3. Physiology
        3.3. Endocrinology
            3.3.1. Pancreas - endocrine
3.3.1.1. Insulin

Insulin

[Ref: WG21:p337-351]

Also see Carbohydrate metabolism

Basics

Insulin structure

Insulin synthesis and secretion

Metabolism

 

Actions

GLUT4

[WG21:p340][See Glucose transporter]

GLUT-4 transporter in muscle and adipose tissue is stimulated by insulin

Normally it is stored in vesicles

When insulin receptors activated
--> Vesicles fuse
--> GLUT4 inserted into membrane
--> Glucose entry into cells

Some pool of GLUT4 are inserted in response to exercise
* Independent of insulin

Effects of insulin (summary)

1. Glucose

2. Potassium

3. Anabolic effect

Effects of insulin by time line

Rapid

Intermediate (minutes)

Delayed (hours)

Effects on insulin by tissues

Adipose tissue

Muscle

Liver

General

Mechanism of action

 

Insulin receptor

NB:

 

Mechanism of action

Insulin binds to alpha subunits
--> Triggers tyrosine kinase activity of beta subunits
--> Autophosphorylation of the beta subunits
--> Triggers phosphorylation and dephosphorylation of various proteins

 

Regulation

Normal amount
= 1U/hour, with increases after meals
= 40U/day

Factors affecting insulin secretion

[WG21:p348] Selective

Stimulators

Inhibitors

 

 

Glucose

Acts directly on pancreatic B cells to increase insulin secretion

Response to glucose is biphasic
* A rapid but brief increase, followed by
* More slowly developing prolonged increase

 

Mechanism

[WG21:p349]

Glucose enters B cells by GLUT2
--> Metabolised
--> ATP generated
--> ATP inhibits ATP-sensitive K+ channels
--> Reducing K+ efflux
--> Depolarizaton of B cells
--> Ca2+ influx (via voltage-gated channel)
--> Exocytosis of granules (with insulin in them)
--> Followed by priming of other secretory granules (via glutamate)

 

Oral hypoglycemic agents

Sulfonylurea

Increase secretion of insulin

Only works when there are B cells remaining

Binds to ATP-inhibited K+ channels in B cells
* Similar mechanism as glucose [see above]

Metformin

Reduce gluconeogenesis
--> Thus decreasing hepatic glucose output

Risk of lactic acidosis

Troglitazone (and other thiazolidinediones)

Increase insulin-mediated peripheral glucose uptake
--> Reducing insulin resistance

 

 

cAMP

Factors that increase cAMP in B cells increase insulin secretion

e.g. glucagon, phosphodiesterase inhibitor (e.g. theophylline)

 

Catecholamine

Inhibits insulin secretion via alpha2-receptor

Stimulate insulin secretion via beta-receptor

Net effect: INHIBITION

In alpha-blockade, effect may be stimulation

 

Intestinal hormones

Stimulation of insulin secretion:

But,

NB:

K+ depletion

Decreases insulin secretion

Thus,

Primary aldosteronism
--> K+ depletion
--> Diabetic glucose intolerance

Other notes

[WG21:p355]

Thyrotoxicosis aggravates clinical diabetes
* Thyroid increase GIT absorption of glucose and cause some hepatic glycogen depletion

Glucocorticoids can worsen diabetes
* Increase in protein catabolism
* Increased gluconeogenesis in liver
* Increased hepatic glycogenesis and ketogenesis
* Decrease in peripheral glucose utilisation

Growth hormone can also worsen diabetes
* Mobilise FFA --> Ketogenesis
* Decrease glucose uptake in some tissues
* Increased hepatic glucose output
* May decrease tissue binding of insulin
* Growth hormone does not stimulate insulin directly, but the hyperglycaemia it produces may stimulate insulin



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