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PBL Notes > PBL 10 - Diabetes > Flashcards

PBL 10 - Diabetes Flashcards

1
Q

During the fed state what are the usual levels of the hormones?

A 
Insulin = high
Cortisol = low
Adrenaline = Low
Glucagon = Low
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2
Q

What are the main functions of insulin?

A
  • Promotes nutrient storage
    • Primary action is anabolic
    • Stimulates uptake of glucose, amino acids and free fatty acids into cells
    ○ 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
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3
Q

What is the effect of insulin on adipose tissue?

A
  • Increases glucose uptake
    • Increases Lipogenesis
    • Decreases lipolysis
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4
Q

What is the effect of insulin on Striated muscle?

A
  • Increased glucose uptake
    • Increased Glycogen synthesis
    • Increased protein synthesis
    ○ Increased amino upstake
    ○ Decrease protein catabolism

Decrease release of glucogenic amino acids

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5
Q

What is the effect of insulin on the liver

A

• Decreased Gluconeogenesis
• Increased glycogen synthesis
Increased lipogenesis

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6
Q

What is the site of insulin synthesis

A

• Pancreatic islets (islets of langerhans)
• Clusters of endocrine cells
• B-cells secrete insulin
A-cells secrete glucagon

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7
Q

How is insulin synthesised and matured?

A

• 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

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8
Q

Describe the insulin receptor

A

• Tyrosine Kinase Receptor - enzyme linked
• Has intrinsic tyrosine kinase activity when insulin binds
Leads to activation of insulin receptor substrates IRS and signalling cascades

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9
Q

What are the cascades that are activated by insulin

A
  • Activation of several cytosolic Ser/Thr Kinases signalling cascades
    • Has widespread tissue-specific effect
    • Rapid effects such as glucose uptake, activating and inhibition of enzymes

Long lasting effects such as protein synthesis and cell growth

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10
Q

How is glucose transported?

A
  • 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)
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11
Q

Where are GLUT 2 proteins located and what are the properties?

A 
Location:
	• Liver
	• Pancreatic beta cells 
	• Basolateral membrane of small intestine 
	• Kidney

Properties
• Low affinity
• High capacity
• Glucose sensor in B-cells

Carrier for fructose

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12
Q

Where are GLUT 4 proteins located and what are the properties?

A

Location:
• Fat
• Skeletal
• Cardiac muscle

Properties
• Activated by insulin
• High affinity

Mediates insulin-stimulated glucose uptake in adipose and muscle tissue

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13
Q

How is glucose up taken in adipose and muscle tissue?

Is it dependent on insulin?

A
  • 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

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14
Q

How is glucose up taken by the liver?

Is this dependent on insulin?

A
  • When glucose levels are > 5mM
    • Enters the liver freely by GLUT2
    • WITHOUT insulin
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15
Q

What happens to insulin and glucose during starvation?

A

• 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

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16
Q

How does insulin effect GLUT 4 transporters?

A
  • 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
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17
Q

What happens to the glucose uptaken by adipose tissue?

A
  • Insulin stimulates glucose uptake and its storage as Fat
    • Enters via GLUT 4
    • Converted to Glycerol 3 phosphate
    • Then converted to Triglycerides
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18
Q

How does insulin effect Glycogen?

A

• 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
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19
Q

What are the actions of glucagon or adrenaline on glycogen?

A
  • Promotes glycogen breakdown
    • Inhibition of glycogen synthesis
    • No receptor for glucagon on muscle

Glycogen in as important buffer between meals

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20
Q

How does insulin stimulate protein synthesis in liver and muscle?

A
  • Increases amino acid uptake
    • Increased net protein synthesis
    • Decreased protein catabolism
    • Decreased release of glucogenic amino acids
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21
Q

What is the role of LPL?
Where is it located?
how is it regulated?

A

• 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
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22
Q

What is the Effect of Insulin on Adipocytes

A

• 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)
23
Q

What regulates muscle LPL?

A

During fasting glucagon increases production and activity of muscle LPL

	○ Increases the FFA available for energy Muscle LPL is inversely correlated with insulin
24
Q

What is Hormonal sensitive Lipase
where is is located?
what action does it have?

A
  • 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
25
Q

What is the effect of Insulin on HSL?

A
  • Inhibits lipolysis by suppressing HSL activity
    • Prevents the inappropriate mobilisation of stored fat

Degree of HSL activity is dependent on hormonal balance

26
Q

What are the potential fates of FFA in the liver?

A 
• B-Oxidation
		○ Energy
		○ Ketogenesis if in excess
	• Storage as Triglyceride
	• TG exported as VLDL
27
Q

Effect of Insulin on the Liver

A

• 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
28
Q

Summary of role of insulin

Generally:
On adipose tissue:
On muscle:
On the Liver:

A

• 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
29
Q

What happens when there is an insulin deficiency in the body?

A
  • 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
30
Q

What are the counter hormones to insulin and where do they act?

A
  • Glucagon = liver only
    • Adrenaline = liver and muscle
    • Cortisol
    • Growth hormone
31
Q

How does Insulin deficiency cause hyperglycaemia

A

• 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
32
Q

How does insulin deficiency effect Lipid Metabolism

A

• 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
33
Q

When does ketogenesis normally occur and why?

A
  • 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
34
Q

What is the normal mechanism of Ketogenesis in the liver?

A
  • 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
35
Q

What are the ketone bodies?

A
  • Acetoacetate
    • Acetone
    • D-B hydroxybutyrate
36
Q

What are the effects of Insulin deficiency on the muscle?

A

• 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

37
Q

What is the Effect of Hyperglycaemia on the kidneys

A
  • 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
38
Q

What causes a hyperosmolar state?

A

• 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

39
Q

What is diabetic Ketoacidosis

A

• 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

40
Q

What are the complications of DKA (Type 1 Diabetes)

A
  • 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
41
Q

What are the electrolyte imbalances that occur in Ketoacidosis?

A
  • Overall electrolyte loss includes potassium, sodium and chloride
    • The most characteristic is potassium loss
42
Q

How is potassium lost in Ketoacidosis

A
  • 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
43
Q

What is Gluconeogenesis?

A
  • Synthesis of glucose from non carb precursors
    • Lactic acid
    • Glycerol
    • Amino acid
    • Liver cells synthesise glucose when carbs are depleted
44
Q

What is Glycogenesis?

A
  • Formation of glycogen

* Glucose stored in liver and skeletal muscle as glycogen important energy reserve

45
Q

What is Glycolysis

A

• The breakdown of glucose into pyruvate into pyruvate by cells for the production of ATP

46
Q

What stimulates insulin release?

A 
• Increased glucose concentrations
	• Increased amino acid concentrations
	• Feed forwards effects of GI hormones
		○ Parasympathetic activity 
		○ Sympathetic activity
47
Q

In the Fed state which hormone dominates

A

Insulin

48
Q

In the Fasted state which hormone dominates?

A

GLucagon

49
Q

Who should be screened for Type Ii diabetes?

A

• 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

50
Q

What is the Pathogenesis of Diabetic Vascular complications

A

• Hyperglycaemia and hyperlipidaemia causes oxidative stress and hypoxia
• Inflammatory signalling cascades are activated
• Location activation of pro-inflammatory cytokines
• Inflammation causes
○ Nephropathy
○ Retinopathy
○ Neuropathy

51
Q

What are the Acute complications of DM?

A
  • Diabetic Keto Acidosis
    • Hyperglycaemic Hyperosmolar state
    • Hypoglycaemia
52
Q

What precipitates Hypoglycaemia in Diabetics?

A
  • Insufficient food; delayed meal or snack
    • Excess alcohol or alcohol consumed without food
    • Excess insulin or excess oral Hypoglycaemic agents
    • Too much physical activity
53
Q

What are the symptoms of hypoglycaemia?

A 
• Autonomic symptoms
		○ Sweats 
		○ Tremors
		○ Shaky
		○ Very hungry
	• CNS symptoms 
		○ Headaches
		○ Altered vision
		○ Unable to concentrate
		○ Altered behaviour
		○ Coma and seizures

PBL Notes (14 decks)

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