1. Insulin ,Glucagon, and Diabetes mellitus

4. Introduction
The pancreas, in addition to it's digestive functions secrets two important hormones, insulin and glucagon that are crucial for normal regulation of glucose, lipids and protein metabolism, although the pancreas secrets other hormones ,somatostatin, and pancreatic polypeptide .

5. Physiologic anatomy of the pancreas
The pancreas is composed of two major types tissues :
1- the acini which secrets digestive juices into the duodenum
2- the islets of Langerhans ,which secrete insulin and Glucagon directly into the blood
The islets contain three major types of cells :alpha ,beta and delta cells , the
- alpha cells secrete glucagon hormone;
- beta cells secrete insulin; (constituting about 60 percent of all cells of the islets. insulin inhibits Glucagon secretion).
- delta cells secrete somatostatin (somatostatin inhibits the secretion of both insulin and Glucagon).

6. Pancreatic Islets and Surrounding Accini

7. Insulin and it’s metabolic effects
insulin has profound effects on :
carbohydrate metabolism
fat metabolism
protein metabolism

8. Insulin is a hormone associated with energy abundance
Increased ingested carbohydrate , increases glycogen storage in the liver and muscles . Although all the excess carbohydrate that cannot be stored as glycogen are converted under the stimulus of insulin into fats and stored in the adipose tissue .
Increased ingested proteins , increases insulin secretion to enhance amino acid uptake by cells and conversion of these amino acids into protein ,in addition ,it inhibits the breakdown of the proteins that are already in the cells.

9. Insulin chemistry and synthesis
Insulin is a small protein. it is composed of two amino acid chains ,connected to each other by disulfide linkage .
Human Proinsulin and its Conversion to Insulin:
By proteolytic cleavage, four basic amino acids (31,32, 64, 65) and the connecting peptide are removed and proinsulin is converted to insulin

10. Three-dimensional Structure of Insulin
The shaded are indicates the receptor-binding face of the insulin molecule

11. Activation of target cell receptors by insulin and the resulting cellular effects
To initiate it’s effects on target cells ,insulin first binds with and activates membrane receptors.
It is the receptor not the insulin , that causes the subsequent effects of insulin.

12. The Insulin Receptor
The actions of insulin are initiated by binding to a cell-surface receptor, and such receptors are present in virtually all mammalian cells.
These include the classical targets for insulin action (liver, muscle, and fat) and such nonclassical targets as circulating blood cells, brain, and gonadal cells.
The number of receptors varies from as few as 40 per cell on erythrocytes to 300,000 per cell on adipocytes (fat cells) and hepatocytes (chief functional cells of the liver).

13. The Insulin Receptor
The insulin receptor is a large transmembrane glycoprotein, composed of two a subunits and two b subunits linked by disulfide bonds to form a b-a- a-b heterotetramer.
These two subunits are specialized to perform the two functions of the receptor:
The a subunits are entirely extracellular and contain the insulin-binding domain;
The b subunits are transmembrane proteins that possess tyrosine protein kinase activity.

14. Insulin Action at the Cellular and Molecular Level

15. Insulin signaling pathways
- Insulin binds to the a subunits of its receptor and stimulates the tyrosine kinase activity of the b subunits.
This results an auto-phosphorylation of the insulin receptor on several tyrosine residues and further activation of kinase activity.
Presumed consequences of these reactions include:
- cascades of protein phosphorylation,
- the generation of secondary messengers of insulin action,
- other signals that ultimately result in insulin's characteristic effects on the metabolism of carbohydrates, lipids, and proteins.

16. Insulin binding to its receptor
Junction of beta subunit of insulin receptor
Postbinding coupling of the insulin receptor to insulin-stimulated cell membrane (by a second messenger or messengers)
Insulin activation of glycogen synthase
Insulin effect in glycolysis and glucose oxidation
Glucose transport

17. When insulin is secreted into the blood ,it’s circulated almost entirely in an unbound form ;it has plasma half life averages only about 6 minutes ,so that it is mainly cleared from the circulation with minutes .
Except for the portion of the insulin that combines with receptors in the target cells ,the remained is degraded by the enzyme insulinase mainly in the liver ,to a lesser extent in the kidneys and muscles .

18. The end effects of insulin stimulation are the following :
1- within seconds after insulin binds with it’s membrane receptors , the membrane of about 80% of the body’s cells markedly increase their uptake of glucose .this is especially true of muscle cells and adipose cells but not true of most neurons in the brain .
2- the cell membrane becomes more permeable to many of amino acids ,potassium ions ,and phosphate ions ,causing increased transport of these substances into cells .

19. Effects of insulin on carbohydrate metabolism
Immediately after a high-carbohydrate meal ,the glucose that absorbed into the blood cause rapid secretion of insulin.
The insulin in turn causes rapid uptake ,storage ,and use of glucose by almost all tissues of the body, but especially by the muscles, adipose tissue and liver

20. Insulin promotes muscle glucose uptake and metabolism
During much of the day ,muscle tissue depends not on glucose or it’s energy but on fatty acids .the principle reason for this is the normal resting muscle membrane is only slightly permeable to glucose ,except when the muscle fiber is stimulated by insulin ,between meals ,the amount of insulin that is secreted is too small to promote significant amounts of glucose entry into the muscle cells .
However under two conditions the muscle do use large amounts of glucose .one of these is during moderate or heavy exercise .This usage of glucose doesn't require large amount of insulin because ,because exercising muscle fibers become more permeable to glucose even in the absence of insulin, because of the contraction process itself .

21. The second condition for muscle usage of large amounts of glucose is during the few hours after the meal .
At this time blood glucose contraction is high and the pancreas is secreting large quantities of insulin .
The extra insulin cause rapid transport of glucose into muscle cells .this cause the muscle cells during this period to use glucose preferentially over fatty acids

22. Storage of glycogen in muscles
If the muscles are not exercising after a meal and yet glucose transport into the muscle cells in abundance ,then most of the glucose is stored in the form of muscle glycogen instead of being used for energy ,up to a limit of 2 to 3 % concentration .the glycogen can later be used for energy by the muscle .

23. - insulin can increase rate of transport of
Quantitative effect of insulin to facilitate glucose transport through the muscle cell membrane
The quantitative effect of insulin to facilitate glucose transport through the muscle cell membrane is high.
the intracellular glucose concentration is increased in response to increased insulin concentration.
- insulin can increase rate of transport of
glucose into the resting muscle by at least
15-fold .

24. Insulin promotes liver uptake, storage ,and use of glucose
insulin causes most of the glucose absorbed after a meal to be stored in the liver in the form of glycogen .
Between meals ,when glucose concentration beings to fall ,insulin secretion decreases rapidly and the liver glycogen is split back into glucose ,which is released back into blood to keep glucose concentration from falling too low .

25. insulin promotes conversion of excess glucose into fatty acids and inhibits gluconeogenesis
When the quantity of glucose entering the liver cells is more than can be stored as glycogen or can be used for local hepatocyte metabolism ,insulin promotes the conversion of all this excess glucose into fatty acids .
Insulin also inhibities gluconeogenesis .it does this mainly by decreasing the quantities and activities of the liver enzyme required for gluconeogenesis .
However ,part of the effect is caused by an action of insulin that release amino acids from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis.

26. Lack of effect of insulin on glucose uptake and usage by the brain
The brain is quite different from most other tissues of the body in that insulin has little effect on uptake or use of glucose ,instead ,the brain cells are permeable to glucose and can use glucose without the intermediation of insulin.
The brain cells also quite different from most other cells of the body in that they normally use only glucose for energy and can use other energy substrates, such as fats, only with difficulty .therefore, it is essential that the blood glucose level always be maintained above a critical level, which is one of the most important function of the blood glucose control system .

27. Lack of effect of insulin on glucose uptake and usage by the brain
When the blood glucose falls too low ,into the range of 20 to 50 mg/100ml ,symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting ,seizers, and even coma.

28. Effects of insulin on carbohydrate metabolism
Insulin increases glucose transport into and glucose usage by most other cells of the body (with the exception of brain cells) in the same way that it affects glucose transport and usage in the muscle cells .
The transport of glucose into adipose cells mainly provides substrate for the glycerol portion of the fat molecule .
Therefore ,in this indirect way ,insulin promotes deposition of fat in these cells.

29. Effect of insulin on fat metabolism
effects of insulin on fat metabolism : it causes extreme atherosclerosis ,often leading to heart attacks cerebral strokes ,and other vascular accidents.

30. Insulin promotes fat synthesis and storage
Insulin has several effects that lead to fat storage in adipose tissue .first insulin increases the utilization of glucose by most of the body’s tissue ,which automatically decrease the utilization of fat,
Insulin also promotes fatty acid synthesis .this is especially true when more carbohydrates are ingested than can be used for immediate energy ,thus providing the substrate for fat synthesis ,almost all these synthesis occur in the liver cells, and fatty acids then transported from the liver by way of the blood lipoproteins to adipose cells to be stored .

31. Role of insulin in storage of fat in the adipose cells
Insulin has two other essential effects that are required for fat storage in adipose cells:
1- insulin inhibits the action of hormone-sensitive lipase .This is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells .
2- insulin promotes glucose transport thought the cell membrane into the fat cells .Some of these glucose is then used to synthesize minute amounts of fatty acids ,it also forms large quantity of alfa-glycerol phosphate.

32. Effects of insulin on protein metabolism and on growth
-insulin promotes protein synthesis and storage :
During the few hours after a meal when excess quantities of nutrients are available in the circulating blood ,not only carbohydrate and fat but protein as well are stored in the tissues ,insulin is required for this to occur :
1- insulin stimulates transport of many of the amino acids into the cells.
2- insulin increases the translation of messenger RNA thus forming new proteins.
3- increase the rate of transcription of selected DNA .
4- insulin inhibits the catabolism of proteins ,thus decreasing the rate of amino acid release from cells especially from the muscle cells .
5-in the liver ,insulin depressed the rate of gluconeogenesis .

33. Insulin lack causes protein depletion and increase plasma amino acids:
. Decreased insulin increases the catabolism of proteins , and decreases protein synthesis ,so large amount of amino acids are dumped into the plasma, and most of the excess of amino acids are used either directly for energy or as substrates for gluconeogenesis.
. This degradation of amino acid also leads to enhanced urea exertion in the urine . The resulting protein wasting is one of the most serious of all effects of severe diabetes mellitus .

34. Factors and conditions that increase and decrease insulin secretion
Increase insulin secretion
-Decrease blood glucose
-fasting
-somatostatin
-Alfa-adrenergic activity
-increase blood glucose
-increase blood free fatty acid
-increase blood amino acid
-gastrointestinal hormones (gastrin, choleccystokinin ,secretin, gastric inhibitory peptide )
-glucagon, growth hormone, cortisol.
-parasympathetic stimulation
-insulin resistance ;obesity

35. Glucagon and it’s functions
Glucagon ,a hormone secreted by the alpha cells of the islets of Langerhans ,when the blood glucose concentration falls. has several functions that are diametrically opposed to those of insulin .Most important of these functions is to increase the blood glucose concentration ,an effect that is exactly the opposite that of insulin
Like insulin ,glucagon is a large polypeptide .it is composed of a chain of 29 amino acids
glucagon is also called the hyperglycemic hormone.

36. Effects on glucose metabolism
The major effects of glucagon on glucose metabolism :
1- breakdown of liver glycogen (glycogenolysis)
2- increased gluconeogenesis in the liver
* Both of these effects greatly enhance the availability of glucose to the other organs of the body.
* Glucagon causes glycogenolysis and increased blood glucose concentration:
* The most dramatic effect of glucagon is it's ability to cause glycogenolysis in the liver ,which in turn increase the blood glucose concentration within minutes

37. Glucagon is very high concentration also:
1- enhanes the strength of the heart
2- increase blood flow in some tissue especially in the kidneys
3- enhances bile secretion
4- inhibits gastric acide secretion
All these effects are probably of minimal importance in the normal function of the body.

38. Regulation of glucagon secretion
- Increased blood glucose inhibits glucagon secretion :
- increase blood amino acids stimulate glucagon secretion :
High concentrations of amino acids as occur in the blood after protein meals stimulate the secretion of glucagon .this is the same effect that amino acids have in stimulating insulin secretion.
Thus in this instance the glucagon and insulin responses are not opposite.

39. -exercise stimulates glucagon secretion :
In exhaustive exercise, the blood concentration of glucagon often increases fourfold to fivefold. A beneficial effect of the glucagon is that to prevents a decrease in blood glucose
One of the factors that might increase glucagon secretion in exercise is increased circulating amino acids .other factors such as beta –adrenergic stimulation of the islets of langerhans ,may also play a role .

40. Somatostatin inhibits glucagon and insulin secretion
somatostatin secretion is increased by the following;.
1-increased blood glucose
2-increased amino acids
3-increased fatty acids
4- increased concentrations of several of the gastrointestinal hormones released from the upper gastrointestinal tract in response to food uptake
In turn somatostatin has multiple inhibitory effects as follow:
1-acts locally within the islets of langerhans themselves to depress the secretion of both insulin and glucagon
2-decreases both secretion and absorption in the gastrointestinal tract
3-decrease the motility of the stomach ,duodenum, and gallbladder

41. Diabetes mellitus
Is a syndrome of impaired carbohydrate ,fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissue to insulin
There are two types of diabetes mellitus
1-type 1 diabetes also called insulin –dependent diabetes mellitus (IDDM) is caused by lack of insulin secretion
2-type 2 diabetes mellitus also called non-insulin- dependent diabetes mellitus (NIDDM) is caused by decrease sensitivity of target tissue to the metabolic effects of insulin (also called insulin resistance )

42. Type I Diabetes Mellitus
Childhood, or early onset, diabetes is caused by deficient insulin synthesis by the B cells of the pancreatic islets.
Injections of insulin can overcome the problem.
The deficiency can also be caused by the absence of normal insulin synthesis due to the production of a structurally abnormal insulin, or a defect in the conversion of proinsulin to insulin.

44. Type II Diabetes Mellitus
Occurs in most non-obese persons with adult onset diabetes
the insulin that is produced is normal but there is a defect in its secretion from the B cells.
Some diabetics make antibodies to the insulin receptor, which affects receptor function.
Such diabetics do not respond to insulin therapy.
In other insulin-resistant diabetics, the target cells have low levels of insulin receptors (down regulation) together with a high chronic excess of insulin secretion.
The cells are unable to respond to the high level of insulin in the blood, with severe metabolic consequences.
The condition is often associated with chronic obesity.

46. Clinical characteristics of patients with type 1 and type 2 diabetes mellitus
feature
Usually more than 30
Obese
Normal to high initially
High ,resistant to suppression
Increase
Reduce
Weight loss, thiazolidinediones
Metformin ,sulfonylureas,insulin
Usually<20 years
Low (wasted) to normal
Low or absent
High, can be suppressed
Increased
Normal
Insulin
Age at onset
Body mass
Plasma insulin
Plasma Glucagon
Plasma glucose
Insulin sensitivity
therapy

47. Physiology of diagnosis of diabetes mellitus
Urinary glucose
Fasting blood glucose and insulin level
Glucose tolerance test
Acetone breath