Hormonal Control of Blood Sugar

Where does our energy come from?

- Carbohydrates

- Lipids

- Proteins (amino acids)

How is energy stored in our body?

- Glycogen

- triglycerides

What is glycogen?

- The form that glucose is stored as if intake is higher than demand

Where is glycogen stored?

- Cytoplasmic granules

What are the types of carbohydrate metabolism?

- Glycogenesis

- Glycogenolysis

- Gluconeogenesis

What is glycogenesis?

- Conversion of glucose to glycogen

Where does glycogenesis occur?

- Liver

- Muscle

What is glycogenolysis?

- Conversion/breakdown of glycogen to glucose

What is gluconeogenesis?

- Synthesising glucose from non-carbohydrate sources

- Lactic acid, amino acids and glycerol can be converted into glucose

What occurs in the liver during fuel metabolism?

- Glucose uptake

- Glycolysis

- Gluconeogenesis

- Glycogen storage

- Glycogen release

- De novo lipogenesis

- Fatty acid oxidation

What occurs in the pancreas during fuel metabolism?

- Insulin secretion

- Glucagon secretion

What occurs in the muscle during fuel metabolism?

- Glucose uptake

- Glycogen storage

- Triglyceride storage

What occurs in the adipose tissue during fuel metabolism?

- Glucose uptake

- Triglyceride storage

- Fatty acid release

Why is blood sugar control?

- Carbohydrate is brain's only source of fuel - body's primary source

- Need for effective/efficient means of metabolising carbohydrate

- Carbohydrates broken down into glucose for use by the cells

- Following its absorption from the intestine (jejunum and ileum), glucose remains in the blood until it is taken up into cells

- Blood levels of glucose must be kept within strict limits

- Therefore even if we eat more carbohydrates than the body needs for fuel, it must be removed from the blood and stored elsewhere

What is the typical level of blood glucose between meals and after meals?

- Between meals ~ 4-6 mmol/L

- After meals ~ 10 mmol/L

What is hyperglycaemia?

- High blood glucose

What are the symptoms of hyperglycaemia?

- Polyuria

- Thirst

- Weight loss

- Fatigue

What are the consequences of hyperglycaemia?

- Neuropathy

- Nephropathy

- Heart disease

- Cataracts and blindness

- Diabetic coma

- Death

What is hypoglycaemia?

- Low blood glucose

What are the symptoms of hypoglycaemia?

- Irritability, fatigue

- Food cravings

- Headaches

- Dizziness

- Shaking

- Confusion

What are the consequences of hypoglycaemia?

- Loss of consciousness

- Accidents and injury

- Weight gain

- reduced IQ

- Brain abnormalities

What is the anatomy of blood glucose control?

(add image)

- Gallbladder

- Small intestine

- Common bile duct

- Pancreatic duct

- Pancreas

- Digestive enzyme-secreting cells

- Pancreatic islet (Islet of Langerhans)

- Hormone-secreting islet cells

What do the islets of langerhans contain?

- Alpha cells

- Beta cells

- Delta cells

What do alpha cells secrete?

- Glucagon

What do beta cells secrete?

- Insulin

What do delta cells secrete?

- Somatostatin

What is the structure of insulin?

- Polypeptide containing two chains of amino acids linked by disulphide bridges

How is insulin processed?

- Preproinsulin has signal peptide removed to form proinsulin

- Proinsulin is synthesised as a single polypeptide chain In the storage granules, the connecting (C chain) peptide is cleaved by proteases to form mature insulin and c peptide

What does insulin allow?

- Allows circulating glucose to be used by cells

How does glucose sensing occur?

- GLUT2 transporter allows glucose to enter the β-cell in proportion to blood glucose concentration

- Glucokinase phosphorylates glucose to glucose-6-phosphate and its activity increases only when glucose levels are high - acting as glucose sensor

How does insulin secretion occur?

- Phosphorylated glucose is metabolised by glycolysis and respiration to produce ATP

- As glucose metabolism increases, more ATP produced, so ATP-sensitive K+ channels close due to binding of ATP

- Increase of K+ in cell (as closed channels stop it from leaving) so inside of cell becomes more positive

- Depolarisation leads to opening of voltage-gated Ca2+ channels

- Calcium influx triggers exocytosis of insulin-containing granules

- insulin secreted into bloodstream

What metabolic effects does insulin have on glucose?

- Increase glucose uptake into cells

- Stimulates glycogenesis

- Stimulates glycolysis

- Inhibits gluconeogenesis

What metabolic effects does insulin have on amino acids and protein?

- Increases amino acid uptake into cells

- Stimulates protein synthesis

- Inhibits protein breakdown

What metabolic effects does insulin have on fat/lipids?

- Promotes triglyceride synthesis

- Increases uptake of free fatty acids

- Inhibits lipolysis

- Reduces fatty acid oxidation

What effects does insulin have on muscle?

- Promotes glucose uptake via GLUT4 and deposition as glycogen - within minutes

- Results in increased expression and translocation of lipoprotein lipase (LPL) - in 2-3 hours

Summarise knowledge of insulin

- Secreted by beta cells of pancreatic islets

- Promotes formation of glycogen

- Inhibits gluconeogenesis

- Enhances movement of glucose inro adipose and muscle cells

- Decreases blood glucose concentrations

- Promotes transport of amino acids

- Enhances synthesis of proteins and fats

- Controlled by blood glucose concentrations

What does glucagon do?

- Increases blood glucose

- Has antagonisitic action to insulin

- Secreted in response to low blood sugar

Where is glucagon secreted?

- Alpha cells of islets of Langerhans

How is glucagon synthesised?

- GCG gene transcribed and translated in alpha cells to produce proglucagon

- Proglucagon contains GRPP, glucagon and major proglucagon fragment

- Proteolytic processing - enzyme PC2 cleaves proglucagon to produce glucagon, GRPP and major proglucagon fragment

- PC2 processing produces glucagon

What are the actions of glucagon?

- Promotes gluconeogenesis

- Promotes glycogenolysis

- Glucagon increases ketogenesis and lipolysis

- Inhibits lipogenesis

What is ketogenesis?

- Formation of ketone bodies from fatty acid oxidation

Where does ketogenesis occur?

- Liver

What is lipolysis?

- Breakdown of triglycerides into free fatty acids

Where does lipolysis occur?

- Adipose tissues

What are the initial substrates in ketogenesis and lipolysis?

- Long chain fatty acids

- Amino acids - e.g leucine and lysine

What cellular activities does insulin increase?

- Glycogenesis

- Lipogenesis

What cellular activities does insulin decrease?

- Glycogenolysis

- Gluconeogenesis

- Ketogenesis

- Lipolysis

What cellular activities does glucagon decrease?

- Glycogenesis

- Lipogenesis

What cellular activities does glucagon increase?

- Glycogenolysis

- Gluconeogenesis

- Ketogenesis

- Lipolysis

What other hormones are involved in glucose homeostasis?

- Growth hormone

- Epinephrine (adrenaline)

- Glucocorticoids

- Somatostatin

- Glucagon-like peptide-1 (GLP-1)

How is glucagon-like peptide-1 (GLP-1) synthesised?

- Proglucagon formation

- Proteolytic processing in pancreatic alpha cells of proglucagon to produce glucagon, GRPP, MPGF

- Proteolytic processing in intestinal L cells to produce GLP-1, GLP-2, glicentin and oxyntomodulin

- GLP-1 secreted after eating and stimulates insulin release

- Quickly broken down by dipeptidyl peptidase IV, making it inactive

What does GLP-1 do and what is it broken down by?

- Stimulates insulin release

- Broken down by Dipetidyl Peptidase IV - makes it inactive

What are GLP-1 analogues?

-> Exenatide (exendin-4)

- Related structure to GLP-1

- Resists DPP IV degradation by sc injection

-> Liraglutide

- Albumin binding

- Decreased by degradation by DPP IV sc injection

What is the SGLT2 and where is it found?

- Sodium-Glucose Co-Transporter 2

- found in the proximal renal tubule of kidney

What does the SGLT2 do?

- Uses sodium gradient to transport glucose and Na+ together from the tubule into the tubule cell

- This is the secondary active transport - powered by Na+/K+ pump that maintains the Na+ gradient

- Reabsorbs 90% of glucose in kidneys when glucose levels are normal

- On basolateral membrane, GLUT2 moves glucose from tubule cell into bloodstream by facilitated diffusion

What happens to glucose reabsorption by SGLT2 in diabetes?

-Amount of glucose filtered through kidneys exceeds reabsorption capacity of SGLT2

- So not all glucose reabsorbed - glucose appears in urine

- Water follows the glucose osmotically which leads to polyuria