 2 diabetes
because the cells do not respond to insulin there is a constant rise in blood glucose levels
the pancreas therefore keeps producing insulin until it exhausts itself
causing islet and beta cells mass to decrease
Type 2 diabetes can be an ……. disease until …..
insidious disease until blood glucose levels become too high and Type 2 diabetes develops
what are the three possible mechanisms which leads to insulin resistant type 2 diabetes
- abnormal insulin molecules
- pre-receptor antagonists of insulin
- target cell defects at receptor or post receptor level
How do abnormal insulin molecules occur
rare mutations in insulin gene (autosomal dominant)
- unable to convert pro-insulin to insulin (C peptide remains)
- secretion of this insulin leads to decreased receptor binding
= mild diabetes (never insulin dependant)
How do defects in insulin receptor contribute to type 2 diabetes
leads to:
- reduced insulin binding due to reduced number of receptors
What are two pre-receptor antagonists of insulin which can contribute to the development of type 1 diabetes
IgG against receptor
Hormones which reduce insulin binding
What are the causes of obesity
- unlimited supplies of energy dense foods and chronic overnutrition
- technology encourages sedentary behaviours
Lifestyle modifications which can help reduce obesity in type 2 diabetes patients
reduced calorie intake and increased physical activity
- not very successful though therefore pharmacological intervention
How does an abnormal metabolism, as is associated with obesity, lead to the development of insulin resistant type 2 diabetes?
excess of free fatty acids in insulin sensitive tissues (liver, tissue and muscle):
- pro-inflammatory cytokine production induced by toxic effects of excess FFA by adipose cells producing peptide hormones
- mitochondrial dysfunction as FFA oxidised in TCA cycle which leads to generation of reactive oxygen species
Ho do FFA interrupt the intracellular insulin receptor pathway?
FFA leads to:
1. production of LCA-CoA
- production of ceramides
- blocking PKB/Akt pathways
2. production of LCA-CoA
- production of DAG which then produces
other proteins blocking insulin receptor, IRS1,
PI3K
- inducing an increase of inflammatory gene
expression
On a systemic level what occurs in type 2 diabetes
- decreased glucose uptake and expression of GLUT 4
- adipose cells release inflammatory mediators
- increase lipolysis
- increased FFA secretion acts on the liver
- increase in glucose production from the liver
- hyperglycemia which leads to the cycle continuing
What are the complications of hyperglycemia
- damage of vascular tissues
What are the main pathways affected by hyperglycemia
increased flux of polyol pathway
glycation of proteins
(formation of advanced glycation end products (AGE’s)
activation of protein kinase C
What is polyol pathway
- high glucose converted by sorbitol by aldose
reductase and NADPH - NADPH becomes depleted therefore there is a
loss of glutathione reductase (needed as an
antioxidant)
sorbitol cannot cross the PM and increases osmotic stress
What is the intracellular production of advanced glycation end-products (AGE’s)
carbohydrate + protein = glycation
intermediate product = amadori group
amadori groups form AGE’s
What damage do AGE’s cause?
modify/denature proteins in and out of cells
causes cells to become stiff and more subject to damage = blood vessel damage
AGE’s pathway
- modification of proteins involved in regulation of gene transcription
- AGE precursors diffuse out of cell and modify extracellular matrix molecules
- changes signalling between matrix and cell
- modify circulating proteins in blood by binding to AGE receptors which produces inflammatory cytokines and growth factors
Pathway of activation of protein kinase C
- intracellular glucose metabolised to glycolytic intermediates
- production of PKC activator diacylglycerol (DAG)
- this leads to many different outcomes but ultimately impairs microvascular function
Different treatments for specific aspects of diabetes
superoxide overproduction = antioxidants
polyol = aldose reductase inhibitors (ARI’s)
glycation = advanced glycation end product (AGE0 inhibitors)
PKC activation = PKC inhibitors
How does the drug Metformin work for type 2 diabetes
mechanism of action not understood but:
- decreases liver glucose production
- increases peripheral glucose uptake
- increases insulin sensitivity
Other treatments for type 2 diabetes
- weight reduction
- dietary changes
- insulin injections/pump
What are some non insulin medications which can help treat type 2 diabetes
amylinomimetic drug
- delaying the time your stomach takes to empty itself
alpha-glucosidase inhibitors
- aid breakdown of starchy food
sulfonylureas
- stimulates secretion of insulin
- by binding and inhibiting K+ channel
