PBL 10 - Diabetes Flashcards
During the fed state what are the usual levels of the hormones?
Insulin = high Cortisol = low Adrenaline = Low Glucagon = Low
What are the main functions of insulin?
- Promotes nutrient storage
- Primary action is anabolic
○ This decreases their concentrations in blood to restore homeostasis• Promotes synthesis and storage of carbohydrates, proteins and lipids
○ Inhibits their degradation and release into blood
What is the effect of insulin on adipose tissue?
- Increases glucose uptake
- Increases Lipogenesis
- Decreases lipolysis
What is the effect of insulin on Striated muscle?
- Increased glucose uptake
- Increased Glycogen synthesis
○ Increased amino upstake
○ Decrease protein catabolism
Decrease release of glucogenic amino acids
What is the effect of insulin on the liver
• Decreased Gluconeogenesis
• Increased glycogen synthesis
Increased lipogenesis
What is the site of insulin synthesis
• Pancreatic islets (islets of langerhans)
• Clusters of endocrine cells
• B-cells secrete insulin
A-cells secrete glucagon
How is insulin synthesised and matured?
• Synthesized as a preprohormone
• Mature insulin is packaged and stored in vesicles until released by exocytosis
• Pancreas senses a rise in blood glucose
• Glucose enters through NON rate limiting, insulin dependent GLUT2 glucose transporter
• Leads to an influx of calcium
Causes insulin release
Describe the insulin receptor
• Tyrosine Kinase Receptor - enzyme linked
• Has intrinsic tyrosine kinase activity when insulin binds
Leads to activation of insulin receptor substrates IRS and signalling cascades
What are the cascades that are activated by insulin
- Activation of several cytosolic Ser/Thr Kinases signalling cascades
- Has widespread tissue-specific effect
Long lasting effects such as protein synthesis and cell growth
How is glucose transported?
- Carrier mediated (too large to diffuse through membranes)
- Na/Glucose Symport in the lumen of intestine or kidney ( SGLT1 - secondary active transport) - requires ATP
- Facilitated transport ie GLUT transport○ No energy required as it follows the concentration gradient
Most tissues import however some can export (liver/kidney)
Where are GLUT 2 proteins located and what are the properties?
Location: • Liver • Pancreatic beta cells • Basolateral membrane of small intestine • Kidney
Properties
• Low affinity
• High capacity
• Glucose sensor in B-cells
Carrier for fructose
Where are GLUT 4 proteins located and what are the properties?
Location:
• Fat
• Skeletal
• Cardiac muscle
Properties
• Activated by insulin
• High affinity
Mediates insulin-stimulated glucose uptake in adipose and muscle tissue
How is glucose up taken in adipose and muscle tissue?
Is it dependent on insulin?
- Pancreas senses glucose levels via GLUT 2
- Secretes insulin via exocytosis
- Glucose enters adipose and muscle cells through GLUT 4
This is dependent on insulin
How is glucose up taken by the liver?
Is this dependent on insulin?
- When glucose levels are > 5mM
- Enters the liver freely by GLUT2
What happens to insulin and glucose during starvation?
• Insulin levels drop
• In the absence of insulin the GLUT 4 receptors are sequestered inside the cell
• GLUT4 mediated uptake of sugar shuts off in muscle and adipose
• Left over glucose is reserved for critical tissue use
Insulin independent, high affinity glucose uptake in brain and RBC
How does insulin effect GLUT 4 transporters?
- Insulin signals the cell to insert GLUT 4 Transporters into the membrane
- This allows glucose to enter the cell
- Insulin stimulates exocytosis of GLUT 4
- This decreases the amount of circulating glucose
What happens to the glucose uptaken by adipose tissue?
- Insulin stimulates glucose uptake and its storage as Fat
- Enters via GLUT 4
- Converted to Glycerol 3 phosphate
- Then converted to Triglycerides
How does insulin effect Glycogen?
• Stimulates conversion of glucose into glycogen
○ This is due to activation of glycogen synthase
• It also inhibits glycogen breakdown ○ Due to inactivation of glycogen phosphorylase
What are the actions of glucagon or adrenaline on glycogen?
- Promotes glycogen breakdown
- Inhibition of glycogen synthesis
- No receptor for glucagon on muscle
Glycogen in as important buffer between meals
How does insulin stimulate protein synthesis in liver and muscle?
- Increases amino acid uptake
- Increased net protein synthesis
- Decreased protein catabolism
- Decreased release of glucogenic amino acids
What is the role of LPL?
Where is it located?
how is it regulated?
• Located:
○ Luminal surface of endothelial cells in capillaries of many tissues
○ Most abundant in adipose tissue and muscle
• It is the RATE LIMITING step for : ○ clearance of TG rich Chylomicrons and VLDL ○ FFA uptake into tissues • Regulation: ○ It has tissue specific regulation in response to energy and hormonal changes • Partitions lipoprotein borne TGs to adipose tissue (FFA uptake then storage back as TG) • If taken up in muscle then used for b-oxidation and used for energy
What is the Effect of Insulin on Adipocytes
• Increases LPL production and activity in adipose tissue capillaries
○ Leads to breakdown of TG in chylomycrons and VLDL to FFA
○ Uptake of FFA for storage as TG in adipocytes (lipid droplets)
○ Glucose taken up by adipocytes also used for TG synthesis
• Inhibits lipolysis by suppressing HSL activity (hormone sensitive Lipase)
What regulates muscle LPL?
During fasting glucagon increases production and activity of muscle LPL
○ Increases the FFA available for energy Muscle LPL is inversely correlated with insulin
What is Hormonal sensitive Lipase
where is is located?
what action does it have?
- Lipase WITHIN the adipocytes that target cleavage of triglycerides to Glycerola nd FFA
- When triglycerides within the cell are required, they are hydrolysed by hormone sensitive lipase into FA and Glycerol
- These then enter the connective tissue spaces of adipose tissue and from there into a capillary
- They are then connected to albumin and transported into the blood
What is the effect of Insulin on HSL?
- Inhibits lipolysis by suppressing HSL activity
- Prevents the inappropriate mobilisation of stored fat
Degree of HSL activity is dependent on hormonal balance
What are the potential fates of FFA in the liver?
• B-Oxidation ○ Energy ○ Ketogenesis if in excess • Storage as Triglyceride • TG exported as VLDL
Effect of Insulin on the Liver
• Inhibits VLDL formation
○ Inhibits HSL mediated lipolysis therefore there is less FFA for use
○ Promotes uptake of FFA as storage as triglycerides
○ Insulin directly suppresses production of ApoB-100
§ Usually helps make the lipoprotein
§ Triglycerides cannot be packaged
• Inhibits Ketone Body formation ○ Don’t release FFA from adipose tissue (usually the biggest source of triglycerides to be broken down) ○ Usually glucagon in the liver would use excess FFA to make acetyl Coa then ketones ○ Because there is no increase in FFA- it does not occur
Summary of role of insulin
Generally:
On adipose tissue:
On muscle:
On the Liver:
• Generally:
○ Stimulates uptake of glucose, amino acids and FA into cells
○ Decreases the concentrations of these items in blood to restore homeostasis
○ Promotes synthesis and storage of glucose, lipids and proteins
○ Inhibits the degradation and release into circulation of proteins, lipids and glucose by modifying activity and expression of key enzymes
○ Action of insulin is opposed by glucagon (liver only), adrenaline (liver and muscle), cortisol and growth hormone
• Adipose tissue ○ Increase glucose and FFA uptake ○ Increase TG synthesis ○ Decreases lipolysis by inhibiting HSL • Muscle ○ Increase glucose uptake and glycogen synthesis ○ Increased amino acid uptake and protein synthesis • Liver ○ Increase glycogen synthesis ○ Decrease glucose release ○ Decrease VLDL formation and ketone body synthesis
What happens when there is an insulin deficiency in the body?
- The body believes that is is starving because there isno peripheral nutrient intake
- Starts following correction procedures by mobilising substrates for gluconeogenesis
- There becomes an excess of glucagon causing a mobilisation of energy reserves
- Increased breakdown of glycogen to glucose (liver)
- Increased breakdown of fats to fatty acids in adipose tissue
- Increased synthesis and release of glucose (liver)
- There is a flooding of glucose and FFA
What are the counter hormones to insulin and where do they act?
- Glucagon = liver only
- Adrenaline = liver and muscle
- Cortisol
- Growth hormone
How does Insulin deficiency cause hyperglycaemia
• Increased glucose synthesis in liver due to glucagon
§ From non carb precursors- lactate, amino acids and glycerol
○ Glycogenolysis
§ Decreased activity of glycogen synthase
§ Increased activity of glycogen phosphorylase
○ Increased supply of precursors due to increased catabolism in muscle (amino acids) and adipose tissue (glycerol)
○ TG hydrolysed by HSL in adipose tissue
• Impaired Peripheral glucose uptake ○ Due to less exocytosis of GLUT 4 and therefore less glucose uptake ○ Glucose that is circulating can still be taken up by brain and liver • Excess Blood Glucose cannot be converted to energy stores ○ No glucose entry in muscle/adipose tissue ○ Decreased glycogen synthesis due to decreased activity of glycogen synthase ○ Decreased storage of glucose in TG in adipose tissue • Increased BLOOD GLUCOSE
How does insulin deficiency effect Lipid Metabolism
• Decreased LPL activity
○ It is usually insulin sensitive
○ Activity decreases in both adipose tissue and skeletal muscle
○ This means that there is reduced clearance of TG rich VLDL and CM
○ Leading to hypertriglyceridemia
• HSL becomes active- not being suppressed by insulin ○ Increases lipolysis within the cell ○ Increased FFA and Glycerol release from adipose tissue § Glycerol in then used for gluconeogenesis in the liver § FFA leads to b-oxidation and ketogenesis in the liver • Over production of hepatic VLDL ○ Normally insulin decreases ApoB-100 and therefore VLDL production ○ Excess FFA are available due to lipolysis and are made into TG ○ TG + ApoB-100 = more VLDL secretion ○ Increases Plasma TG • Absolute lack of insulin promotes Ketosis ○ Normally insulin turns off ketone body formation in the liver ○ Usually insulin suppresses HSL and lipolysis ○ Abnormal increase in FFA = ketosis
When does ketogenesis normally occur and why?
- Only Promoted by glucagon when BSL is low
- Only occurs in the liver
- Ketones instead of glucose is burnt as fuel in the periphery
- Is a normal response to prolonged fasting or lack of Carbs
What is the normal mechanism of Ketogenesis in the liver?
- Prolonged lipolysis leads to increased FFA for liver uptake
- Overloaded catabolic pathways cannot handle the excess Acetyl-CoA
- Oxaloacetate is diminished and Acetyl CoA is then converted to ketone bodies
- Exported to other cells- ie heart and brain in fasting state
- Not used by the liver itself
What are the ketone bodies?
- Acetoacetate
- Acetone
- D-B hydroxybutyrate
What are the effects of Insulin deficiency on the muscle?
• Increased proteolysis and release of amino acids
• Decreased amino acid uptake and protein synthesis
• Used as gluconeogenic precursors
• Due to the body wrongly believing it is starving
• There are some ketogenic amino acids used for ketogenesis
○ Can be converted to Acetyl CoA through transamination
○ Leucine and Lysine
• Body prefers to use lipids not proteins but will if it is starving
What is the Effect of Hyperglycaemia on the kidneys
- High blood glucose leads to an increased amount of glucose filtered by the kidneys
- If it exceeds the threshold of the kidneys ie 10mM then glucose spills into the urine
- Excess glucose also stays in the lumen causing OSMOTIC DIURESIS
- Glucose is excreted into the urine along with fluids drawn from the tissues
- Causes frequent urination
- Dehydration and increased thirst
What causes a hyperosmolar state?
• It is a complication of high blood sugar levels
• Can occur in both types of diabetics
• Due to High urine output caused by osmotic diuresis
• Blood becomes very concentrated (hyperosmolar) and dehydration increases
• Patient becomes drowsy- can lead to hyperglycaemic coma
○ Only linked to glucose
• Fat metabolism is not a predominant feature- non ketotic
• Patients treated with insulin and large amounts of fluids
What is diabetic Ketoacidosis
• Metabolic acidosis due to an abnormal accumulation of ketone bodies
• Most common in type 1 diabetes
• Ketonemia = rise in blood ketones
• Acetone gives fruity breath
• Ketonuria = accumulated ketones overflow into the urine
○ Can use acetoacetate urine test
What are the complications of DKA (Type 1 Diabetes)
- Metabolic acidosis: Excess ketone bodies acidify blood
- Drop in PH
- Induces nausea and vomiting - aggravate fluid and electrolyte loss
- Respiratory compensation - rapid shallow breathing- Kussmaul respiration
- Exacerbated by hyperglycaemia leads to dehydration, osmotic diuresis and serum hyperosmolarity
- Acidosis and dehydration lead to electrolyte imbalance ie Na and K depletion
- Decrease in phosphate and bicarbonate
- Severe metabolic alteration affect level of consciousness
- Leads eventually to coma and death
- Treatment includes Insulin infusion, rehydration and potassium supplementation
What are the electrolyte imbalances that occur in Ketoacidosis?
- Overall electrolyte loss includes potassium, sodium and chloride
- The most characteristic is potassium loss
How is potassium lost in Ketoacidosis
- Caused by a shift of potassium from intracellular to extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis
- Much of the shifted extracellular potassium is lost in urine because of osmotic diuretesis
- Initially serum K is normal or elevated because of extracellular migration of K in response to acidosis
- If the patient has initial hypokalaemia they have SEVERE total body potassium depletion
- K levels usually fall further during treatment because insulin therapy drives K into cells
- If serum K is not monitored and replaced as needed can become lifethreatening
- High serum osmolarity also drives water from intracellular to extracellular space
- Causes dilutional hyponatremia
- Sodium is also lost in the urine during osmotic diuresis
What is Gluconeogenesis?
- Synthesis of glucose from non carb precursors
- Lactic acid
- Glycerol
- Amino acid
- Liver cells synthesise glucose when carbs are depleted
What is Glycogenesis?
- Formation of glycogen
* Glucose stored in liver and skeletal muscle as glycogen important energy reserve
What is Glycolysis
• The breakdown of glucose into pyruvate into pyruvate by cells for the production of ATP
What stimulates insulin release?
• Increased glucose concentrations • Increased amino acid concentrations • Feed forwards effects of GI hormones ○ Parasympathetic activity ○ Sympathetic activity
In the Fed state which hormone dominates
Insulin
In the Fasted state which hormone dominates?
GLucagon
Who should be screened for Type Ii diabetes?
• Age above 45
• Age above 50 with other CV risk factors of HTN and dyslipidemia
• Over 35 from at risk ethnic groups
○ Asians
○ Indians
○ Pacific islanders
○ ATSI
• Strong family history of diabetes- first degree family members
• Women with history of gestational diabetes
○ Increased risk in the first five years after pregnancy
• Women with PCOS
• Obese individuals with metabolic syndrome
• Previous diagnosis of IGT or IFG
What is the Pathogenesis of Diabetic Vascular complications
• Hyperglycaemia and hyperlipidaemia causes oxidative stress and hypoxia
• Inflammatory signalling cascades are activated
• Location activation of pro-inflammatory cytokines
• Inflammation causes
○ Nephropathy
○ Retinopathy
○ Neuropathy
What are the Acute complications of DM?
- Diabetic Keto Acidosis
- Hyperglycaemic Hyperosmolar state
- Hypoglycaemia
What precipitates Hypoglycaemia in Diabetics?
- Insufficient food; delayed meal or snack
- Excess alcohol or alcohol consumed without food
- Excess insulin or excess oral Hypoglycaemic agents
- Too much physical activity
What are the symptoms of hypoglycaemia?
• Autonomic symptoms ○ Sweats ○ Tremors ○ Shaky ○ Very hungry • CNS symptoms ○ Headaches ○ Altered vision ○ Unable to concentrate ○ Altered behaviour ○ Coma and seizures
