Diabetes Flashcards
Classic symptoms of IDDM
Thirst (polydipsia)
Tiredness
Weight Loss
Polyuria- with glucose and ketone bodies
Hyperglycaemic coma
Etiology of IDDM
Autoimmune destruction of pancreatic beta-cells
Prevents secretion of insulin, hence no feedback mechanism on alpha cells that secrete glucagon- hyperglucagonaemia
Pathophysiology of weight loss/ muscle weakness in IDDM
Low insulin:glucagon ratio leads to increased proteolysis.
Amino acid levels in the plasma rises
Causes loss of muscle mass
Hyperglycaemic mechanism in IDDM
Low insulin:glucagon ratio causes: - Increased glycogenolysis - Increased proteolysis - Decreased uptake of glucose by tissues
High amino acid levels in the blood from proteolysis causes an increased stimulation of gluconeogenesis.
All factors increase glucose levels in the blood.
Mechanism for ketoacidosis in IDDM
Low insulin:glucagon ratio increases lipolysis.
- Increases free fatty acids in the plasma
High FAs level stimulates ketogenesis and ketouria
IDDM effects on the liver
- Metabolic state
- Glycolysis
- Gluconeogenesis
- Glycogenolysis
- Fatty acids
- Acetyl CoA
Liver remains gluconeogenic due to low insulin:glucagon ratio
Liver takes in substrates to make glucose:
- Alanine (proteolysis)
- Glycerol (lipolysis)
Glycogen synthesis and glycolysis are inhibited due to no insulin.
Fatty acids used to provide energy for the liver or converted to TGs and VLDL.
- Can lead to hypertriglyceridaemia
- FAs also oxidised to Acetyl CoA
XS Acetyl CoA used to form ketone bodies to provide energy source
- Can lead to ketoacidosis
IDDM effects on the muscle
- Metabolic state
- Glycolysis
- Gluconeogenesis
- Glycogenolysis
- Fatty acids
- Acetyl CoA
Due to no insulin, Glucose entry is very low (GLUT-4)
- Intensifies hyperglycemia
Glycolysis and glycogenolysis are inhibited.
Fatty acids from lipolysis used for fuel.
Ketone bodies made from Acetyl CoA also used as a fuel for energy.
Increased proteolysis causes muscle wasting to support gluconeogenesis.
IDDM effects on the adipose tissue
- Metabolic state
- Glycolysis
- Gluconeogenesis
- Fatty acids
- Acetyl CoA
No insulin= very low glucose entry via GLUT-4
Lipolysis very high to release FAs and glycerol from TGs
- FAs used as fuel and also released for fuel in other tissues
- Glycerol released for gluconeogenesis
Glycolysis and glycolysis inhibited
IDDM state in plasma and urine
High glucagon levels= hyperglycaemia
Too much glucose for the kidneys to process
- Excreted in urine glycosuria
- Water is loss in urine via osmotic uresis = thirst
Lipoprotein lipase activity not regulated due to lack of insulin
- Fatty acid synthesis inhibited
- Increased VLDL = hypertrigylceridaemia
Short term life-threatening consequence of IDDM
Hyperglycaemia
Ketoacidosis
Short term life-threatening consequence of NIDDM
Non-ketoic hyperosmolar coma
- Hyperglycaemia without ketosis
Long term life-threatening consequence diabetes
Neuropathies
Nephropathy
Predisposition to CVD and organ damage
Retinopathy
Effects of hyperglycaemia
Increases generation of ROS.
Causes osmotic damage to cells.
Glycosylation of proteins (attachment of glucose to proteins) which alters their functions.
Formation of advanced glycation end products (AGE)
- glycated lipids or lipids
= increased ROS and inflammatory proetins
Two major tests in diagnosing diabetes
Fasting blood glucose levels
- Overnight fast
- When blood glucose levels is 126mgl/dL (7mM) and above on at least 2 ocassion = diabetes
Glucose tolerance test:
- Morning after overnight fast
- Fasting blood sampled before giving glucola drink (75g glucose)
- Blood glucose sampled 20mins, 1 hr and 2 hr after drink
Treating TI diabetes
Insulin given to mimic normal daily insulin secretion.
Insulin treatment regimes
Premixed insulin
- Requires less injecting
- Meal timing has be very meticulous
Insulin and food together
- Greater flexibility
- Potential nocturnal hypoglycaemia
Rapid acting insulin:
- Reduces risk of nocturnal hypoglycaemia due to short half life
- More expensive
Types of insulin
Fast acting
Intermediate acting
Long acting
Etiology of NIDDM
Impaired insulin secretion
- Due to amyloid deposits
Increased peripheral insulin resistance
Increased hepatic glucose output
Mechanisms of insulin resistance
Could be caused by:
- Mutation in insulin receptor gene (most rare)
Defects in insulin signalling pathway
- Defects in cellular translocation of GLUT-4
- Prevalent in obesity and diabetes
Peripheral insulin reisstance
- XS fatty acids
- Inhibits peripheral glucose disposal
- Enhances hepatic glucose output
Features of NIDDM
Often prevalent in older and obese population.
Can survive for a long time without insulin
Associated with macrovascular disease, stroke and atherosclerosis
Low ketone bodies
Metabolism in NIDDM
Some insulin presence so glucagon secretion suppressed to an extent.
Hyperglycaemia due to lack of glucose uptake
VLDL production from liver increases
- hypertriglyceridaemia
- macrovascular disease
No uncontrolled lipolysis = no ketone body formation
- Due to some insulin left to suppress glucagon
Treatment of NIDDM
Diet and exercise- improves translocation of glucose in GLUT 4
Oral hypoglycaemic agents
Sulphonylureas
Hypoglycaemic agent that stimulates insulin secretion.
Example: Gliclazide
Mechanism, works on pancreatic beta cells:
When glucose is >7mM…
- Drug binds to close ATP-dependant K+ channels.
- This stimulates depolarisation and influx of Ca2+ via voltage gated channels
- Ca2+ influx stimulates insulin secretion.
Biguanides
Drugs that increases insulin sensitivity of the tissue
Example: Metformin
Supresses appetite.
Only effective when insulin is present as it increases tissue sensitivity.
Thiazolidinediones
Drug that enhances tissue effectiveness of endogenous insulin
- Reduces hepatic glucose output
- Increase glucose uptake in muscle
Mechanism:
Binds to peroxiome proliferator-activated receptor-gamma on the nucleus
- Regulates gene expression
Example
- Pioglitazone
GIP and GLP-1
Glucose- dependent insulinotropic peptide
- Produced by endocrine cells in the intestines after food ingestion to stimulate insulin release
Very short half life makes it ineffective to use therapeutically
Stimulators of GLP-1
Extendin-4
Exenatide (Byetta)
- Synthetic extendin-4 with longer half-life
Vildagliptin (Galvus)
- Inhibits inactivation of GLP-1 and GIP
- Combined with oral hypoglycaemic agents
