Lecture 12- Type 2 diabetes Flashcards
type 2 diabetes definition
- metabolic disorder characterised by chronic hyperglycemia
- relative lack of insulin action/response (insulin resistance), insulin production or both
- leads to impaired glucose metabolism
3 ways to diagnose diabetes
- glycated haemoglobin test (HbA1c test)
- oral glucose tolerance test (oral GTT)
- impaired fasting blood glucose levels
HbA1c test
glycated haemoglobin test
- measures how much glucose is bound to Hb in RBCs
- diabetes >6.5%
oral glucose tolerance test (oral GTT)
consumption of 75g of anhydrous glucose, test plasma glucose 2 hrs later
-11.1mmol/L- diabetes
impaired fasting blood glucose levels
plasma glucose>7.0mmol/L following 8 hr fast
type 1 diabetes
autoimmune disease, immune mediated Beta cell destruction
- insulin deficiency, 5-10%
type 2 diabetes
insulin resistance and insulin deficiency, 90-95%
gestational diabetes
insulin resistance and relative insulin deficiency in pregnancy
- 3-5% of all pregnancies
genetic defects affecting Beta cell function
1-2% of cases
glucose homeostasis
balance of glucose intake/production and uptake/storage/usage
when high blood glucose
gets stored in liver and muscle (as glycogen) and fat/WAT
when low blood glucose
glucose released from stores- liver, muscle, WAT
where is insulin produced?
produced and secreted by Beta cells of pancreatic islets
beta cells of pancreatic islets
75-80% of the islet cells
produce and secrete insulin
glucagon
alpha cells in pancreatic islets
- raises blood glucose level (acts opposite to insulin)
somatostatin
gamma cells
insulin synthesis pathway
- genes encoding for insulin transcribed to mRNA in nucleus
- Pre-proinsulin synthesised (in beta cell), excision of signal peptide, formation of disulphide bonds in ER (b/w A and B chain)
- Transport of proinsulin to Golgi apparatus, cleaved by pro-hormone convertase
- Formation of separate C-peptide and mature biologically active insulin (A and B chain)
- Insulin stored in storage granules , secretion of insulin granules by exocytosis when calcium influx
Insulin secretion pathway
- glucose enters beta cells (via GLUT2 transporter)
- glycolysis (breakdown of glucose) increases ATP:ADP ratio, increase energy supply to beta cells
- Closes ATP-sensitive K channels (K cant go outside of beta cell now)
- increase K in cells, makes cell more positively charged, depolarisation of cells
- Opens voltage dependent Ca channels, influx of calcium, promotes exocytosis of insulin granules form storage granules
glycogen synthesis
convert glucose into glycogen
glycogenolysis
break down of glycogen
gluconeogenesis
production of glucose from fat
lipogenesis
convert/synthesise glucose into fat
Normal glucose levels- liver
- increased glycogen synthesis
- decreased glycogenolysis
- decreased gluconeogenesis
normal glucose levels- muscle
- increased glucose uptake
- increased glycogen synthesis
normal glucose levels- WAT/fat
- increased glucose uptake
- increased lipogenesis
vagus nerve
parasympathetic control of digestive tract e.g. liver
high glucose levels- pancreas
decrease beta cell function
normal glucose levels- brain
decrease appetite
high glucose levels- liver
- decreased glycogen synthesis
- increased gluconeogenesis
high glucose levels- muscle
- decreased glucose uptake
- decrease glycogen storage
high glucose levels- WAT/fat
- decrease fat/TG storage
- increased lipolysis
- increase FFA in blood
lipolysis
breakdown of fats and other lipids by hydrolysis to release FAs
high glucose levels- insulin
- lots produced but not used by liver, muscle, WAT or brain
high glucose levels- brain
increased appetite
GLUT4 vesicle
used in glucose uptake by fat, muscle
Akt
responsible for increasing glycogen synthesis
- Akt activates FOXO and GLUT4 vesicle
FOXO
decreases gluconeogenesis in liver
PI3K
activates Akt–>FOXO and GLUT4 vesicle
how does insulin lead to changes in glucose production in organs and tissues?
insulin receptor (IR) binds to IRS (insulin receptor substrate)–>PI3K–>Akt–>
- GLUT4 vesicle- increase glucose uptake
- increased glycogen synthesis
- FOXO- decrease gluconeogenesis
chronic inflammation
triggers recruitment of immune cells–>increase pro inflammatory cytokine levels (IL-1, IL-18, TNF) in affected tissues (muscle, liver, islets, adipose tissue)
- islets (resident macrophages become activated, increased immune T and B cells)
anti- inflammatory drugs
TNF, IL-1 blockers- beneficial for T2D- clinical trial
ER stress
chronic overnutrition and increased FA (due to adiposity)–>accumulation of unfolded/misfolded proteins in ER lumen –>ER stress
ER
central organelle in which trans-membrane and secretory proteins are synthesised and folded
unfolded protein response- UPR
mitigate ER stress
- reduces protein synthesis through (PERK/ATF4)
- increase ER molecular chaperones through (ATF6)
- Activation of ER-associated degradation proteins through (IRE1/XBP1)
- CHOP- apoptosis
PERK/ATF4
reduces translation, protein synthesis to reduce ER stress
ATF6
increases ER molecular chaperones
IRE1/XBP1
activates ER-associated degradation proteins (ERAD)
CHOP
apoptosis of unfolded/misfolded proteins in ER
BiP/GRP78
ER chaperones
therapeutic potential for ER stress
chemical chaperones to reduce ER stress- clinical trial
risk factors for T2D
lifestyle, age, genetics, history of gestational diabetes
hallmarks of T2D
insulin resistance
hyperinsulinemia
hyperglycemia
acute complications of T2D
hyperglycemic hyperosomlar state (HHS)
- high blood glucose levels–>high osmolarity–>extreme dehydration (dry skin, drowsy)
chronic complications of T2D
micro- diabetic retinopathy/nephropathy/neuropathy
macro- stroke, heart disase, peripheral vascular disease
key principle in treatment of T2D
control blood glucose levels
3 key components of T2D treatment
- lifestyle modification
- oral glucose-lowering therapy
- insulin therapy
lifestyle modification
diet- healthy eating
exercise- reduce weight to improve insulin sensitivity and glucose uptake
oral glucose lowering therapy
metformin
- safe, cheap, first line oral treatment (mono/combo therapy)
- activates AMP-activated kinase (AMPK)
metformin
activates AMP-activated kinase (AMPK)
- liver- suppresses gluconeogenesis and lipogenesis
- skeletal muscle- increases insulin sensitivity and glucose uptake
- side effects- liver disease and GIT issues (diarrhoea)
lipogenesis
formation of fat
metformin- liver
suppresses gluconeogensis and lipogenesis
metformin- skeletal muscle
increases insulin sensitivity and glucose uptake
metformin side effects
liver disease and GIT issues
incretin hormones
stimulate insulin production and trigger insulin release in response to meals
GLP-1
gut derived glucagon peptide 1
- rapidly degraded by DPP-4
function of GLP-1
activates GLP-1R–>decrease blood glucose levels and improve glycemic control
DPP-4
degrades GLP-1 within minutes
GLP-1R action on brain
decrease appetite
GLP-1R action on stomach
decrease gastric emptying
GLP-1R action on pancreas
- increase insulin secretion/synthesis
- decrease glucagon secretion
- increase beta cell proliferation
- decrease beta cell apoptosis
GLP-1R agonists/ DPP-4 inhibitors
act on GLP-1R and DPP
GLP-1R agonist
Exenatide
- inject subcutaneously
- side effects- hypoglycemia (act directly on beta cells)
DPP-4 inhibitor
Gliptin
- Tablets, reduce GLP-1 degradation
- side effects- sinusitis, nausea, allergic issues
sulfonylureas
safe, cheap, second generation
e.g. glimepiride, glipizide, glyburide
function of sulfonylureas
- inhibit opening of ATP-sensitive K channels (no K goes out)
- increase Ca influx–>depolarisation
- increase insulin release from beta cells in pancreas
side effects– hypoglycemia, weight gain
acarbose
alpha glucosidase inhibitor
- cheap, effective
function of acarbose
lowers blood glucose, prevent T2D
- reduces rate of digestion of carbs in intestine–>less glucose is absorbed
- side effects- flatulence, diarrhoea
alpha glucosidase
intestinal enzyme that breaks down carbs into glucose
future therapies
prevention- public health policies, lifestyle modification
basic science- further understanding for causes of diabetes
