Diabetes Flashcards
What does insulin inhibit?
- Gluconeogenesis
- Glycogenlysis
- Ketogenesis
- Lipolysis
- Proteolysis
What does insulin signal?
Plenty/fed state
What does insulin promote?
- Glycolysis
- Glycogen synthesis
- Glucose uptake (use of glucose)
- Fatty acid synthesis
- Protein synthesis
What tissues particularly rely on glucose as an energy source?
Brain, RBCs
What is effect of glucagon on glycolysis?
Inhibits it
What is effect of glucagon on gluconeogenesis?
Stimulates it
What is effect of glucagon on glycogenolysis?
Stimulates
How does insulin promote glycolysis?
Activates phosphofructokinase and pyruvate kinase
How does insulin promote the storage of glucose as glycogen?
Inhibits glycogen phosphorylase
How does insulin promote the uptake and use of glucose by cells?
Promotes movement of GLUT4 to cell membrane to facilitate glucose entry
How does insulin promote the conversion of glucose to triacylglycerols?
Stimulates pyruvate dehydrogenase –> increases conversion of pyruvate to acetyl CoA
Stimulates acetyl CoA carboxylase which catalyses the first step in fatty acid synthesis
Why does low blood glucose lead to increased acetyl CoA?
Glucagon leads to break down of triacylglycerol to form free fatty acyl CoA –> acetyl CoA
In diabetes 1, why is blod glucose high?
Insulin levels are low
- No movement of GLUT4 so no uptake
- Glycogen breakdown and gluconeogenesis stimulated (body reacts as if its starving)
In diabetes, why does glucose appear in urine?
Blood glucose exceeds the concentration that can be reabsorbed in the proximal tubule
In diabetes, why is muscle protein broken down?
Insulin normally inhibit protein breakdown and promotes protein synthesis (at the level of translation)
Without insulin, protein breakdown occurs and the amino acids provide substrates for gluconeogenesis
In diabetes, why are ketones formed?
Fatty acid breakdown accelerated without insulin
This causes high conc of Acetyl CoA
TCA intermediate levels are low due to their removal for gluconeogenesis (which is going on at same time) so Acetyl CoA builds up as it can’t feed easily into Krebs cycle
Ketones are formed from acetyl CoA which can be used by brain etc for energy during prolonged fasting
What are dangers of high levels of ketone bodies?
Risk of ketoacidosis
What is ketoacidosis?
Drop in pH of blood due to circulating ketones
At pH <7.0, many enzymes are affected
Can be fatal
What is HbA1C?
Glycated form of Hb (glucose added to Hb non-enzymatically)
What is the rate of glycation of Hb determined by?
Prevailing glucose conc during life of erythrocyte
How can measuring HbA1C aid in monitoring diabetes?
Test provides insight into average blood glucose conc over period of time instead of ‘spot test’
High levels indicates diabetes
What is the main cause of death in diabetes related to?
Macrovascular complications (myocardial infarcation, stroke and peripheral vascular disease)
How can hyperglycaemia lead to long term dangers?
- Increased use of minor metabolic pathways
- Glycation
Why does hyperglycaemia lead to increased use of minor pathways (e.g. polyol pathway)
If glucose levels are abnormally high, polyol pathway may occur
Polyol pathway –> some tissues have the enzymes to convert glucose to sorbitol and fructose
What are the dangers of sorbitol and fructose?
These are osmotically active and lead to swelling
Sorbitol may be toxic
What is glycation?
The covalent attachment (non-enzymatic) of a sugar to a protein or lipid.
How can glycation caused by high glucose levels lead to damage?
Non-enzymatic addition of glucose to proteins can cause protein damage
E.g. HbA1C
How can changes in insulin levels lead to long term dangers?
Involved in long term growth / proliferation of tissues
Why can insulin levels be raised in type I even though the pancreas isn’t producing insulin?
Levels are often raised in type II but also in type I as the administered dose may be above normal physiological levels
Why does diabetes lead to high levels of circulating chylomicrons and VLDLs?
Lipoprotein lipase activity is low since the enzyme is normally induced by insulin
This leads to high circulating levels of VLDL and chylomicrons in the blood
Why does diabetes lead to high levels of circulating chylomicrons and VLDLs?
Lipoprotein lipase activity is low since the enzyme is normally induced by insulin
This leads to high circulating levels of VLDL and chylomicrons in the blood
Can lead to coronary heart disease
What is lipoprotein lipase responsible for?
Breaking down triacylglycerols in VLDL and chylomicrons to allow these to be absorbed by tissues
Why does diabetes lead to excess lipolysis? What does this lead to?
Excess lipolysis as hormone sensitive lipase in adipose tissue is not being inhibited
This leads to high circulating fatty acids and increased VLDL production in liver
Why does diabetes lead to excess lipolysis? What does this lead to?
Excess lipolysis as hormone sensitive lipase in adipose tissue is not being inhibited
This leads to high circulating fatty acids and increased VLDL production in liver
Can lead to coronary heart disease
How can glycation of proteins lead to increased circulating LDL?
Glycation of proteins (LDL apoproteins and LDL receptor) lead to lower rates of LDL uptake
Therefore, increased levels of circulating LDL
How can increased levels of circulating LDL increase risk of coronary heart disease?
Increased LDL infiltrating into space behind arterial walls where it is oxidised and taken up by macrophages
This is the first step in formation of atherosclerotic plaques
This increases risk of heart attacks and strokes
How can glycation of proteins in blood lead to increased risk of coronary heart disease?
Glycation of proteins in blood capillary membranes and RBCs also gives less flexibility
More risk of slow blood flow, stasis and blood clotting
How does diabetes damage the kidneys?
Thickening of basement membranes leads to disruption of filtering ability
This leads to leakage of large molecules into urine –> kidney damage (diabetic nephropathy)
How does diabetes cause thickening of basement membrane?
Due to glycation of proteins in blood capillary membranes
How does diabetes affect the eyes?
Affects the retina and the lens
How does diabetes affect the retina?
Retinopathy –> damaged basement membrane and increased permeability of retinal capillaries leads to small haemorrhages
New vessel formation
How does diabetes affect the lens?
Cataracts –> glycation of lens proteins and/or osmotic changes in lens due to accumulation of sorbitol
How is sorbitol produced?
Via polyol pathway
What is diabetic neuropathy?
A type of nerve damage that can occur if you have diabetes. High blood glucose can injure nerves throughout your body. Diabetic neuropathy most often damages nerves in your legs and feet
How can feet be damaged by diabetic neuropathy?
Nerves affected by damage to small blood vessels surrounding sheath
Accumulation of sorbitol and fructose in Schwann cells disrupts function and structure –> leads to demyelination
What is the effect of neuropathy?
Loss of sensory perception at extremities leads to minor injuries going unnoticed
Why must diabetics check their feet?
Ulceration and infection can result in amputation
Why is healing in the feet diminished?
Due to vascular degeneration (due to glycation)
What is meant by tight control?
Keeping blood glucose within a narrow target range
E.g. 4-7mM before meals, <10mM after meals
Keeping HbA1C below 6.5%
How is tight control achieved?
Varying insulin doses to fit with meals and activities, plus frequent and accurate blood glucose monitoring
What are the advantages of tight control?
Decreases risk of complications by 40-75%
What are the problems with tight control?
- Increased risk of hypoglycemia
- Increased risk of weight gain (body storing calories that were previously lost from excreting glucose in urine)
What is supporting evidence for type II diabetes diagnosis?
- Age >30
- Race (type II more common in Asia, Africa and Caribbean)
- Obesity
- Poor wound feeling
- Glucosuria
- No ketones (therefore not type I)
- Family history (strong genetic component in type II)
- Slow onset
What is treatment for type II?
Diet and exercise to promote weight loss
Drug therapy
Monitor blood glucose (HbA1c), lipids, bp
How can orals agents reduce blood glucose?
- Slowing digesting and absorption of carbohydrates
- Stimulating pancreas to produce more insulin
- Increasing sensitivity to insulin
- Suppressing glucose secretion by the liver
- Increase glucose excretion by the kidneys
Why is monitoring HbA1c important?
Allows clinician to gather information about long term glucose levels
How do a-glucosidase inhibitors (acarbose) work?
Treat type II
Delay digestion and absorption of carbohydrates in GI tract by inhibiting a-glucosidase
What does a-glucosidase do?
Metabolism of complex carbs into absorbable monosaccharides
How do sulphonylureas work?
Treat type II
Lower fasting fasting blood glucose conc by stimulating insulin secretion from pancreas
How do biguanides (e.g. metformin) work?
Treat type II
Suppress hepatic glucose output through gluconeogenesis or glycogenolysis
Also enhance insulin sensitivity and stimulate insulin-mediated glucose disposal without stimulating insulin secretion
I.e. This works to lower the amount of sugar in the blood of people with diabetes. It does this by lowering the amount of sugar produced in the liver, and also increasing the sensitivity of muscle cells to insulin
What is metformin used to treat?
Type II diabetes
How does Pioglitazone work?
Treat type II
Decrease insulin resistance in tissues (e.g. adipose and skeletal muscle and liver) –> direct insulin sensitisers
Also may benefit beta cell function in pancreas
What is GLP-1?
Glucagon-like peptide
Is a GI hormone that increases insulin secretion from pancreas and inhibits glucagon release
How do DPP-4 inhibitors work?
Block DPP enzyme that would normally inactivate GLP-1
What is supporting evidence for type I diabetes diagnosis?
- Younger
- Weight loss
- Thirst, polyuria
- Positive for ketones
- No family history
- Rapid onset
Treatment for type I?
- Dietary control
- Insulin injections
- Regular monitoring of blood glucose, and periodic HbA1c
