MB ChB Year 1: Nutrition and Energy

Lecture 21: Pancreatic islets, release of insulin and its effects.

Dr John Illingworth

Click here to download the printed handout sheets for lectures 21 & 22.


Berne & Levy "Principles of Physiology" page 822 onwards.
Kumar & Clark "Clinical Medicine" pages 959-989.
Nelson & Cox "Lehninger: Principles of Biochemistry" pages 445-447.
Rang & Dale "Pharmacology" pages 385-397.
Sherwood "Human Physiology" pages 592 - 595.
Tortora & Derrickson "Essentials of Anatomy and Physiology " pages 592 - 595.
Young et al "Wheater's Functional Histology" pages 324-325.

The pancreas has two separate functions: an exocrine activity performed by the acinar cells which manufacture and secrete digestive enzymes into the gut, and an endocrine activity of the islet cells which manufacture and release several peptide hormones into the portal vein.


Islet stem cells are now thought to have a local gut origin, and are not neural crest cells as was once imagined. The nerves that control them develop from neural crest. All varieties of islet cell are ultimately derived from the same type of stem cell.

The four principal peptide hormones are insulin, glucagon, somatostatin and amylin, of which insulin is the most important. There are many other minor products.


20% α cells - glucagon
70% β cells - insulin
5% δ cells - somatostatin
5% other minor cell types

Conventional histology does not reveal the differences between these cell types. β cells also produce a second hormone amylin that helps to regulate feeding. In addition there are a variety of minor products including motilin, pancreatic polypeptide, vasoactive intestinal peptide and substance P from the other cell types. All these products are peptide hormones, made on ribosomes, and packaged into storage / secretory granules.

Insulin and amylin are both manufactured by the β cells, and primarily released in response to raised blood glucose, although there are many other stimuli.


Glucose is the most important, and has a permissive effect on the other stimuli which include amino acids (alanine, leucine, arginine), 2-keto acids, peptide hormones (glucagon, GIP, GLP, CCK) and acetyl choline.

Free fatty acids have a biphasic effect: a short-term stimulation of insulin secretion is superseded by a long-term inhibition of insulin release.

Somatostatin and the catecholamines (adrenalin, noradrenalin) inhibit insulin release.

Insulin suppresses glucose output from the liver, and promotes glucose metabolism by most tissues other than brain, thereby returning blood glucose to the target value near 5mM. It has numerous other actions on fat and protein metabolism.

Amylin acts on the brain to regulate appetite and body weight. This is discussed in lecture 26.

Glucagon is produced by the α cells and secreted in response to low blood glucose. It has widespread anti-insulin effects, but it is not a complete opposite. Somatostatin from the δ cells is also produced by the pituitary and is discussed in lecture 24.

The β cells contain a glucose sensing system, which requires glucose to be metabolised. Islet cells have a membrane potential. They are excitable and communicate with one another.

Insulin release is biphasic there is a rapid release of stored product, followed by a second slower peak when new hormone has been synthesised. Amylin is released at the same time. The C-peptide generated during insulin manufacture is also released, and its absence from the circulation can distinguish injected from endogenous insulin.


Biphasic - immediate transient release of stored hormone from secretory granules, followed after about 30 minutes by a slower response requiring the completion of new product. Secretory granule docking at the plasmalemma requires calcium ions. The mechanism probably resembles other protein secreting cells.

The ATP concentration in most cells is high and constant, and it is very difficult to detect any variations. Glucose metabolism in β cells is inefficient, so that ATP levels in β cells depend on glucose availability. This is an important part of the sensing mechanism.

Glucose entry into β cells uses low-affinity transporters, so that the uptake rate varies with the blood glucose concentration. Intracellular glucose concentration tracks the external supply.


PorterMechanismGlucose KmLocationTissuesCharacteristics



20 mM


brain, red cells, endothelium, β cells

constitutive porter



42 mM


kidney, ileum, liver, pancreatic β cells

low-affinity porter



10 mM


neurones, placenta (trophoectoderm)

high-affinity porter



2 - 10 mM


skeletal muscle, heart, adipocytes






widely distributed

fructose transport


Na+ dependent

high affinity


small intestine, kidney tubules

high affinity uptake


Na+ dependent

low affinity


kidney proximal tubule

high capacity uptake

In epithelial cells, the high affinity and / or sodium-dependent glucose porters are located "outside" the body on the apical membrane of the cells, whereas the low-affinity passive porters are found on the baslolateral membrane, in contact with the blood. Non-polarised cells only express the passive porters. GLUT-2 can apparently translocate from the basolateral to apical membrane in the gut to deal with unusually high glucose concentrations. In addition, a vesicular glucose transport system from the endoplasmic reticulum to the extracellular space has recently been demonstrated in liver cells and enterocytes. This pathway requires glucose phosphorylation inside the cells and microsomal glucose 6 phosphatase.


The pancreatic islets are innervated by the autonomic nervous system and some of the pathways have been traced. Islet cells are excitable and their membrane potentials may oscillate.

Glucose is transported into β cells through GLUT1 and GLUT2 plasma membrane transporters. It is claimed that GLUT1 is the major pathway in humans, but this is not yet settled. Whatever the route, it is important that this is an inefficient transport system, so that the cells are normally starved of glucose. Any increase in plasma glucose consequently increases glucose availability within the cells.

Glucose phosphorylation in β cells uses low-affinity glucokinase. The enzyme is not saturated with its substrate. The phosphorylation rate varies with intracellular glucose concentration, so in β cells the glycolytic rate ultimately depends on the glucose concentration in arterial blood.

Glucose starvation affects the mitochondrial fuel supply, so in β cells the ATP concentration increases when blood glucose is high.

Glucose is activated within the β cells by the low-affinity glucose-phosphorylating enzyme, glucokinase. Once again, it is important that this system works slowly at low glucose concentrations, so that the energy supply inside the β cells varies with the external glucose concentration. The same low affinity enzyme is found in liver cells, where it serves to "cream off" the peaks in the portal blood glucose supply, while passing lower glucose concentrations straight through to the rest of the body. In most other tissues insulin regulates glucose entry into cells through the high-affinity GLUT4 transporters, and these tissues have the high-affinity hexokinase phosphorylation system.

Potassium efflux channels in β cells are inhibited by ATP. The channels close as ATP rises, thereby depolarising and activating the cells. (These channels are widely distributed in other excitable cells: in most tissues they are permanently closed at normal ATP levels, and open only rarely during adverse conditions, hyperpolarising and protecting the cells.)

Glucose metabolism raises ATP which closes ATP-sensitive potassium channels. (The same type of ion channel opens to protect overloaded heart muscle when ATP levels fall.) The resulting membrane depolarisation leads to opening of voltage dependent calcium channels (VDCCs) and calcium influx, triggering exocytosis of insulin secretory granules.

Depolarisation activates voltage-dependent calcium channels (VDCCs), triggering calcium spikes and action potentials. This leads to exocytosis and insulin release from stored secretory granules.

Islet tissue is also controlled by the autonomic nervous system. Many other compounds affect insulin release, using various signaling pathways. Local gut hormones that stimulate insulin release are known as incretins.

Several amino acids are insulin secretagogues. Leucine raises ATP through metabolism, but alanine and arginine directly depolarise the cells.

Acetylcholine and cholecystokinin stimulate via phospholipase C, diacyl glycerol and IP3.

Glucagon, GLP and GIP stimulate through G-proteins, adenyl cyclase and cyclic AMP.

Catecholamines signal via β-receptors, G-proteins and adenyl cyclase, but inhibit the granule docking system via a-receptors. The inhibitory effect normally prevails.

Free fatty acids have a biphasic action: a short term stimulation of insulin release through ATP generation, followed by a long-term inhibitory effect.

Glucose and 2-keto acids also stimulate through potassium channel independent routes.


Type 1 or "juvenile onset" diabetes is caused by autoimmune destruction of the islet cells. It is an acute life-threatening condition that always requires insulin injections. Crystallised or zinc insulin is used to delay absorption, because the half-life in plasma is only a few minutes.

Approximately 10% of diabetics first develop symptoms during childhood, as a result of an autoimmune attack upon their islet tissue. This juvenile onset or type 1 diabetes is typically severe, more likely to result in ketoacidosis, and involves the complete absence of circulating insulin in untreated individuals. As a result these patients always require insulin injections. Although some tissue types carry an increased risk, there is only partial correlation between identical twins, and an environmental trigger (probably a virus infection) is also necessary. Autoimmune β-cell destruction can happen at any age, but it is much rarer in later life.

Type 2 or "maturity onset" diabetes is much more common, and is associated with abdominal obesity. It is due to insulin resistance in the target tissues. Symptoms may be milder, but it still causes many deaths. Type 2 diabetes is now appearing in obese children. It may require insulin, but is often treated by diet, exercise and possibly oral hypoglycaemic drugs.

The majority of diabetics suffer from maturity onset or type 2 diabetes, which typically develops in older individuals who are commonly overweight. The β-cells continue to function in type 2 diabetics, but their peripheral tissues exhibit insulin resistance, so that circulating insulin may be higher than normal but their body fails to respond properly. Prolonged over-stimulation may eventually exhaust the β-cells and some type 2 diabetics may eventually require insulin, but the majority of patients can be treated with a combination of diet, exercise and oral hypoglycaemic drugs.

Type 2 diabetes may be part of the metabolic syndrome, a poorly-understood inflammatory process which also includes dislipidaemia, obesity, hypertension and cardiovascular disease.


Sulphonylureas such as tolbutamide and glibenclamide close the ATP-sensitive potassium channel by binding to a sulphonylurea receptor (SUR) closely associated with the channel.

Sulphonylureas (e.g. tolbutamide, glibenclamide) bind to a sulphonylurea receptor SUR associated with the ATP-sensitive potassium channel in islet cells. This closes the channel, depolarises the β-cells and stimulates insulin release. This is only useful in type 2 diabetics who retain some functional islet tissue. In type 1 diabetics there are no β-cells left to respond.

Biguanides such as metformin sensitise tissues to insulin. They reduce hepatic and intestinal glucose output, and stimulate glucose uptake by muscle.

Biguanide hypoglycaemic drugs such as metformin reduce hepatic glucose output, modulate glucose absorption and stimulate muscle glucose uptake. Their major effect is on the liver. Although these insulin-sensitisers need some circulating insulin, they do not require functional islet tissue. Metformin is relatively safe and cheap, so is the preferred therapy in most cases.

Thiazolidinediones (TZDs) such as rosiglitazone bind to peroxisome proliferator activated receptor gamma (PPAR-γ) altering gene expression and improving insulin sensitivity.

The thiazolidinediones (TZDs) such as rosiglitazone are a new class of oral hypoglycaemic drugs which bind to peroxisome proliferator activated receptor gamma (PPAR-g). Click here for a recent review. Their precise mechanism is still uncertain, but they are believed to alter the phosphorylation pattern on the insulin receptor and improve the insulin sensitivity of peripheral tissues. Weight gain is an unwanted side effect and metformin is still the preferred therapy.

Acarbose belongs to a fourth class of oral hypoglycaemic drugs which inhibit a-glycosidase in the gut and delay carbohydrate absorption.

Acarbose belongs to yet another class of oral hypoglycaemic drugs that delay carbohydrate absorption in the gut. These drugs do not require functional islet tissue. Acarbose inhibits a-glucosidase and reduces post-prandial glucose concentrations. The side-effects are flatulence and diarrhoea because delayed carbohydrate breakdown favours the growth of intestinal micro-organisms.

The various types of oral hypoglycaemic drug differ in their mode of action and so may be used in combination therapy with each other or with insulin.


We don't expect you to learn every last detail of these pathways, but you should appreciate the insulin has multiple targets, with different durations of action, and also realise how subtle these signalling mechanisms can be. Click the links below to see the details.

Insulin binds to a plasmalemma receptor in target tissues, which autophosphorylates itself on a tyrosine residue. This activates a protein kinase cascade, ultimately leading to a multitude of complex effects.

High affinity glucose carriers GLUT4 move quickly from storage vesicles to plasmalemma, increasing glucose uptake. (This does NOT happen in liver cells, which lack GLUT4.)

Insulin effects on glucose transport

Insulin causes a rapid stimulation of glucose uptake in adipose tissue and muscle tissue by re-locating GLUT4 glucose transporters from intracellular storage vesicles into the plasmalemma. The resulting glucose uptake helps to stabilise blood glucose levels.

Insulin activates the insulin receptor which phosphorylates Insulin Receptor Substrate (IRS). Phosphorylated IRS-P activates phosphatidylinositol 3 kinase in the plasmalemma, which converts phosphatidylinositol 4,5 bisphosphate (PIP2) into phosphatidylinositol 3,4,5 trisphosphate (PIP3). PIP3 activates PDK-1 (3-phosphoinositide dependent kinase 1) in the plasmalemma, and PDK-1 in turn phosphorylates protein kinase B (PKB) in the cytosol. PKB then stimulates the relocation of the storage vesicles to the plasmalemma.

Liver cells are freely permeable to glucose in both directions and liver glucose transporters do not respond to insulin. (Liver cells have high-Km glucokinase, like β cells, and operate with a high intracellular glucose concentration, but most tissues that regulate glucose entry have the low-Km hexokinase and keep their internal glucose concentration very low.)

Glycogen synthase is quickly activated in most tissues, increasing glucose storage.

Insulin effects on glycogen storage

In the absence of insulin, glycogen synthase kinase 3 phosphorylates and inactivates glycogen synthase. Insulin activates the insulin receptor which phosphorylates Insulin Receptor Substrate (IRS). Phosphorylated IRS-P activates phosphatidylinositol 3 kinase in the plasmalemma, which converts phosphatidylinositol 4,5 bisphosphate (PIP2) into phosphatidylinositol 3,4,5 trisphosphate (PIP3). PIP3 activates PDK-1 (3-phosphoinositide dependent kinase 1) in the plasmalemma, and PDK-1 in turn phosphorylates protein kinase B (PKB) in the cytosol. Activated PKB phosphorylates and inactivates glycogen synthase kinase 3. In the absence of kinase 3 activity, endogenous phosphatases remove the inhibitory phosphates from glycogen synthase, allowing this enzyme to return to full activity.

The glycolytic and lipogenic pathways are also activated, converting glucose into fat.

There is suprisingly little information on this topic. In adipocytes it may be a simple consequence of increased availability glucose and glycerol after enhanced glucose entry into cells, but this explanation cannot be true for liver.

Mitogen activated protein kinase (MAPK) moves into the nucleus, phosphorylating DNA binding proteins, and causing widespread changes in gene expression in about 24 hours.

Insulin effects on gene expression

Insulin activates the insulin receptor which phosphorylates Insulin Receptor Substrate (IRS). Phosphorylated IRS-1 forms a complex with Grb2, Sos and Ras. GTP turnover leads to activation of Raf-1. Activated Raf-1 phosphorylates MEK. Activated MEK phosphorylates MAPK (alias ERK). Insulin eventually leads to long term changes in gene expression via mitogen-activated protein kinase (MAPK) and sterol regulatory element binding proteins (SREBPs).

Sterol regulatory element binding proteins (SREBPs)

Some of this is very new research, which has not yet appeared in text books. My main sources of information for the following summary were a search for the keyword "SREBP" in the OMIM database and a review article by Goldstein et al (2006) Protein sensors for membrane steroids. Cell 124, 35 - 46. A new review has just been published by Bengoechea-Alonsoa and Ericsson (2007) SREBP in signal transduction Current Opinion in Cell Biology 19(2), 215-222.

Basic story: Insulin induces the sterol regulatory element binding protein SREBP-1 as a 125-kD precursor which is directed to the endoplasmic reticulum (ER). The ER also contains an "SREBP cleavage-activating protein" (SCAP) which possesses a sterol binding domain. In the absence of cholesterol, SCAP packages SREBPs into transport vesicles and escorts them from the ER to the Golgi, where they are cleaved by site-1 and site-2 specific proteases (S1P and S2P). The water soluble 68-kD SREBP cleavage product translocates to the nucleus and promotes transcription of a wide range of genes involved in fatty acid and sterol metabolism.

SREBP controlled genes include INSIG-1 (insulin induced gene 1) and HMG-CoA reductase, which is the first committed step in steroid biosynthesis. Both proteins are directed to the ER. When cholesterol is present, SCAP undergoes a conformational change and binds to INSIG-1, so SCAP can no longer chaperone SREBP to the Golgi. SREBP therefore remains in the ER and proteolytic conversion into the active soluble form ceases. Existing binding protein already in the nucleus is degraded. In the absence of the appropriate DNA binding protein, expression of the genes coding for cholesterol biosynthetic enzymes is switched off.

HMG-CoA reductase also possesses a sterol binding domain, which can associate with INSIG-1. In contrast to SCAP (above) association between HMG-CoA reductase and INSIG-1 is more sensitive to lanosterol than to cholesterol. The resulting protein complex is tagged with ubiquitin for proteolytic destruction in the proteosomes, and HMG-CoA reductase activity falls very steeply when lanosterol is present in excess. Ubiquitin is a small protein "tag" that is covalently attached to other proteins to mark them out urgent proteolysis and rapid removal from the cell.

Extra information: INSIG-1 is ubiquitinylated and rapidly degraded if it does not bind to SCAP. As a result the amount of INSIG-1 in the ER membrane and the transcription of INSIG-1 mRNA within the nucleus are reciprocally related. Liver also expresses a second isoform INSIG-2a which is repressed by insulin. Expression of INSIG-2a is not regulated by SREBPs.

Three SREBP isoforms are present in liver. It is believed that SREBP-1c is manly concerned with the regulation of fatty acid biosynthesis, and that SREBP-2a is mainly concerned with cholesterol biosynthesis. SREBP-1a appears to be involved in both pathways. These complications are apparently necessary to allow fatty acid production to continue when cholesterol production is suppressed, and also to permit synthesis of other isoprenoid compounds (such as ubiquinone) when sterol concentrations are adequate.

Lanosterol is potentially toxic, and the rapid proteolytic destruction of HMG-CoA reductase in the presence of lanosterol may prevent over-production, while ensuring that other steroid conversion enzymes are still transcribed to process the lanosterol that has already been produced.

HMG-CoA reductase is easily released from the ER by proteolysis during tissue homogenisation. It was therefore imagined to be a soluble enzyme, because it retains catalytic activity although its delicate regulatory properties are completely lost in the solublised version.


Here is a practice Extended Matching Question (EMQ) on hormonal signaling. This formative example can be completed electronically with feedback, but your summative examination after completing the course will be a purely paper exercise.

Theme: insulin signaling mechanisms

Examine the cartoon below which depicts some of the systems that help to stablise blood glucose concentration in humans. Select the most appropriate labels from the list provided that most accurately describe the signaling mechanisms. Each option may be used once, more than once or not at all.

  1. protein kinase A

  2. protein kinase B

  3. protein kinase C

  4. extracellular regulated kinase (ERK, MAPK)

  5. glucokinase

  6. GLUT2

  7. GLUT4

  8. glycogen phosphorylase

  9. glycogen synthase kinase 3

  10. heterotrimeric G protein

  11. hexokinase

  12. RAS

  13. sulphonyl urea receptor

Which component is which?

cellular proteins options

    feedback options:

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Insulin signaling the basic essentials.

  1. Insulin is secreted by β cells in the pancreatic islets in response to arterial glucose >5mM.

  2. Glucose must be metabolised and increase ATP in β cells in order to stimulate insulin release.

  3. ATP depolarises β cells by closing potassium channels associated with sulphonylurea receptors.

  4. Depolarisation opens calcium channels, releases storage vesicles and increases insulin production.

  5. Incretins such as cholecystokinin and enteroglucagon from the gut wall potentiate insulin release.

  6. Glucose uptake by hepatocytes and β cells uses low-affinity, passive glucose transporters.

  7. Glucose phosphorylation by hepatocytes and β cells uses low-affinity, high-capacity glucokinase.

  8. Glucose uptake by extra-hepatic tissues uses high-affinity, insulin-dependent GLUT4 transporters.

  9. Glucose phosphorylation within most extra-hepatic tissues uses high-affinity hexokinase.

  10. Glucose uptake from the gut lumen and kidney tubules uses sodium-dependent glucose transporters.

  11. Type 1 "juvenile onset" diabetes is caused by an auto-immune T-cell attack on the β cells.

  12. Type 1 diabetics easily develop life-threatening ketoacidosis and always need to take insulin.

  13. Type 2 "maturity onset" diabetes is associated with obesity, low-grade inflammation and insulin resistance.

  14. Type 2 diabetics rarely get ketoacidosis, may not need insulin, are often treated by diet, exercise and hypoglycaemic drugs.

  15. Sulphonylureas require some functional islet tissue, so can only be used for type 2 diabetics.

  16. Biguanides such as metformin increase insulin sensitivity, can be used in type 1 and type 2 diabetes.

  17. Thiazolidinediones such as rosiglitazone are new hypoglycaemic drugs which bind to PPAR-g.

  18. Acarbose delays carbohydrate digestion and absorption in the gut and reduces insulin requirements.

  19. Insulin sharply reduces blood glucose and promotes the synthesis of glycogen, fats and proteins.

  20. Insulin binds to a plasmalemma receptor in target tissues, initiating three main actions:


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