Diabetes

Question 1

Cellular mechanisms of beta cell insulin release

Answer 1

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.

Question 2

What pathways regulate insulin release in independently of the ATP-dependent K channel?

Answer 2

cAMP levels and PKA, regulated by the incretins, glucagon, adrenalin, somatostatin, the neurotransmitter PACAP.

PKC, regulated by Acetylcholine

Free Fatty acids acting through GPR40.

Question 3

Insulin effects in

skeletal muscle

Answer 3

GLUT4 translocation, increased glucose uptake

Activates glycogen synthase

Question 4

Insulin effects in

Adipocytes

Answer 4

SREBP activation, increased lipid synthesis

PKA activation, inhibited lipolysis, no lipid release

Question 5

Insulin effects in

Hepatocytes

Answer 5

Akt decreased gluconeogenesis, increased glycogen synthesis

SREBP activation, increased lipid synthesis

mTOR activation, increased protein synthesis.

Question 6

Consequence of insulin deficiency

Answer 6

Ketoacidosis

Hyperglycemia

• fatigue,
• seizures
• coma

Osmotic diuresis, polyuria and polydipsia

Increased lipolysis and decreased cell growth, loss of body weight

Question 7

Why is insulin resistance and total insulin deficiency differ?

Answer 7

Insulin resistance does not equally inhibity all of insulin signalling pathways.

Question 8

What pathways are affected most and affected least in insulin resistance?

Answer 8

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.

Question 9

What kinds of extracellular signals can activate intracellular serine kinases that inhibit IRS signaling?

Answer 9

Fatty acids
Cytokines
Leptin

Question 10

Insulin effect on

Beta-cells?

Answer 10

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.

Question 11

What causes inflammation of adipose, hypertrophy or hyperplasia?

Answer 11

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.

Question 12

What are the signals induced by TNFalpha and IL-6, IL1beta

Answer 12

IKKbeta,
JNK
SOCS
all inhibitory to IRS signaling

NF-kappaB
AP-1
Pro-inflammatory signals.

Question 13

What happens when insulin signaling is lost from adipocytes

Answer 13

There is increased lipolysis and FFA release.

Decreased glucose uptake.

Decreased Adiponectin

Increased Leptin

Question 14

How are free fatty acids toxic to cells?

essential card

Answer 14

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.

Question 15

What is the most important factor for development of type 2 diabetes

Answer 15

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.

Question 16

How is visceral/central/abdominal adipose different from subcutaneous adipose?

Answer 16

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.

Question 17

Metabolic syndrome 5 characteristics

Answer 17

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).

Question 18

What are the pre-receptor conversions of glucocorticoids in

Liver
Muscle
Adipose

Answer 18

11-beta-Hydroxysteroid Dehydrogenase 1
11B-HSD1

Converts cortisone to cortisol, activating it

Question 19

What are the pre-receptor conversions of glucocorticoids in

Kidneys
and
Intestines

Answer 19

11-beta-Hydroxysteroid Dehydrogenase TWO
11B-HSD2
Converts cortisol to cortisone, inactivating it.

Question 20

How does 11b-HSD1 knockout affect mice

Answer 20

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.

Question 21

How does 11b-HSD1 overexpression affect mice

Answer 21

generates metabolic syndrome

if expressed just in the liver, then metabolic syndrome without obesity.

Question 22

What drugs induce insulin secretion

Answer 22

“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)

Question 23

What are the anti-diabetic drugs?

Answer 23

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

Question 24

Anti-diabetic drug list

Answer 24

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!