Week 1 Endocrine Lectures Flashcards
How long are the quantities of ATP present in tissues sufficient for?
A few seconds only unless replenished
How can ATP in tissue be replenished?
- Creatine phosphate (muscle - short term)
- Anaerobic metabolism of CHO to lactate
- Aerobic metabolism of CHO, fat and/ or protein (amino acids) (in mitochondria)
What are examples of carbohydrates in the diet?
- Polysaccharides • Starch • Cellulose - Disaccharides • Maltose • Sucrose • Lactose = glucose and galactose linked - Monosaccharides • Glucose • Fructose
What does D-glucose refer to?
the way a solution of glucose will rotate a plane of polarised light - to the right (dextro)
What does a-D-glucose refer to?
Whether the OH group is below (a) or above (B) the C1 atom
Summarise the process of carbohydrate digestion?
Saliva breaks it up partially, stomach does nothing (basically all about digesting proteins), then into the small intestine where enzymes released by the pancreas begin to work. (95% of pancreas is about digestion).
What is the glycaemic index?
shows how quickly different foods affect your blood sugar
Digestibility of starch
What are some reasons that starches may be digested slowly?
- trapped in intact starch granules/plant cell wall structure (e.g. raw cereals, vegetables)
- resistant to amylase as 3D structure too tightly packed (some processed foods, raw/cold potato)
- associated with dietary fibre (slows absorption/digestion as gut contents become viscous (e.g. beans/legumes)
- CHO foods containing high levels of fat may have delayed gastric emptying
What is the transport form of carbohydrate in humans?
Glucose
What is the storage form of carbohydrate in humans?
Glycogen
What tissues in the body are dependent on a constant supply of glucose?
Brain and erythrocytes
Why is glucose required in the brain?
It has a specific architecture meaning that lipids cant cross into the brain
a lot of neurotransmitters are also made from glucose
What are plasma glucose levels tightly regulated within?
4-5mM (fasted state)
8-12mM after a meal
What are the principle regulators of glucose homeostasis?
Insulin (after a meal for storage)
Glucagon (in fasted state to release glucose)
Where can glucose be synthesised to buffer plasma glucose levels?
The liver and possible the kidney in starvation
How is glucose transported into cells down the concentration gradient?
by facilitated diffusion
- GLUT1-14 (1-5 well characterised in humans 6-14 not so much)
How is glucose transported into cells against the concentration gradient?
using energy provided by cotransport of sodium (SGLT1 and 2)
Where is glucose required to be transported against the concentration gradient?
Required in intestine to absorb from gut lumen and kidney, to reabsorb from filtrate
Where are SGLT-1/2 transporters found?
Intestinal mucosa, kidney tubules
How do SGLT-1/2 transporters work?
Co-transport one molecule of glucose or galactose with sodium ions.
Does not transport fructose
Where is GLUT-1 found?
Everywhere
How does GLUT-1 work?
Transports glucose (high affinity) and galactose, not fructose
Where is GLUT-2 found?
Liver, pancreatic beta cell, small intestine, kidney
How does GLUT-2 work?
Transports glucose, galactose and fructose. Low affinity high capacity transporter
Where is GLUT-3 found?
Brain, Placenta, Testes
How does GLUT-3 work?
Transports glucose (high affinity) and galactose, not fructose. It is the primary transporter for neurons
Where is GLUT-4 found?
Skeletal and cardiac muscle and adipocytes
How does GLUT-4 work?
GLUT-4 is insulin responsive. It has a high affinity for glucose
Where is GLUT-5 found?
Small intestine, sperm
What does GLUT-5 transport?
Only fructose
Why does the kidney require SGLT-1/2?
Because this is where absorption and reabsorption of glucose takes place
What are pentoses used for?
Making DNA and RNA
What is the first step for all processes involving glucose?
Phosphorylation of glucose to glucose-6-phosphate - this gives it a negative charge
Why must glucose be phosphorylated as the first step?
This traps glucose in the cell - it cannot be transported out
What is the phosphorylation of glucose catalysed by?
Hexokinases I-IV
What is glucokinase?
Hexokinase IV
Where is glucokinase (hexokinase IV) expressed?
Expressed by b-cells of the pancreas and the liver
How does glucokinase (hexokinase IV) behave?
High Km (low affinity for glucose)
Where is hexokinase I-III expressed?
All tissues (except b-cells of pancreas and liver)
How do hexokinase I-III behave?
Have low Km (high affinity for glucose)
What inhibits hexokinases I-III?
G6P
What is glycolysis?
The breakdown of glucose to yield energy (ATP)
Where does glycolysis take place?
Occurs in the cytoplasm of the cells
What inhibits phosphofructokinase (PFK)?
ATP and citrate
What is the input and output of glycolysis?
Uses 2ATP
Produces 4ATP and 2NADH
What is the committed step for glycolysis?
Phosphofructokinase
Why must NADH be used up?
So that NAD+ is replenished
What happens to NADH under anaerobic conditions?
Lactate formation to use up NADH (no further ATP produced) some NAD must be maintained
What happens to NADH under aerobic conditions?
NADH can be used to make more ATP in mitochondria
How is Fructose used for energy production?
Fructose—> fructose-1-phosphate (F1P) by fructokinase
F1P—>DHAP and Glyceraldehyde-3phosphate
DHAP and Glyceraldehyde-3phosphate are intermediates of glycolysis
How is galactose used for energy production?
Converted to Glucose-1-phosphate, then G6P by a number of steps (normal metabolism after conversion)
What are the fates of pyruvate?
- Lactate (anaerobic conditions)
- Pyruvate –> acetyl-CoA
How is pyruvate turned into acetyl-CoA
- Occurs in mitochondria by Pyruvate Dehydrogenase – complex enzyme
- Produce CO2 and NADH + H+
- Aerobic
- Acetyl-CoA (coA is a big structure that binds to the acetyl) used in the TCA cycle
What is the pentose phosphate pathway important for?
- Synthesis of fatty acids
- Synthesis of nucleotides (RNA/DNA)
- Dehydrogenation of glucose 6-phosphate is the committed step
What is gluconeogenesis?
The synthesis of glucose from a noncarbohydrate (nonhexose) source
What are examples of substances used in gluconeogenesis?
- Lactate
- Pyruvate
- Glycerol – broken down triglycerides – only glycerol from break down can be used to make glucose (fatty acids used for fuel)
- Certain amino acids
What are three irreversible reactions of glycolysis?
Hexokinase/glucokinase (1st one)
PFK (committed step)
Pyruvate kinase (final step of glycolysis)
How is hexokinase bypassed in gluconeogenesis?
Bypassed by Glucose-6-phosphatase
How is PFK bypassed in gluconeogenesis?
Fructose 1,6-bisphosphatase
Where is Glucose 6-phosphatase found?
The lumen of ER
What is expression of Glucose 6-phosphatase stimulated by?
adrenaline, glucocorticoids ((e.g. cortisol – the stress hormone, increases gluconeogenesis), glucagon
What supresses Glucose 6-phosphatase?
Insulin
What are examples of substrates for gluconeogenesis?
- Lactate to pyruvate
- Glycerol to dihydroxyacetone phosphate (DHAP)
- Amino acids in various locations in TCA cycle and pyruvate
What cells are found within an islet of Langerhans?
- a cells
- B cells
- delta cells
What is the function of a cells in the pancreas?
Secrete glucagon
What is the function of B cells in the pancreas?
Secrete insulin
What is the function of delta cells in the pancreas?
Secrete somatostatin
What are insulin and glucagon initially synthesised as?
Pro-hormones
What steps does insulin go through before becoming insulin?
Pre-proinsulin —> proinsulin —> insulin
How is pre-proinsulin turned into proinsulin?
The signal sequence is removed
How is proinsulin turned into insulin?
The c chain is cleaved off
How is insulin released into the blood?
It is synthesised in vesicles which eventually fuse with the cell membrane and is released.
How is the release of insulin controlled?
When ATP/ADP increases in the beta cell this inhibits the potassium channel on the cell surface. This causes the calcium channel to open and an influx of calcium which causes exocytosis of the insulin vesicles
What type of receptors are the glucagon receptors?
G-protein coupled receptors
Where are the receptors for glucagon found?
In hepatocytes (the liver is the only tissue that really responds)
What happens when glucagon binds to its receptor?
Increases cAMP which stimulates cAMP-dependent protein kinase (PKA).
Adding a phosphate group changes the shape of the receptor.
change in structure of the receptors releases enzymes/ secondary receptors
What happens to glycogen stored in muscles?
Used only by the muscle itself for local energy production
How is pyruvate kinase bypassed in gluconeogenesis?
Using two enzymes:
- Pyruvate carboxylase (PCOX)
- Phosphoenolpyruvate (PEPCK)
What hormones are involved in gluconeogenesis?
- Glucagon
- Adrenaline
- Insulin
What are the effects of glucagon and adrenaline in gluconeogenesis?
- Decreases glucokinase activity
- Increases G6pase and PEPCK activity
What is the effect of insulin on gluconeogenesis?
- Increases glucokinase activity
- Decreases G6Pase and PEPCK activity
- stops gluconeogenesis
What are the principle actions of insulin on the liver?
- Increases glycogen synthesis
- Increases fatty acid synthesis
- Inhibits gluconeogenesis (PEPCK & G6Pase)
What are the principle actions of insulin on muscle?
- Increases glucose transport (GLUT4)
- Increases glycogen synthesis
What are the principle actions of insulin on adipose?
- Increases glucose transport (GLUT4)
- Suppresses lipolysis
- Increases fatty acid synthesis
What causes type 1 diabetes?
Autoimmune destruction of b-cells
What is the only current therapy for type 1 diabetes?
Insulin injection/pumps to maintain blood glucose
What causes type 2 diabetes?
occurs if someone becomes insulin resistant no longer as sensitive to endogenous insulin
What is associated with causing type 2 diabetes?
Obesity
How does metformin work?
- Mimics insulin by inhibiting hepatic gluconeogenesis
- Mechanism of action uncertain but all involve inhibition of liver mitochondrial function
This means the mitochondria don’t make enough ATP and this causes the cells to stop processes that require ATP (gluconeogenesis is one of these processes)
What do thiazolidinediones do?
- Ligand for peroxisome proliferator-activated receptor-g (PPARg). PPARg is a transcription factor, stimulating expression of genes involved in triglyceride storage.
- Stops inappropriate deposition of lipid in non-adipose tissues (which leads to insulin resistance) – therefore improves insulin sensitivity
- Troglitazone and Rosiglitazone withdrawn/no longer used
- Pioglitazone still used
What do incretins do?
- Gastrointestinal hormones that potentiate insulin secretion (food is coming make insulin)
• Glucagon-like peptide-1 (GLP-1)
• Gastric inhibitory peptide (GIP).
• Rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Short lived and only last a matter of minutes
What drugs mimic incretins?
- exenatide, liraglutide
• Mimic incretins (GLP-1)
• Not cleaved by DPP-4
• Injected
• Improve insulin secretionWhat are DPP-4 inhibitors?
- Sitagliptin, vildagliptin
• Inhibit DPP-4
• Increase endogenous incretin-mediated increase in insulin secretion
• Oral drugs
What do SGLT2 inhibitors do?
- Inhibit renal re-uptake of glucose from filtrate in kidney by SGLT2
- Reduces hyperglycaemia
- Also reduced blood pressure and EMPA-REG (Empagliflozin) and CANVAS (Canagliflozin) trials suggests reduces cardiovascular mortality and hospitalisation due to cardiovascular events
Cause more glucose to be excreted in the urin
What are examples of SGLT2 inhibitors?
Canagliflozin, Dapagliflozin, Empagliflozin
What are the diagnostic criteria for diabetes mellitus?
FASTING BLOOD GLUCOSE
- < 6.0mmol/l: normal
- 6.1-6.9mmol/l: impaired
- > 7mmol/l: diabetes
What are the diagnostic criteria for diabetes mellitus?
75g ORAL GLUCOSE TOLERANCE TESTING (2hr glucose)
- < 7.7mmol/l: normal
- 7.8-11mmol/l: impaired
- > 11.1mmol/l: diabetes
What are the different types of diabetes?
- Type 1
- Type 2
- MODY
- Gestational
- Secondary
What are some potential causes of secondary diabetes?
- Pancreatitis
- Cystic fibrosis
- haemochromatosis
- Steroid-induced
- Acromegaly (tumour that secretes excess growth hormone)
What are the types of diabetes that are insulin deficient?
- Type 1
- MODY
- Pancreatitis
- Cystic fibrosis
- Haemochromatosis
What types of diabetes are insulin resistant?
- Type 2
- Gestational
- Steroid-induced
- Acromegaly
What are the auto-antibodies in type 1 diabetes?
- ICA - Islet cell antibody
- I-A2 - (insulinoma-associated antigen-2)
- IAA (insulin auto-antibody)
- GAD65 - Glutamic acid decarboxylase 65)
- ZnT8 (zinc transporter)
What does it mean if someone test positive for auto-antibodies involved in type 1 diabetes?
This provides a diagnosis of diabetes
What are genes that can make someone susceptible to type 1 diabetes?
- HLA
- insulin (VNTR)
- PTPN22
- IL2RA
- CTLA-4
- IFIH1
What are examples of precipitating events for type 1 diabetes?
- Enteroviruses (esp. Coxsackie)
- Rotavirus
- Bacteria (e.g. Mycobacteria Avium paraTB)
- Environmental
• Cow’s milk
• Wheat proteins - Vitamin D deficiency
- Insulin resistance (e.g. puberty)
- ? Psychological stress
How can tyoe 1 diabetes be predicted?
- HLA
- Auto-antibodies
- First-phase insulin response to glucose
- T-cell function
- Reduced B-cell mass (by PET)
What other autoimmune diseases is type 1 diabetes associated with?
- Thyroid disease (hypo and hyper)
- Coeliac disease
- Addison’s disease
- Pernicious anaemia
- Inflammatory Bowel Disease
- Premature Ovarian Failure
What is MODY?
Maturity-onset diabetes of the young
What causes MODY?
A genetic disorder - autosomal dominant. If one the parents has the gene 25% of their children will develop diabetes before they’re 22
MODY covers 1-2% of people with diabetes
What are the different types of MODY?
HNF-1a Glucokinase HNF-4a HNF-1B Neonatal
What happens in glucokinase MODY?
There is an issue with the gene that is involved in sensing glucose. People with this can’t detect glucose fluctuations
What does an insulin pump do?
Uses rapid acting insulin analogue only (novorapid)
