Insulin and GlucagonInsulin and Glucagon

Steroid HormonesSteroid Hormones

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Pancreas

Exocrine pancreas Endocrine pancreas

Digestive enzymes Insulin Glucagon Somatostatin Pancreatic polypeptide

The pancreas contains two distinctly different tissues. The bulk of the mass is exocrine tissue and associated ducts which produce an alkaline fluid with digestive enzymes that is delivered to the small intestine. Scattered throughout the exocrine tissues are clusters of endocrine cells which produce, among others, the hormones insulin and glucagon.

Cell types in the endocrine pancreatic Islets of Langerhans

A cell () Glucagon, proglucagon, glucagon-like peptides (GLP-1, GLP-2)

B cell () Insulin, C peptide, proinsulin, amylin, -aminobutyric acid (GABA)

D cell () Somatostatin

F cell (PP cell) Pancreatic polypeptide

Cell types Secretory Products

Three Islets of Langerhans in the pancreas of a horse

Beta cells usually occupy the central portion of an islet and are surrounded by alpha and delta cells.

In 1916 Nicolae Paulescu, a Romanian professor of physiology, In 1916 Nicolae Paulescu, a Romanian professor of physiology, developed an aqueous pancreatic extract which, when injected developed an aqueous pancreatic extract which, when injected into a diabetic dog, proved to have a normalizing effect on blood into a diabetic dog, proved to have a normalizing effect on blood sugar levels. He had to interrupt his experiments because the sugar levels. He had to interrupt his experiments because the World War I and in 1921 he wrote four papers about his work World War I and in 1921 he wrote four papers about his work carried out in Bucharest and his tests on a diabetic dog. Later that carried out in Bucharest and his tests on a diabetic dog. Later that year, he detailed his work by publishing an extensive whitepaper year, he detailed his work by publishing an extensive whitepaper on the effect of the pancreatic extract injected into a diabetic on the effect of the pancreatic extract injected into a diabetic animal, which he called: "Research on the Role of the Pancreas in animal, which he called: "Research on the Role of the Pancreas in Food Assimilation“.Food Assimilation“.

The Nobel Prize committee in 1923 credited the practical extraction of insulin to a team at the University of Toronto and awarded the Nobel Prize to two men: Frederick Banting and J.J.R. Macleod.

Synthesis and secretion of insulin

Preproinsulin

Preproinsulin is a long-chain polypeptide (MW 11,500) produced by mRNA-directed translation in the rough endoplasmic reticulum.

Proinsulin

Preproinsulin is cleaved immediately after synthesis to proinsulin (MW 9000). Proinsulin is transported to the Golgi and packaged into secretory granules.

Insulin and C peptide

Maturation of the secretory granule involves proteolytic cleavage of proinsulin into insulin and C peptide. Normal mature secretory granules contain these in equimolar amounts and only small quantities of proinsulin.

Processing of Insulin

Proinsulin consists of a single chain of 86 amino acids which includes the A and B chains of insulin, and a connecting segment of 35 amino acids.

Insulin hexamer with two Zn atoms

The hexameric form of insulin is thought to exist in the secretory granules of the

pancreatic B cells.

Glucose Transporters

All cells require proteins to transport glucose across the lipid bilayers into the cytosol.

The intestine and kidney have an energy dependent

Na+/glucose cotransporter.

All other cells have non-energy dependent transporters that facilitate diffusion of glucose from a higher concentration to a lower concentration across cell membranes. At least five “facilitative glucose transporters” have been described, and these have different affinities for glucose (GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5).

Human glucose transporters

GLUT1 Brain vasculature, red blood cells, all tissues

High

GLUT2 Liver, pancreatic B cells, serosal surfaces of gut and kidney

Low

GLUT3 Brain neurons, all tissues High

GLUT4 Muscle, fat cells Medium

GLUT5 Jejunum, liver, spermatozoa Medium

Transporter Major sites of expressionAffinity for glucose

GLUT1 is present in all tissues especially brain vascular system (blood-brain barrier). Its high affinity for glucose ensures adequate uptake even at low blood glucose levels (basal levels).

GLUT3 is the main neuronal glucose transporter. It has a very high affinity for glucose and is responsible for transferring glucose from the cerebrospinal fluid into neuronal cells.

GLUT2 has a low affinity for glucose. It is the major transporter in the liver and pancreatic B cells. This insures that insulin is secreted only when blood glucose levels are high. It also prevents hepatic uptake when levels are basal or low as during fasting.

GLUT4 is found in two major insulin-targeted tissues, muscle and adipose tissue. It is not present to a great extent on the cell surface until an insulin signal relocates these transporters to the cell membrane. Thus GLUT4 functions primarily after a high carbohydrate meal when insulin is secreted.

GLUT5 appears to function biochemically as a fructose transporter.

Glucose is the most potent simulate to pancreatic B cells for insulin secretion.

Glucose enters B cells through GLUT2 (low affinity for glucose). The metabolism of glucose is apparently required for insulin secretion. The rate limiting step for glucose utilization in the B cells is phosphorylation to glucose-6-phosphate by the low-affinity enzyme glucokinase.

Glucose induces cAMP formation in B cells. However, increased [cAMP] will not induce insulin in the absence of glucose.

Insulin release also requires Ca2+ ( microtubules that

contract in response to Ca2+ may play a role in the ejection of insulin granules).

Stimulus for insulin secretion

Multiphasic response of the in vitro perfused pancreas during constant stimulation with glucose

Insulin Receptors

Insulin action begins with the binding to specific cell surface receptors.

Insulin receptors are membrane glycoproteins composed of two subunits: a larger subunit which extends beyond the cell surface and is involved in the binding of insulin, and a smaller subunit which is predominately intracellular and contains tyrosine kinase activity.

Upon insulin binding, signal transduction results in autophosphorylation of the receptor tyrosine kinase. This now activated complex, interacts with and phosphorylates a network of as many as nine intracellular proteins.

The insulin receptor is a tyrosine-specific kinase

Upon insulin binding, signal transduction causes

autophosphorylation of the receptor, activating the complex. The target

proteins, IRS-1 and IRS-2, are then phosphorylated.

The immediate targets for the activated insulin receptor tyrosine kinase are insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2).

IRS-1 becomes the point of nucleation for a complex of proteins that carry the signal from the insulin receptor to end targets in both the cytosol and the nucleus.

IRS-1: insulin receptor substrate-1

PI-3K: phosphatidylinositiol 3-kinase (phosphorylates

phosphatidylinositol-4,5-bisphosphate (PIP2) to form

phosphatidylinositol-3,4,5-trisphsophate (PIP3).

PKB: protein kinase B

PDK1: a protein kinase

GSK3: glycogen synthase kinase 3

GS: glycogen synthase

GluT4: glucose transporter 4

Abbreviations used in previous figure

Metabolic effects of insulin

The major function of insulin is to promote storage of ingested nutrients. Blood glucose is converted to glycogen (muscle and liver) and into triacylglycerols (adipose tissue).

Liver

Promotes glucose storage as glycogen

Increases triglyceride synthesis and VLDL formation

Inhibits glycogen breakdown

Inhibits conversion of fatty acids and amino acids to keto acids

Inhibits conversion of amino acids to glucose

Muscle

Increases ribosomal protein synthesis

Increases amino acids uptake

Increases glucose transport

Increases glycogen synthesis and inhibits glycogen breakdown

Adipose tissue

Increases triglyceride storage

Inhibits intracellular lipase

Promotes uptake of fatty acids

Increases glucose transport

Reduces fatty acid flux to the liver

Metabolic effect Target enzyme

Glucose uptake (muscle) Glucose transporter

Glucose uptake (liver) Glucokinase

Glycogen synthesis (liver, muscle) Glycogen synthase

Glycogen breakdown (liver, muscle) Glycogen phosphorylase

Glycolysis, acetyl-CoA production (liver, muscle)

Phosphofructokinase-1, pyruvate dehydrogenase complex

Fatty acid synthesis (liver) Acetyl-CoA carboxylase

Triacylglycerol synthesis (adipose) Lipoprotein lipase

Metabolic effects of insulin

Glucagon

Synthesized in the A cells of the Islets of Langerhans, the precursor molecule, proglucagon, is composed of 160 amino acids. Within this prohormone are several other peptides connected in tandem:

glicentin-related polypeptide (GRPP)

glucagon

glucagon-like peptide-1 (GLP-1)

glucagon-like peptide-2 (GLP-2)

Levels of GLP-1 and GLP-2 both increase after meals.

A truncated derivative of GLP-1 (residues 7-37) is an extremely potent stimulator of pancreatic B cells. This molecule is thought to be the major physiological “gut” factor which potentiates glucose-induced insulin secretion.

Intact GLP-1 and GLP-2 do not stimulate insulin secretion.

Tissue specific secretory products of human proglucagon

Secretion of glucagon

The release of glucagon is controlled primarily through suppression by glucose and insulin.

Glucagon secretion is inhibited by glucose. This may be direct, or indirect via the release of insulin and somatostatin.

Several hours after the intake of dietary carbohydrates, blood glucose levels fall below 4.5 mM and trigger the secretion of glucagon. Basically, this signal says: glucose is gone.

Other substances that stimulate glucagon release:

catecholamines (epinephrine)

the gastrointestinal hormones (cholecystokinin, gastrin, and gastrin-inhibitory peptide)

glucocorticoids (cortisol)

Many amino acids stimulate glucagon release:

Arginine: releases both insulin and glucagon

Leucine, a good stimulant for insulin release, does not release glucagon.

Alanine stimulates glucagon primarily.

High levels of fatty acids are associated with suppression of glucagon release.

Glucagon Receptors

The liver is one of the major target organs for glucagon.

Glucagon binds to hepatic receptors in the cell membrane and stimulates adenylyl cyclase and thus increases the intracellular concentration of cAMP.

Metabolic effects of glucagon

Glucagon acts to maintain fuel availability in the absence of dietary glucose.

Glucagon stimulates the breakdown of stored glycogen, maintains hepatic output of glucose from amino acid precursors (gluconeogenesis), and promotes hepatic output of ketone bodies from fatty acid precursors (ketogenesis).

Uptake of alanine by liver cells is facilitated by glucagon and fatty acids are directed away from reesterification to triacylglycerols and toward ketogenic pathways.

Metabolic effects of glucagon

Glycogen breakdown (liver) Glycogen phosphorylase

Glycogen synthesis (liver) Glycogen synthase

Glycolysis (liver) Phosphofructokinase-1

Gluconeogenesis (liver) Fructose-1,6-bisphosphatase

Pyruvate kinase

Fatty acid mobilization

(adipose tissue)

Triacylglycerol lipase

Metabolic effect Target enzyme

Blood glucose, insulin, and glucagon levels after a high carbohydrate meal.

Release of insulin and glucagon after a high

protein meal (100 grams of protein after

an overnight fast)

Insulin levels do not increase nearly as much as after a high carbohydrate meal.

Glucagon increases above fasting levels.

Steroid hormonesproduction

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