Diabetes Flashcards
Cellular mechanisms of beta cell insulin release
two main pathways:
1) High glucose, influx through GLUT2 transporter
Increased ATP/ADP ratio
ATP CLOSES the ATP sensitive K+ channel.
CLOSING of this channel keeps K+ in preventing it from hyperpolarizing the cell. CLOSING of this channel causes DEPOLARIZATION of the cell.
Activates the Voltage dependent calcium channel.
Insulin secretory granule release, activation of Ca++ sensitive TF pathways to induce insulin production.
2) Incretin proteins GLP-1 or GIP bind their receptors, increasing cAMP levels, activating PKA.
PKA phosphorylates proteins involved in the secretory process, potentiating Ca++ induced insulin release.
What pathways regulate insulin release in independently of the ATP-dependent K channel?
cAMP levels and PKA, regulated by the incretins, glucagon, adrenalin, somatostatin, the neurotransmitter PACAP.
PKC, regulated by Acetylcholine
Free Fatty acids acting through GPR40.
Insulin effects in
skeletal muscle
GLUT4 translocation, increased glucose uptake
Activates glycogen synthase
Insulin effects in
Adipocytes
SREBP activation, increased lipid synthesis
PKA activation, inhibited lipolysis, no lipid release
Insulin effects in
Hepatocytes
Akt decreased gluconeogenesis, increased glycogen synthesis
SREBP activation, increased lipid synthesis
mTOR activation, increased protein synthesis.
Consequence of insulin deficiency
Ketoacidosis
Hyperglycemia
- fatigue,
- seizures
- coma
Osmotic diuresis, polyuria and polydipsia
Increased lipolysis and decreased cell growth, loss of body weight
Why is insulin resistance and total insulin deficiency differ?
Insulin resistance does not equally inhibity all of insulin signalling pathways.
What pathways are affected most and affected least in insulin resistance?
SREBP signaling is retained
The effects of insulin on carbohydrate metabolism are mostly lost, while its affects increasing the syntehsis of fatty acids and triglycerides in the liver and adipose are retained.
What kinds of extracellular signals can activate intracellular serine kinases that inhibit IRS signaling?
Fatty acids
Cytokines
Leptin
Insulin effect on
Beta-cells?
Enhances glucose sensitivity
Ras/MAPK signaling, trophic/mitotic factor
Akt signaling inhibits apoptosis
These effects are part of the reason why T2DM can progress to T1DM, since insulin resistance inhibits these trophic signals, causing beta cell apoptosis.
What causes inflammation of adipose, hypertrophy or hyperplasia?
Hypertrophic growth, swelling of individual cells.
This is the kind that causes inflammation and is the kind stimulated by excessive eating.
Causes a degree of adipocyte apoptosis and increases macrophage infiltration of the tissue, increasing inflammation.
What are the signals induced by TNFalpha and IL-6, IL1beta
IKKbeta,
JNK
SOCS
all inhibitory to IRS signaling
NF-kappaB
AP-1
Pro-inflammatory signals.
What happens when insulin signaling is lost from adipocytes
There is increased lipolysis and FFA release.
Decreased glucose uptake.
Decreased Adiponectin
Increased Leptin
How are free fatty acids toxic to cells?
essential card
weakly activate cytokine receptors
Activate FAT/CD36 membrane receptor
Cause ER stress -> activate unfolded protein response -> activates JNK,
also activate TLRs, inducing pro-inflammatory signaling.
What is the most important factor for development of type 2 diabetes
Genetic predisposition
This is exacerbated by obesity, inflammation, and FFA induced insulin resistance.
But type 2 diabetes and insulin can develop on its own in non-obese people.
How is visceral/central/abdominal adipose different from subcutaneous adipose?
Visceral adipose:
Higher cytokine secretion
More macrophage infiltration which are also more inflammatory
Converts cortisone into glucocorticoid cortisol
Hormone and cytokin outflow from abdominal fat hits the liver first via portal blood flow, contributing to hepatic insulin resistance much more than subcutanoues fat.
Metabolic syndrome 5 characteristics
Central obesity
Hypertension
High TAG level
Low HDL
High fasting glucose above 5.6 (indicates insulin resistance)
It is like Cushings syndrome but without elevated cortisol (not as high).
What are the pre-receptor conversions of glucocorticoids in
Liver
Muscle
Adipose
11-beta-Hydroxysteroid Dehydrogenase 1
11B-HSD1
Converts cortisone to cortisol, activating it
What are the pre-receptor conversions of glucocorticoids in
Kidneys
and
Intestines
11-beta-Hydroxysteroid Dehydrogenase TWO
11B-HSD2
Converts cortisol to cortisone, inactivating it.
How does 11b-HSD1 knockout affect mice
protective against obesity and insulin resistance even in overfeeding.
indicates that cortisol signaling in the liver, adipose, and muscle is a key component to developing metabolic syndrome and insulin resistance.
How does 11b-HSD1 overexpression affect mice
generates metabolic syndrome
if expressed just in the liver, then metabolic syndrome without obesity.
What drugs induce insulin secretion
“insulin secretagogues”
Sulfonylurea drugs bind to the ATP-sensitive K+ channel (Katp channel) and keep it shut irrespective of ATP levels. Causing cell depolarization and secretion
NSIS, Non-sulfonylurea types, also bind the Katp channel, but at a different site than the sulfonylureas.
GLP-1 receptor agonists,
DPP4 inhibitors, (DPP4 degrates incretins GLP-1 and GIP, so DPP4 inhibitors increase incretins)
What are the anti-diabetic drugs?
PPAR-gamma agonists, Metformin, Sodium glucose co-transporter inhibitors (SGLT2 inhibitors).
Thiazolidinediones, PPAR-gamma agonists.
These make cells more sensitive to insulin,
Decrease lipolysis, decrease serum FFAs,
Decrease TNF-alpha levels
Decrease Leptin levels
Increase Adiponectin.
Biguanides:
Only one, its Metformin
Metformin activates AMPK, which overal lowers hepatic lipids, and inhibits PKC, which is part of insulin resistance
Decreases liver gluconeogenesis Decreases SREPB1 expression Decreases ACC activity Decreases Fatty acid synthesis Decreases VLDL synthesis
Increases fatty acid oxidation
Increases liver insulin sensitivity.
Increases glucose uptake by muscle
Anti-diabetic drug list
GLP-1 receptor agonists
DPP-4 protease inhibitors
Alpha glucosidase inhibitors
Insulin secretagogues
Sulfonylurea
Non-sulfonylurea insulin secretagoges
SGLT2 inhibitors
Biguanides, Metformin
Thiazolidinediones, PPAR gamma agonists.
Insulin!
