Diabetes and the pancreas Phil Copeman and Alex Hammant

Glucose Transport How do they work? GLUT family: How do they work? Allow facilitated diffusion GLUT 1,3 and 4 allow movement at basal glucose levels Which GLUT is responsible for insulin dependent response in fat and muscle? GLUT 4 Which GLUT is present on Beta-islet cells? GLUT 2 SGLT (sodium dependent glucose transporter) family: Use sodium to move glucose against concentration gradient. SGLT1 –in intestines SGLT2 –in kidney GLUT 4 predominantly stored in intracellular vesicles Insulin promotes their insertion into cell walls Thus facilitates glucose transport into cells

Glucose Balance Substrates are: Where does it happen? Gluconeogenesis: Substrates are: Lactate (from non-oxidative metabolism – Cori cycle) Glycerol (from fats) Glutamine and alanine (from protein) Where does it happen? both liver and kidneys Glycogen & glycogenolysis Energy storage molecule in humans Where are the 2 main storage sites? liver and muscle cells

Hormonal Control of Glucose Homeostasis Glucose Production Glucose Utilisation Lipolysis Insulin ↓ ↑ Glucagon Adrenaline Cortisol Growth Hormone FFA -

Insulin Produced by β-cells of Islets of Langerhans Provide pancreatic endocrine function Contain 3 major cell types α-cells : produce glucagon β-cells : produce insulin δ-cells : produce somatostatin Strong inhibitor of insulin and glucagon. Exact role is unclear.

Insulin Release Extracellular glucose is transported into the β -cell via GLUT-2. Glucose is metabolised which increases adenosine triphosphate to diphosphate (ATP:ADP) ratio within the cell. This leads to closure of ATP-dependent K+ channels Closure of K+ channels leads to cell membrane depolarisation Membrane depolarisation leads to opening of voltage dependent Ca2+ channels and Ca2+ influx Ca2+ influx leads to exocytosis of stored insulin vesicles Glucose GLUT 2 Glucose Metabolism ↑ ATP Ca2+ K+ K+ ins ins ins Depolarisation insulin insulin insulin

Insulin Release Release of pre-docked and primed vesicles  First phase response Release of insulin from granules is complex Transport  Docking  Priming  Fusion Second phase Time Insulin secretion Basal 1st phase 2nd phase High glucose levels 5 min

Roles of insulin Glycogen synthesis (via activation of glycogen synthase) Promotes protein synthesis and inhibits protein breakdown Promotes lipogenesis and inhibits lipolysis Also promotes mitogenesis (induces cell division)

Glucagon Produced by pancreatic islet α-cells Suppressed by: Actions: insulin secretion Hypoglycaemia results in loss of insulin secretion and suppression Actions: Stimulates gluconeogenesis and glycogenolysis Increases hepatic fatty acid oxidation and ketone formation Stimulates lipolysis in adipose cells, increasing circulating free fatty acids, and reduces adipocyte glucose uptake.

Entero-insular axis Fed state: L-cells produce… GLPs and GIPs These act to increase insulin secretion in response to oral glucose load Degraded by DPP4

Diabetes Mellitus Type I = problem with insulin secretion Autoimmune destruction of β-cells Type 2 = problem with insulin resistance Loss of first phase insulin response 4 stages: Normal Impaired fasting glycaemia Impaired glucose tolerance Diabetes

Cases Barry is a 18 year old student who has the following symptoms: Tiredness for around 6 weeks Unquenchable thirst Weight loss of 2 stone in the last month Has to get up >4 times per night to urinate What is your likely diagnosis? Type 1 Diabetes

Cases Simone is a 63 year old Greggs store manager with a BMI of 38. She presents with: Tiredness Polyuria Oral thrush What is the likely diagnosis? Type 2 Diabetes

Diabetes Symptoms Broadly the same for both types: Polyuria Polydipsia Lethargy Type 1 more likely in younger, more lean people and may have: Weight loss Dehydration Ketonuria Hyperventilation Type 2: Longer duration of symptoms, subacute presentation

Diabetes II Risk factors Modifiable Non-modifiable BMI >25 Age >40 Central obesity Family History Lack of physical activity Ethnicity Smoking Gestational diabetes or baby >4.5 kg at birth Poor diet Previous Hx of mental health conditions Low socioeconomic status Cardiovascular, hypertension, stroke history Low birth weight PCOS

Type 2 Diabetes - Management Diet/exercise/lifestyle Oral Hyperglycaemics Biguanides (e.g. metformin): decreases hepatic gluconeogenesis Sulfonyureas (e.g. gliclazide): increase insulin secretion Thiazolidinediones (e.g. ? ): reduce insulin resistance Injectable agents Insulin GLP-1 analogue

Complications of DM Hypoglycaemia Microvascular Macrovascular Nephropathy Retinopathy Neuropathy Macrovascular Ischaemic heart disease Cerebrovascular Peripheral Vascular disease

Other functions of the pancreas Alkali – from Duct Cells An isotonic solution rich in HCO3-. Neutralizes duodenal contents. Digestive Enzymes – from Acinar Cells Trypsin (endopeptidase) Chymotrypsin (endopeptidase) Carboxypeptidase (ectopeptidase) Pancreatic amylase (breaks down starches) Lipases (break down fats) – remember you need these to break down fat soluble vitamins! Other enzymes (phospholipase, cholesterol esterase, ribonuclease etc) These are all exocrine functions

Control of pancreatic secretion Enzyme secretion Controlled by: CCK and ACh Alkali secretion Controlled by: Secretin and potentiated by CCK and ACh pancreas bile production HCO3- secretion enzyme secretion gall bladder contraction