Endocine Lecture 4 - Pancreas

Front 1

What is the normal glucose concentration in the blood?

Back 1

-plasma glucose is normally maintained within a relatively normal narrow range of 3.9-6.1 mmol/L (700 mg/L-1100 mg/L)

Front 2

Describe the the anatomy & cell types found in the pancreas

Back 2

-the pancreas is anatomically located such that hormones are secreted into pancreatic vein → preferentially affects liver

1. Glucagon: Catabolic hormone secreted by α cells. These cells make up 25% of the islets

2. Insulin: Anabolic hormone secreted by β cells. These cells make up 60% of the islets

3. Somatostatin secreted by δ ells. Inhibits digestive processes and other pancreatic hormones. These cells make up 10% of the cells in the islets

4. Pancreatic polypeptide: Secreted by F cells. Increases gut motility and gastric emptying

Front 3

Describe the pancreatic interactions

Back 3

-within the islets, cells are in close proximity to one another
-this isimportant for regulating secretion as it promotes paracrine interactions and allows cell-cell contact and signalling via gap junctions to occur
-β cells occur at the core and α cells toward the outer mantle

1. Insulin secretion → decreased glucagon secretion

2. Glucagon secretion → increased insulin & increased somatostatin secretion

3. Somatostatin secretion → decreased insulin & glucagon secretion

Front 4

Describe the synthesis of insulin

Back 4

-insulin contains an α and a β chain joined by 2 disulfide bridges
-proinsulin is synthesized as a single-chain peptide
-within storage granules, a connecting peptide (C peptide) is removed by proteases to yield insulin
-the C peptide is packaged and secreted along with insulin
-insulins from different species differ in little activity
-bovine, porcine, and human insulin can be used interchangeably to treat diabetes in humans, dogs and cats

Front 5

Describe the regulation of insulin secretion

Back 5

A) Blood glucose concentration
-is the major factor that regulates insulin secretion
-increased blood glucose stimulates insulin secretion. An initial burst of insulin is followed by sustained secretion
-in the acute phase (10 min) release of preformed insulin occurs
-in the chronic phase (rises over the next hour) release of newly formed insulin occurs
-insulin is secreted into the portal vein which ensures the liver receives higher concentrations of insulin
-1/2 life of insulin in blood is 5-8 mins
-metabolised by kidney and liver by the enzymes insulinase that splits disulphide bonds

B) Blood amino acid (arginine and alanine)

C) Gastrointestinal hormones (e.g. cholecystokinin)

D) Parasympathertic stimulation

✩Insulin secretion is inhibited by:
-low plasma glucose (fasting, exercise)
-somatostatin sympathetic stimulation
-sympathetic α-adrenergic activity

Front 6

Describe the mechanism of secretion of insulin

Back 6

-glucose, the stimulant of insulin secretion, binds to the Glut2 receptor on the beta cells
-inside the beta cells, glucose is oxidized to ATP, which closes K+ channels in the cell membrane and leads to depolarization of the beta cells
-depolarization opens Ca2+ channels, which leads to an increase in intracellular [Ca2+] and then to secretion of insulin

Front 7

Describe the insulin receptor

Back 7

-is found on target tissues for insulin
-is a tetramer with 2 α subunits and 2 β subunits
-the β subunits span the cell membrane and have tyrosine kinase activity. When insulin binds to the receptor, tyrosine kinase autophosphorylates the β subunits. The phosphorylated receptor then phosphorylates intracellular proteins.
-the insulin-receptor complex enters target cells
-insulin down-regulates its own receptors in target tissues
-therefore the number of insulin receptors is increased in starvation, and decreased in obesity

Front 8

Describe the actions of insulin

Back 8

✩INSULIN DECREASES BLOOD GLUCOSE CONCENTRATION
-it increases uptake of glucose into target cells by directing the insertion of glucose transporters into cell membranes. As glucose enters the cells, the blood glucose concentration decreases
-it promotes formation of glycogen from glucose in muscle & liver, and simultaneously inhibits glycogenolysis
-it decreases gluconeogenesis. Insulin increases the production of fructose 2,6 bisphosphate, increasing phosphofructokinase activity. In effect, substrate is directed away from glucose formation

✩INSULIN DECREASES BLOOD FATTY ACID AND KETOACID CONCENTRATIONS
-in adipose tissue, insulin stimulates fat deposition and inhibits lipolysis
-stimulates glucose uptake via carrier system (GLUT 4)
-stimulates glycolysis
-some effect on protein metabolism
-insulin inhibits ketoacid formation in the liver because decreased fatty acid degradation provides less acetyl CoA substrate for ketoacid formation
-important role in upregulating lipoprotein lipase which promotes breakdown of triglycerides in blood (VLDL & chylomicrons) to free glycerol and free fatty acids. The fatty acids are taken up by adipocytes for triglyceride formation. Also inhibits hormone sensitive lipase which is needed for triglyceride uptake.

✩INSULIN DECREASES BLOOD AMINO CONCENTRATIONS
-insulin stimulates amino acid uptake into cells, increases protein synthesis, and inhibits protein degradation. Thus insulin is ANABOLIC

✩INSULIN DECREASES BLOOD K+ CONCENTRATIONS
-insulin increases K+ uptake into cells, thereby decreasing blood [K+]

✩MUSCLE
-simulates glucose uptake via carrier system (GLUT 4). With prolonged exercise and lower blood glucose ie. low insulin levels glut 4 transport molecules are still needed to promote glucose entry into muscle cells but are mobilized by low O2 levels
-stimulates glycolysis
-stimulates glycogen synthesis
-stimulates protein synthesis
-promotes protein synthesis

✩LIVER
-stimulates glycolysis: glucose → pyruvate + lactate (glycolysis)
-reduced glucose output (reduced glycogenolysis)
-some effect on amino acid metabolism to promote protein synthesis
-simulates fat synthesis; anti-ketogenic (inhibits β-oxidation)

Front 9

Describe the regulation of glucagon secretion

Back 9

-the major factor that regulates glucagon secretion is the blood glucose concentration
-decreases in blood glucose stimulate glucagon secretion
-secretion is mediated by Ca2+ like in β cells
-when α-cell metabolism is low, K+ channels are open but because α-cells possess voltage-gated Na+ channels and T-type Ca2_ channels, which are activated at more negative membrane potentials, α=cells fire action potentials in the absence of glucose
-consequently Ca2+ rises inside the cell and secretion is stimulated
-when glucose levels increase glycolysis increases (ATP increases) and K+ channels close = membrane depolarization & inactivation of voltage gated Na+ channels and T-type Ca2+ channels and inhibition of glucagon secretion

Front 10

Describe the actions of glucagon

Back 10

-acts on the liver and adipose tissue
-the second messenger for glucagon is cAMP

✩GLUCAGON INCREASES BLOOD GLUCOSE CONCENTRATION
-it increases glycogenolysis and prevents recycling of glucose into glycogen
-it increases gluconeogenesis. Glucagon decreases the production of fructose 2,6 bisphosphate, decreasing phosphofructokinase activity; in effect, substrate is directed toward glucose formation rather than toward glucose breakdown

✩GLUCAGON INCREASES BLOOD FATTY ACID AND KETOACID CONCENTRATION
-glucagon increases lipolysis. The inhibition of fatty acid synthesis in effect "shunts" substrates towards gluconeogenesis
-ketoacids (β-hydroxybutyrate and acetoacetate) are produced from acetyle coenzyme A (CoA), which results from fatty acid degredation

✩GLUCAGON INCREASES UREA PRODUCTION
-amino acids are used for gluconeogenesis (stimulated by glucagon) and the resulting amino groups are incorporated into urea

Front 11

What is type I diabetes mellitus, what is it characterized by? What causes it?

Back 11

-destruction of β-islet cells:
1) immune destruction (autoimmunity)
2) Severe pancreatitis (dogs). Progressive loss of exocrine & endocrine cells & replacement by fibrous connective tissue
3) Amyloidosis (cats). Specialized degenerative lesions in the islets of Langerhans. Insulin secreted with islet-associated polyprotein (IAAP). IAAP not removed properly in cats and it gets converted into amyloid and interferes with β cell function

Characterized by:
Damage to β-cells
1. Mononuclear cell infiltration
2. Autoantibodies (insulin, glutamic acid decarboxylase, islet cell cytoplasmic proteins)

Destruction → no insulin or secretion severely impaired may result in development of a ketoacidosis)
-treatment is by exogenous insulin replacement

Front 12

What is type II diabetes mellitus?

Back 12

1. Non-insulin dependent or maturity onset
-down regulation of insulin receptors → decreased sensitivity to insulin. Insulin + receptor internalized. Insulin destroyed and 90% receptor recycled. Continual stimulation → decreased receptor density → reducd response (at target cell and β cell)
-lack of appropriate response by insulin receptors
-also fault in degree of response by β cell (inadequate secretion)

Front 13

What are the acute effects of diabetes mellitus?

Back 13

-hyperglycemia (elevated blood glucose levels) due to reduced uptake of glucose by cells and increased output of glucose from liver

1) Glucosuria (glucose in urine) due to exceeding reabsorption capacity of kidneys

2) Osmotic diuresis. Glucose in urine is associated with H2O and polyuria → dehydration → peripheral circulatory failure due to reduced blood volume

3) Circulatory failure can lead to low cerebral blood flow or secondary renal failure due to inadequate filtration pressure

4) Cell shrinking as extracellular fluid becomes more hypertonic → nervous system damage

5) Lipolysis increases → increased mobilization of fatty acids (as an alternative energy source) & increased ketogenesis → ketosis (excessive ketone bodies in blood). Ketone bodies include several different acids e.g. acetoacetic acid → metabolic acidosis → diabetic coma & death

6) Protein degradation → muscle wasting

Front 14

What are the long term effects of diabetes mellitus?

Back 14

1. As blood glucose increases some tissues such as neurons, kidneys, blood vessels and lens of the eye convert glucose into sorbitol via polyol pathway and aldose reductase. This pathway is activated in hyperglycaemia because the KM of glucose for aldose reductase is high (70 mM). Sorbitol does not cross cell membranes, accumulates intracellularly and produces osmotic swelling hypoxia and damage. Results in reduced transparency of the lens (cataracts). Also affects vascular endothelial cells of the retina, kidney and nervous tissue

2. Non enzymatic glycosylation of basement membrane proteins results in altered protein functions and advanced glycation end products. Can lead to thickening of basement membrane, leaky blood vessels, microaneurysms, hemorrhage and infarcts.

Results in a range of microangiopathy diseases (mainly in humans) such as non proliferative & proliferative retinopathy, nephropathy, glomerulosclerosis angiopathy, atherosclerosis and neuropathy.