Session 10 - diabetes Flashcards
- Describe the actions of insulin and glucagon.
- Describe how the ultrastructure of the B cell relates to the synthesis and storage of insulin synthesis and storage of insulin.
- Explain the roles of insulin and glucagon in the control of metabolism.
- Describe the condition of Diabetes Mellitus.
- List the main differences between Type 1 and Type 2 Diabetes.
- Describe and explain the typical pattern of presentation of Type 1 & Type 2 Diabetes.
- Explain the sequence of events leading to ketoacidosis in the uncontrolled diabetic.
- Explain the causes and consequences of hypoglycaemia & hyperglycaemia.
- Describe, in broad outline, the principles of management of diabetes.
- Explain the principle and practice of measuring glycosylation of haemoglobin as an index of blood glucose control in the diabetic.
- List the common long term side effects of diabetes, including: cardiovascular problems, diabetic eye disease, diabetic kidney disease, diabetic neuropathy and the diabetic foot.
- Discuss the aetiology of metabolic syndrome and its consequences for health.
• Describe how the ultrastructure of the B cell relates to the synthesis and storage of insulin LO
The endocrine pancreas
- Is the pancreas an endocrine or exocrine gland?
- What is its endocrine function? And which cells perform it?
- How do these cells store their hormonal products?
- In addition, they have ultrastructural features characteristic of tissues that synthesise proteins for export, such as?
- Both
- Islets of Langerhans
(spherical structures, ~6,000 cells & are found scattered throughout the exocrine tissue)
- Produce different polypeptide hormones.
B-cells (~75%) = insulin
a-cells (~20%) = glucagon
- intracellularly in membrane-limited vesicles (storage granules) prior to secretion & each cell may contain up to 13,000 storage vesicles.
- extensive RER, Golgi apparatus, many mitochondria, microtubules & microfilaments.
Structure, what it is and function of microtubules
- part of a cell’s cytoskeleton
- gives the cell shape
- keeps its organelles in place
- cell movement
- cell division
- transporting materials within cells.
Structure, what it is and function of microtubules
- cytoskeleton
- actin filaments, long polymerized chains of the molecules are intertwined in a helix
- functions include cytokinesis, amoeboid movement and cell motility in general, changes in cell shape, endocytosis and exocytosis, cell contractility and mechanical stability.
Insulin
- Structure?
- Why does this affect the way the molecule is synthesised?
polypeptide hormone:
- two polypeptide chains (A and B chains) linked covalently by two disulphide bonds (inter-chain)
- third intra-chain disulphide bond within the A chain
2. disulphide bridges have to connect the correct cysteine residues to ensure the biological activity of the molecule.
• describe how the ultrastructure of the B cell relates to the synthesis and storage of insulin synthesis and storage of insulin. LO
- How is insulin synthesised? Describe how it modified and secreted.
- The storage vesicles contain
- What can be used as a useful marker of endogenous insulin release?
- synthesised as pre-proinsulin (a single-chain polypeptide of 109 aa) on ribosomes associated with the rough endoplasmic reticulum. The pre-part (23 amino acids) is a signal peptide that ensures the newly synthesised protein enters the cisternal space of the ER. The signal peptide is removed once the molecule enters the endoplasmic reticulum.
- proinsulin (86 aa, single-chain polypeptide) folds to ensure that there is correct alignment of the cysteine residues & the correct disulphide bonds form.
- Proinsulin is transported from the ER to the trans- Golgi apparatus & packaged into storage vesicles.
- Proteolysis in the storage vesicles removes a connecting peptide (C-peptide) of 31 amino acids together with four basic amino acids (3 arginine and 1 lysine) from near the middle of the chain. This breaks the single chain into two chains that are held together by disulphide bridges i.e. the matureinsulin molecule. - The products of proteolysis i.e. insulin and C-peptide in equimolar amounts and a small amount of unchanged proinsulin.
C-peptide is released with insulin in equimolar amounts, its level in plasma is a
- Measurement of plasma C-peptide levels in patients receiving insulin can be used to monitor any endogenous insulin secretion.
Transport
- Insulin is stored in the B-cell storage granules as a ?
- How is it transported?
- crystalline zinc- insulin complex
- When released it dissolves in the plasma & circulates as a free hormone (i.e. not bound to a transport protein).
Target tissues
- The major target tissues for insulin action are ?
- Insulin is required for the normal ? of most tissues of the body. Insulin interacts with receptors on the surface of its target cells. The insulin receptor is a member of the ? receptor family.
- liver, skeletal muscle & adipose tissue.
- growth and development
tyrosine kinase
Describe the actions of insulin and glucagon LO
Actions
- Insulin has a wide range of effects on its target tissues and affects ? metabolism.
- These effects are largely ? & are related to insulin’s major function of clearing absorbed nutrients from the blood following a meal. Most of the effects occur rapidly (sec/hr) in response to an increase in the concentration of insulin in the circulation and are produced by changes in the activities of pre-existing functional proteins such as enzymes and transport molecules in target tissues. In addition, insulin has long-term (hr/days) effects on cell growth and division that relate to its ability to stimulate the synthesis of new protein molecules and to stimulate DNA replication.
- carbohydrate, lipid and amino acid
anabolic
The major actions of insulin on carbohydrate, lipid & aa metabolism are: (10) LO
- Increase glucose transport into adipose tissue & skeletal muscle.
- Increase glycogenesis & decrease glycogenolysis in liver & muscle.
- Decrease gluconeogenesis in liver.
- Increase glycolysis in liver & adipose tissue ?
- Decrease lipolysis in adipose tissue.
- Increase lipogenesis & esterification of fatty acids in liver & adipose tissue.
- Decrease ketogenesis in liver. - Increase lipoprotein lipase activity in the capillary bed of tissues such as adipose tissue.
- Increase aa uptake & protein synthesis in liver, muscle & adipose tissue.
- Decrease proteolysis in liver, skeletal muscle & heart muscle.
Control of Insulin Secretion
- What stimulates & inhibits secretion
Stimulates secretion:
metabolites
(glucose, aa, fatty acids)
GI tract hormones (gastrin, secretin, cholecystokinin)
Neurotransmitters (acetyl choline)
inhibit secretion:
adrenaline & noradrenaline
Glucagon
- Structure?
- Synthesis?
- single chain peptide hormone.
NO disulphide bonds
flexible 3D structure active conformation on binding to its receptor
- Synthesised by Pancreatic alpha cells as a larger precursor molecule (pre-proglucagon) that undergoes post- translational processing to produce the biologically active molecule.
The major actions of glucagon are: (4) LO
- Increase glycogenolysis & decrease glycogenesis in liver.
- Increase gluconeogenesis in liver.
- Increase ketogenesis in liver.
- Increase lipolysis in adipose tissue.
Describe the actions of insulin and glucagon. LO
- What type of receptor does glucagon bind to?
- What intracellular effect does this have?
- GPCR
- adenylate cyclase, cyclic AMP (cAMP), activates protein kinase A (PKA), phosphorylates & activates a number of important enzymes in target cells
Secretion
- What causes an increase in the rate of glucagon secretion?
- Secretion is inhibited by?
- Dec in blood glucose conc
- Insulin & an increase in blood glucose conc
Describe the condition of Diabetes Mellitus LO
Diabetes mellitus
- What is diabetes mellitus
- There are two major types of the disease, clearly distinguished by their epidemiology & probable causation, but not always so easily separated clinically:
- Diabetes mellitus is a group of metabolic disorders characterised by chronic hyperglycaemia (elevated blood glucose conc), due to insulin deficiency, insulin resistance, or both
- Type 1 diabetes & Type 2 diabetes
Describe and explain the typical pattern of presentation of Type 1 and Type 2 Diabetes LO
Type 1 diabetes LO
- Effects which age group?
- Cause
- What is insulitis & why is it important?
- The classic picture of type 1 diabetes is a ? who presents a triad of symptoms:
- Auto-antibodies:
- Diabetes is easily diagnosed by ?
- The high blood glucose will lead to the appearance of ?
- Teenagers
- loss of pancreatic β-cells.
In ~90% of cases destruction of β-cells is caused by an autoimmune response
~10% of cases are idiopathic
- Insulitis - inflammation of the islets
Chronic inflammatory mononuclear cell infiltrate consisting of T-lymphocytes & macrophages is found associated with the islets of newly diagnosed type-1 diabetics
- lean, young person with a recent history of viral infection
Polyuria - excess urine production. In the nephron of a healthy individual all of the glucose filtered from the blood is reabsorbed at the end of the proximal most section of the nephron, the proximal tubule. The reabsorption in this part of the kidney is
isosmotic. In diabetes mellitus where large quantities of glucose in the blood are filtered by the kidney not all of this glucose is reabsorbed. The extra glucose remains in the nephron tubule. This places an extra osmotic load on the nephron, & means that less water is reabsorbed to maintain the isosmotic character of this section of the nephron. This extra water then remains with the glucose in the nephron tubule & is excreted as copious urine.
- Thirst (polydipsia drinking a lot) - due to excess water loss and the osmotic effects of glucose on the thirst centres.
- Weight loss as fat & protein are metabolised by tissues because
insulin is absent.
- ICAs- Islet Cell Auto-antibodies
IAAs- Insulin Auto-Antibodies
IA2- an islet secretory protein
GAD- Glutamic Acid Decarboxylase
Detected before onset of diabetes (months-years).
- Measurement of plasma glucose levels.
- glucose in the urine (glycosuria also called glucosuria). If not dealt with urgently, these individuals will progress to a life-threatening crisis (diabetic ketoacidosis).
Progression of Type 1 Diabetes mellitus
- Autoimmune process occurring in individuals with a ? to the disease.
- What is found in the blood that indicates the disease process is underway
- Progressive ?
manifested by progressive deterioration of glucose metabolism
- Complete the flow
- genetic predisposition
- Humoral autoantibodies
- impairment of β-cell function
Tests
- Urine – glucose & ketones
- Finger prick – glucose (glucometer) & ketones
- Smell of acetone on breath
- Blood sample for measurement of Glucose urea, electrolytes HbA1c
- Check for signs of dehydration
- BP, pulse, chest sounds.
- Check respiration rate
Describe, in broad outline, the principles of management of diabetes. LO
Management of Type 1 DM
- Two major components in the treatment of Type 1 DM:
- Oral glucose-lowering drugs generally avoided in Type 1 DM due to ?
- Islet transplants? (possible future therapy) how does it work?
- Considerations when giving insulin therapy
- Dietary considerations?
- Social considerations
- What is one VERY important factor I.e. Life or death situation
- • Diet & Exercise
• Insulin Therapy
- risk of hypoglycaemia
- Extraction of islet cells from deceased donor and implanting in liver of Type 1 DM sufferer.
Not widely used yet. Only 23 patients received islet transplants in UK in 2014-2015.
- Type of insulin, units & frequency.
- Once injected, effects of insulin are largely irreversible. Remind about the need for regular food - Regular meal times
- Unrefined carbohydrate in preference to refined
- Carry sugar/ sweets to avoid hypos - Education – help groups, family & friends
Regular check-ups by GP – HbA1c, feet eyes, BP & kidneys
- Regular self-monitoring of blood glucose & feet (neuropathy).
List the common long term side effects of diabetes LO
What are the two types of chronic complications?
- Macrovascular complications
- Microvascular complications
- Macrovascular complications:
- Microvascular complications:
- • Increased risk of stroke.
- Increased risk of MI
- Poor circulation to the periphery (particularly the feet)
- • Diabetic eye disease: Changes in the lens due to osmotic effects of glucose
- Retinopathy: Damage to blood vessels in retina, leading to blindness.
- Nephropathy: Damage to glomeruli (poor blood supply) can lead to microalbuminuria.
- Neuropathy: Peripheral nerve damage producing loss of sensation.
- Diabetic foot: Poor blood supply, damage to nerves, increased risk of infection. Foot ulcers.
Explain the sequence of events leading to ketoacidosis in the uncontrolled diabetic.
- Why do patients get ketoacidosis?
- The features of keto-acidosis are ?
- High rates of B-oxidation of fats in the liver coupled to the low insulin/anti-insulin ratio leads to the production of huge amounts of ketone bodies, such as acetoacetate, acetone & B-hydroxybutyrate. Acetone, which is volatile may be breathed out, and can be smelt on the patient’s breath. As this ketosis develops, the H+ associated with the ketones produce a metabolic acidosis - keto-acidosis.
2. prostration, hyperventilation, nausea, vomiting, dehydration & abdominal pain.
Describe and explain the typical pattern of presentation of Type 1 and Type 2 Diabetes LO
Type 2 Diabetes mellitus
- Cause
- How does this disease differ in individuals?
- >85% of type-2 diabetics are ?
- When is the onset
- Is ketoacidosis present?
- Do patients with DM2 gain or lose weight?
- Rate of fatality slower/faster than type 1?
- ? replacement not immediate
- Patients may present with the classical triad of symptoms, but are more likely to present with a variety of symptoms such as ?
- Insufficient insulin production from β cells in the setting of insulin resistance.
- Proportion of insulin resistance vs β cell dysfunction differs among individuals. Some have primarily insulin resistance with a minor defect in insulin secretion
whilst others have slight insulin resistance & primarily a lack of insulin secretion
- obese
- Late
- No
- No acute weight loss – often obese
- Slower
- Insulin
- lack of energy, persistent infections, particularly thrush infections of the genitalia, or infections of the feet, slow healing minor skin damage, or visual problems.
List the main differences between Type 1 and Type 2 Diabetes LO
Explain the causes and consequences of hypoglycaemia and hyperglycaemia LO
Metabolic consequences of persistent hyperglycaemia
- Which tissues are at risk due to hyperglycaemia? Why?
- What happens to the glucose in the tissues?
- How does hyperglycaemia effect plasma proteins?
- peripheral nerves, the eye & kidney
The uptake of glucose does not require insulin & is determined by the extracellular glucose conc.
- glucose is metabolised via the enzyme aldose reductase which catalyses the reaction:
Glucose + NADPH + H+ -> Sorbitol + NADP+
- depletes cellular NADPH
- leads to increased disulphide bond formation in cellular proteins, (altering their structure & function)
- accumulation of sorbitol causes osmotic damage to cells
3. glycation (non-enzymatic glycosylation) of plasma proteins (e.g. lipoproteins) -> reduced function
Explain the principle and practice of measuring glycosylation of haemoglobin as an index of blood glucose control in the diabetic LO
Why do we perform a HbA1c test?
Measure of glycated haemoglobin reflects average glycaemia (presence of glucose in the blood) over a period of weeks.
- Glucose in the blood will react with the terminal valine of the haemoglobin molecule to produce ?
- The percentage of haemoglobin that is glycated is a good indicator of how effective blood glucose control has been. As red blood cells normally spend about 3 months in the circulation the % HbA1c is related to the average blood glucose concentration over the preceding 2-3 months.
In normal healthy individuals ? of haemoglobin is glycated and in poorly controlled diabetics this value ?
- Glycated haemoglobin (HbA1c)
- 4-6%
can increase above 10%.
What’s the difference between glycosylation & glycation?
Management of type 2 DM LO
- Three major components in the treatment of Type 2 diabetes:
- What two drugs do type 2 diabetics take?
- • Diet and Exercise
- Oral hypoglycaemic therapy
- Insulin Therapy
- sulphonylureas that increase insulinrelease from the remaining B-cells, & reduce insulin resistance & particularly metformin that reduces gluconeogenesis.
Management of type 2 DM
1st line
2nd line
3rd line
James comes to you to report his concerns.
- What questions will you ask him, & what examinations & tests will you perform?
- Any changes in weight?
Increase in fluid intake?
Sleep/ frequency going to the toilet?
(Triad of symptoms need to ask triad of questions)
- What do you think is wrong with James?
Why does he require immediate referral? What will happen to
James if he is not treated rapidly?
- Describe the sequence of events if James is not treated rapidly & explain the metabolic basis of these events.
How, in principle, might you expect his treatment to proceed?
- Why do you think poor adherence to treatment regimes is common in type 1 diabetes?
- In the long term, what other problems might James face?
- What is the difference between Type 1 and Type 2 diabetes? Why is Margaret’s case not as urgent as that of James?
- What is of Margaret’s haemoglobin A1c value of 10% ?
Over non- diabetic range
Over diabetic range
In the range of diabetic at risk of with hypoglycaemia
Over non- diabetic range
Over diabetic range
In the range of diabetic at risk of with hypoglycaemia
Discuss the need for care with interpretation of biochemical variables. (Hint: think about the blood sample going to the laboratory, assays performed & the reporting of results)
Major cell types in islets:
Within the Golgi, proinsulin is exposed to several specific ? which excise the C peptide, thereby generating the mature form of insulin + C peptide.
endopeptidases
How is Insulin secreted from β− cells? (Not synthesised)
Describe the insulin receptor LO
Not sure if below is true!!!
– Insulin binds to the insulin receptor on cell surfaces
– receptor is a dimer
– two identical subunits spanning the cell membrane.
– two subunits are made of one α-chain & one β-chain, connected together by a single di-sulphide bond.
– α-chain on exterior of the cell membrane,
– β-chain spans the cell membrane in a single segment,
Janus kinase
