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1

When is insulin produced?

Basally and in response to nutrient intake by beta cells in the islets of langherhans
   - With meals, incretins produced by the intestine further enhance insulin secretion.

 

2

Where are the insulin producing cells located (islets of langerhans)?

The insulin-producing b-cells (in blue) are in the center close to the blood supply. They are surrounded by the glucagon-producing α-cells (in orange). The delta (δ) cells (in yellow) make somatostatin, and the PP cells (in green) make pancreatic polypeptide.

3

Where does insulin travel upon secretion by the pancreas?

Upon secretion by the pancreas, insulin travels to the liver via the portal system, and then to the periphery

4

What are insulin's target tissues?

Insulin target tissues are liver, muscle, and fat. 

5

Where is insulin degraded?

1) About half of the insulin secreted by the pancreas is degraded in the liver. 

   - This organ is therefore normally exposed to a higher concentration of insulin than are peripheral target tissues. 

2) Insulin is also rapidly degraded in the periphery.
 

6

Where in pancreatic beta cells is insulin produced?

Insulin in the pancreatic beta cells is stored in secretory granules in a complex with zinc.

7

How is insulin released by beta cells?

 

Insulin can be rapidly released by fusion of the secretory granules with the cell membrane. 
   - Secretion occurs by exocytosis of the secretory granules from pancreatic Beta cells. 

   - Exocytosis is triggered through an increase in ATP (e.g., stimulated by glucose). 

   - This increase causes a potassium (K+) channel to close, which prevents K+ exit and causes depolarization of the cell. 

   - This in turn causes a Ca++ channel to open, and Ca++ promotes exocytosis.

[Continued insulin production can result in a second phase of sustained release. ]

 

8

Describe the protein organization/formation of insulin. 

Mature insulin is composed of two polypeptide chains (the A + B chains) connected by disulfide links.

   - Insulin is initially synthesized as preproinsulin.    
   - Removal of the pre-sequence yields proinsulin.  
   - Proinsulin is then cleaved to form mature insulin plus C‑peptide (connecting peptide).
      - C-peptide is present in the granules and is released along with the insulin.

9

How does insulin exert it cellular effects?

Insulin exerts its effects by binding to the insulin receptor on the surface of target cells. 

   - This receptor consists of 2 alpha subunits and 2 beta subunits. 

      - The alpha subunits contain the insulin binding domains and the beta subunits have tyrosine kinase activity. 

         - Binding of insulin to the alpha subunits promotes autophosphorylation of the beta subunits. 

10

What is the glucose transporter of muscle and fat cells?

Glut 4: Muscle and fat cells contain preformed vesicles with glucose transporters 

11

What are the global actions of insulin?

1) Insulin promotes the storage of glucose as glycogen, amino acids as proteins, and fatty acids as triglycerides.  

2) Insulin inhibits the breakdown of glycogen, proteins, and fats. 

      - Thus, insulin promotes the build-up and storage of cellular nutrients, and inhibits their breakdown (can do this at the gene transcription/inhibitor level)

12

What proteins in the insulin cascade activate (de)phosphorylation?

IRS proteins: The insulin receptor phosphorylates target proteins, including IRS proteins (Insulin Receptor Substrates).  These activate phosphorylation and dephosphorylation.

13

Who is insulin given to?

1) Insulin is a necessary drug for patients with Type 1 diabetes. 

2) Insulin can also be used for Type 2 diabetes not controlled by other measures such as diet, exercise, weight loss, and oral agents.

14

How is insulin administered?

Insulin is a protein and would be subject to degradation upon oral administration.  It is generally administered subcutaneously. 

15

How are the levels of insulin different in an insulin controlled diabetic and non-diabetic patients?

1) In a non-diabetic where insulin is secreted via the portal system, the liver is exposed to a higher concentration than are other target tissues.

 

2)   However, when insulin is administered subcutaneously to a diabetic patient, the liver is not exposed to a higher concentration than other target tissues.  It may therefore be necessary to maintain higher than normal blood levels of insulin in these patients to appropriately suppress hepatic glucose output. 

16

Describe the time course of various types of insulin. 

Rapid acting: Insulin Lispro

Short acting: Regular insulin; solution/dissolved (can be given IV)

Intermediate acting: NPH (Neutral Protamine Hagedorn); precipitated

Long acting: Insulin detemir and Insulin glargine

 

 

 

 

17

What is NPH?

Precipitation of insulin with protamine produces NPH insulin (Neutral Protamine Hagedorn). 

   - Insulin is present in a precipitated form in this preparation

   - It is not absorbed as rapidly as regular insulin after subcutaneous administration.  (This is because of the time required for the insulin to dissolve into solution in order to be absorbed.)  

   - Because of its slower absorption, NPH insulin has a delayed onset and a longer duration of action than regular insulin. 

18

What is insulin lispro?

In Insulin Lispro, Lys and Pro are reversed at amino acid positions at 28 and 29 of the B chain.

   - Regular insulin forms aggregates (e.g. hexamers in a complex with zinc), which require time for disaggregation and absorption. 

   - Insulin Lispro aggregates less, which allows for more rapid absorption.

      - The rapid absorption of Insulin Lispro helps decrease hyperglycemia after the meal. 

19

What are the advantages of insulin lispro?

 - Insulin Lispro aggregates less, which allows for more rapid absorption.

- Regular insulin is taken 30-60 minutes before a meal, to insure that it is present when the meal is eaten.    
      - Insulin Lispro is taken 0‑15 minutes before a meal.
    - The rapid absorption of Insulin Lispro helps decrease hyperglycemia after the meal. 

20

What is insulin glargine?

 The modifications made in Insulin glargine cause it to precipitate at the pH present subcutaneously.  It is called a “peakless” insulin because it is absorbed very slowly over time such that there is no distinct peak in insulin level. 
   - long acting insulin

 

21

What is insulin detemir?

-  Insulin Detemir is a long-acting insulin. 
- It contains a fatty acid added to amino acid residue 29 of the B chain among other changes. 

- It binds to albumin in the blood, which prolongs its action.

22

What approach is used to normalize glucose levels in diabetics?

This objective can be approached by using a “basal-bolus” approach to provide a basal level of insulin (to suppress hepatic glucose output) plus additional insulin with meals. 

   - This often involves the use of an intermediate- or long-acting insulin plus a rapid- or short-acting insulin.

[insulin pumps achieve this same effect]

23

What is the benefit of intensive/tight insulin control?

Less immediate and long term effects of diabetes

24

What is the potential adverse side effect of intensive insulin therapy?

hypoglycemia