The Endocrine Pancreas:

Although the pancreas is 98% exocrine it also does have 2% endocrine function. The islets of langerhans are responsible for this endocrine function. The islets are composed of alpha and beta cells. Core of B cells Alpha cells on periphery Juxtaposition of endocrine cells facilitates cell cell communication. This communication is paracrine i.e. hormonal or via gap junction coupling i.e. electrochemical. The structure of the islet allows tight coupling between insulin and glucagon secretion in relation to plasma glucose

Cell types cells (20%) secrete glucagon cells (70%) secrete insulin Delta cells (8%) secrete somatostatin in response to decreased GH in the hypothalamus Pp cell (1%) secrete pancreatic polypeptide Epsilon cells (1%) secrete ghrelin in response to increased GH

Islet vasculature

The vasculature of the islets flows from core to mantle involving fenestrated capillaries. This radial blood flow to the periphery facilitates paracrine regulation of glucagon secretion by insulin (from B cells)

Innervations Innervated by both branches of ANS Sympathetic = splanchnichave a variable effect on a and B cell hormone secretion. A2 adrenergic activation results in decreased insulin and increased glucagon secretion. B adrenergic activation results in increased insulin secretion. Parasymp = vagusstimulate insulin and glucagon secretion via muscarinic receptors Many peptidergic neurons somatostatin, vasoactive intestinal peptide, calcitonin gene related peptide

Insulin: Synthesis: Preproinsulin Processed to mature insulin (and C peptide) in golgi apparatus and secretory granules Enzymes: prohormone convertase 1, 2, 3, carboxypeptidase E cleaves basic aa from C terminus Proinsulin (<10% bioactivity of insulin)

B cell glucose sensing and insulin secretion glucose binds to heteroligomeric insulin receptors stimulating autophosphorylation of the receptor Leads to phosphorylation of the docking proteins IRS1/2 These proteins are coupled to mitogen activated protein (MAP) kinase and phosphoinositol 3 (PI3) kinase signaling cascades Leads to translocation of the vesicles containing GLUT4 glucose transporter to the plasma membrane, facilitating glucose uptake by target tissues Taken into the B cell through the membrane bound GLUT2 transporter Phosphorylated to glucose-6 phosphate by glucokinase to induce glycolysis Metabolized to produce ATP

ATP binds to and inactivates K+ channel Membrane depolarization and opening of voltage dependent Ca++ channels Increase in intracellular Ca++ triggers exocytosis of the insulin from secretory granules Sulphonylurea drugs act at this ATP sensitive potassium channel Insulin is stored in vesicles and released by exocytosis

Regulation of insulin secretion Direct Nutrients glucose, amino acids and fatty acids increase secretion Neural sympathetic activity decreases secretion, parasymp increases secretion Hormonal gastric inhibitory peptide, glucagon like peptide increase secretion, somatostatin decreases secretion Indirect any agent which influences blood glucose levels

Insulin secretion is biphasic. 98% secretion is stimulated while 2% is basal secretion.

1st phase corresponds to the exocytosis of docked granules 2nd phase requires mobilization from a reserve pool

Metabolic action

Glucagon Synthesized as precursor or processed in extrapancreatic tissue to generate glucagon like peptide (GLP) and other glucoregulatory peptide hormones Stimulus to secretion is decreased blood glucose levels i.e. less than 5mM Its actions oppose that of insulin

Regulation of secretion Direct.. Nutrients low glucose and amino acids (arginine) stimulate secretion. High glucose inhibits glucagon secretion in presence of insulin. Fatty acids inhibit secretion Hormones gastrointestinal hormones: GIP or cholecystokinin are stimulatory, GLP-1 or somatostatin are inhibitory. Islet hormones insulin and somatostatin are inhibitory. ANS activation of sympathetic and parasymp stimulate secretion

Metabolic actions It is a counter regulatory hormone that opposes the aactions of insulin. It mainly acts on the liver carbohydrate metabolism: increases gluconeogenesis and glycogenolysis and decreases glycogenesis.

Lipid metabolism: increases ketogenesis i.e. increased fatty acid break down Protein metabolism: decreases hepatic protein synthesis and increases breakdown

Pancreatic polypeptide 36 amino acid peptide Secretion stimulated by Mixed meal protein content of meal + protein stimulation Fasting Exercising Acute hypoglycaemia Function is not really known but thought to be a satiety factor

Somatostatin 14 amino acid peptide Synthesized as a prehormone in the pancreas, gut and brain Signals via Gia protein coupled receptor & effects are inhibitory

HORMONAL REGULATION OF CARBOHYDRATE METABOLISM: Glucose: Storage Glycogen is storage form Polymeric, highly branched structure 10% liver mass, 1-2% muscle mass Short to medium term energy reserve can be rapidly mobilized, NB role in maintaining blood glucose between meals Metabolism is hormonally regulated

as a metabolic fuel Yields a significant amount of energy when oxidized Efficiently stored Can be used by virtually all cells Obligatory fuel substrate for the brainuses 25% of oxidized glucose, neurons cannot store glucose so need a constant supply Sources diet & glycogen reserves After a prolonged period of fasting or intense exercise when these sources are depleted the body has to have a mechanism to mobilize its reserves and to make its own glucose de novo

blood glucose levels hyperglycaemia supply exceeds demand normoeuglycaemia supply and demand matched hypoglycaemia demand exceeds supply euglycaemia is a balancing act between opposing hormonal and biochemical actions

Metabolic fates of glucose

Glycogenesis making glycogen from glucose for storage o Stimulated by insulin o Insulin signals energy abundance o Activates protein phosphatase 1 which in turn increases glycogen synthase and decreases glycogen phosphorylase and phosphorylase kinase o Increased glycogen synthesis and decreased glycogenolysis

Glycogenolysis breaking down glycogen for energy Stimulated by glucagon (from pancreas) and epinephrine (from adrenal medulla) Glucagon acts via the Gs coupled receptor in the liver to increase cAMP and thus increase PKA Epinephrine acts on the B2 adrenergic receptor (Gs) in muscle to increase cAMP and Ca++ thus increasing PKA. In liver and adipose tissue it acts on a1 receptor to increase PIP and Ca++ Activate GP by activating GPK Inhibit GS mediated by PKA

PKA activates/inhibits key enzymes in glucose/glycogen metabolism Opposite effect to insulin

Gluconeogenesis new glucose from non-carbohydrate sources Most active in fasting state, during prolonged exercise and conditions of carbohydrate starvation Livers and a little bit in kidneys Pyruvate NB so that brain and muscle (unable to make own glucose) can get sufficient glucose to maintain their metabolic needs Brain and muscle supply the metabolic intermediates (raw ingredients) 7 steps of glycolysis + 3 are replaced

Hormonal regulation of gluconeogenesis and glycolysis

Glycolysis breaking down glucose for energy

Occurs in all cells No requirement for O2 In cytosol 10 reactions in 2 phases

Hormonal regulation of fatty acid synthesis: Acetly CoA carboxylase is rate limiting enzyme It is a precursor of malonyl CoA. This is a precursor for FA synthesis which works by inhibiting carnitine acyl transferase I and thus reduces FA entry into mitochondria ACC is regulated by hormones that control activity of protein kinases and phosphatases Glucagon (and epinephrine) activates protein kinases which inhibit ACC (& thus decreases malonyl A levels) switches lipid metabolism from FA synthesis to oxidation no more glucose to switch to FAs as an energy source activate hormone sensitive lipase which hydrolyses triacylglycerols to FAs and glycerol

Insulin activates protein phosphatases with activate/dephosphorylate ACC (so increased malonyl CoA) switches lipid metabolism from oxidation to FA synthesis

DIABETES: A disorder caused by the presence of too much glucose in the blood. Chronic disorder of carbohydrate, fat and protein metabolism Characterized by hyperglycaemia, altered metabolism of lipids, ketonuria, carbohydrates and proteins, increased risk of complications from vascular disease It is a rising global burden and the number of people with diabetes will double in the next 25 years to reach a total of 366 million. The link between insulin secreted from the pancreas and diabetes was discovered by Frederick Banting and Charles Best in 1921.

2 main forms: Type I and II diabetes have very similar symptoms but have very different causes. Type 1 = absolute insulin deficiency, unable to produce the insulin signal Type 2 = relative insulin deficiency with peripheral tissue resistance, do produce insulin but have lost the ability to respond to the insulin. However the end result of both is that blood sugar levels become dangerously high.

Other forms include MODY and gestational diabetes Diagnosis of diabetes

Random plasma glucose of >11.1 mmol Fasting plasma glucose (measures blood glucose in a person who has not eaten anything for 8 hours) >7.5mmol and/or impaired glucose tolerance

Symptomatic frequent urination, blurred vision etc Family history

Type 1: o Accounts for 5-10% Cause o o o o o Autoimmune destruction of B cells with loss of insulin production Thus there is insulin deficiency Reduced entry of glucose into peripheral tissues Increased hepatic glucose production and release into circulation There is an extracellular glucose excess and an intracellular glucose deficiency in many cells starvation in the midst of plenty o Disturbances of carbohydrate, protein and lipid metabolism also contribute to the insulin deficiency Genetic and environmental risk factors There is linkage to the HLA locus. The DR3 locus increases susceptibility x3, the DR4 locus x4. The DR2 locus reduces the risk by >80% Environmental triggers include childhood viral infections such as mumps or rubella.

Pathophysiology of Type 1:

Complex metabolic derangements Hyperglycaemia Protein breakdown Ketoacidosis Complete insulin deficiency causes unrestrained lipolysis in adipose tissue thus increasing FA levels Increased B oxidation of FAs generates an excess of ACC some of which is diverted from TCA cycle into ketone body formation There can be some spillover into the urine (ketonuria) Organic keto acids cause metabolic acidosis at levels of 13mM or more Symptoms Nausea & vomiting, confusion, excessive thirst, headache, acetone on breath, ketonuria, metabolic acidosis (can lead to coma)

Treatment = insulin replacement therapy Acts to normalize blood glucose and also to delay the onset of complications Originally isolated from pigs/cows but now made as a recombinant human protein in bacteria

Oral administration is not successful as insulin is degraded in the GIT Thus it is usually administered subcutaneously, intravenously or intramuscular. Main aim is to avoid large fluctuations in the levels of insulin/glucose. Insulin preparations: Best = a mixture of short and medium lasting insulin injected before meals

Type 2: Etiology Genetic susceptibility polygenic

Lifestyle risk factorsphysical inactivity, obesity (WHO claim that a BMI of <25 would prevent 64% of type 2 diabetes in US men and 74% in women)

Cause of type 2: Hepatic Lipotoxicity Excess lipid deposition in non adipose tissue causing cell/tissue dysfunctionliver, skeletal muscle and B cells Increases FA beta oxidation

Decreases insulin sensitivity therefore causing increased gluconeogenesis Increased inflammation Increased oxidative stress

Characteristic features of type 2: Classical symptoms polydypsia (increased fluid intake due to excessive thirst) , polyphagia (increased appetite), polyuria Hyperglycaemia, hyperinsuliaemia Impaired glucose tolerance Dyslipidemia (high cholesterol levels)increased LDL and decreased HDL

Treatment for Type II Lowering BP, controlling diet and increased exercise Oral hypoglycaemic agents Biguanides metformin Lowers blood glucose by increasing uptake into skeletal muscle and inhibiting gluconeogenesis in the liver Mediated by AMP dependent protein kinase Liver: decreases A CoA (inhibition of FA synthesis), decreases SREBP-1 (down regulates expression of lipogenic genes), increases FA oxidation and decreases hepatic lipotoxicity Sulfonylureas glibenclamide Stimulate first phase insulin release from the B cells so is only useful if islets are still functional. Bind to the KATP receptor on B cells and mimic ATP by blocking the channel, triggering membrane depolarization, Ca++ entry and insulin release

TZDs (PPAR agonists) pioglutazone Enhance insulin sensitivity by increasing GLUT4 and decreasing TNF-a, IL-6 and resistin in liver and muscle Enhances glucose metabolism by net transfer of FAs into adipose tissue alpha-glucosidase inhibitors control postprandial hyperglycaemia by inhibiting digestion of complex CHOs in the brush border of the villi. Thus slowing the rate of CHO absoption insulin up to 1/3 of patients the efforts of the pancreas to overcome insulin resistance cause exhaustion of the beta cells so they cant make insulin anymore if the oral hypoglycaemics dont work well or if there are serious side effects, insulin is prescribed similar regime to type 1

Long term diabetes complications (Type 1 & 2) 1. Microvascular complications - Retinopathy, neuropathy, nephropathy - Related to detrimental effects of chronic hyperglycaemia on endothelial cells in retinal, renal and microvasculature supporting peripheral nerves Retinopathy Poor glycaemic control is a major risk factor Changes in retinal microvasculature Increased vascular permeability/macular oedema (non proliferative retinopathy) Retinal hypoxia and ischaemia stimulate angiogenesis (proliferative)

Nephropathy Progressive disease caused by damage to renal microvasculature More common in Type 1 Leading cause of end stage renal disease Pathological changes glomerular basement membrane thickening, mesangial cell expansion, ECM accumulation/fibrosis

Progressive decline in glomerular filtration rate

Neuropathy Development is related to degree of glycaemic control Endothelial hyperplasia and basement membrane thickening Increased vasoconstriction and oxidative stress Hypoxia and ischaemia

2. -

Macrovascular complications Arteriosclerosis Leading cause of death in Type 1 and 2 Ischaemic heart disease Stroke

3. Metabolic complications (Type II) HHS = hyperosmolar hyperglycaemic syndrome HONK = hyperosmolar non ketosis Caused by stress, infection and/or insufficient insulin DKA = diabetic ketoacidosis