Insulin & Diabetes Flashcards
Hormones that increase blood glucose levels
- Glucagon
- chatecholamines
- somatotrophin
- cortisol
Hormone that decreases blood glucose
Insulin
What is type 1 diabetes defined as
Elevated glucose levels where insulin is required to prevent ketoacidosis
What is type 2 diabetes
Elevated glucose levels, related to hypertension and dyslipidaemia
Does T1DM require insulin?
YES
Does T2DM require insulin?
No, mature onset diabetes
Does MODY require insulin
(Monogenic) maturity onset diabetes of the Young, usually not insulin dependant
Types of MODY
HNF1alpha, mutation stops transcription factor which aids insulin production - sulfonylureas used
Glucokinase, activates at higher glucose level than normal (4mmmol) doesn’t require medication usually
Permanent neonatal diabetes, kcnj11 mutation which keeps K+ ion channels open all the time
Maternally inherited diabetes and deafness
Most common type of diabetes
Type 2
Then type 1
Then monogenic
How can glucose me measured
Capillary glucose monitoring
How does hypoglycaemia occur?
Lack of balance between diet, exercise and insulin
Why is glucose so important
Major energy substrate for CNS, brain function impaired if less than 4-5mM
Unconscious and Coma occurs at less than 2mM
Most of the pancreas produces what kind of secretions?
Exocrine from accini via ducts to small intestine
Islets of langerhans are endocrine areas of the pancreas, what type of cells do they consist of?
Alpha cells produce glucagon
Beta cells produce insulin
Delta cells produce somatostatin
What cellular structures allow for paracrine signalling?
GAP junctions allow signalling molecules to pass between cells
What is the function of somatostatin
Calms the insulin or glucagon secretion, inhibiting release of both of too much is produced.
Glucagon has a metabolic effect of increasing blood glucose, insulin’s metabolic effect is to decrease blood glucose sand what else?
Stimulates growth and development, the mitogenic effect of insulin.
Beta cells can be stimulated to produce insulin by what?
- Increased blood glucose
- certain amino acids
- gastrointestinal hormones
- parasympathetic activity
Beta cells are inhibited to produce insulin by?
- Glucagon
- somatostatin
- sympathetic activity
What does insulin do?
Decreases lipolysis and promotes lipogeneis
Increased amino acid transport and increased protein synthesis
Inhibits ketogenesis
Increased glycogenesis, increased glycolysis, increased glucose transport into cell via GLUT4
What stimulates glucagon production from alpha cells?
- decreases blood glucose
- certain amino acids
- sympathetic activity
- certain gastrointestinal hormones
What inhibits glucagon release by alpha cells?
Insulin, somatostatin and parasympathetic activity
What does glucagon do?
Increased amino acid transport to liver for GLUCONEOGENESIS
Increased lipolysis, increased gluconeogenesis
Increased hepatic glycogenolysis
What is the glucose sensor in the beta cell?
Glucokinase, it is the enzyme involved in the rate limiting step hence increase in glucose influx via GLUT2 means rate of ATP production increases and closure of more ATP sensitive K+ ion channels leading to influx of Calcium and exocytosis of insulin.
What makes up proinsulin and it’s clinical relevance?
ProInsulin has C-peptide attaches to it which is cleaved to produce insulin. Hence c peptide in blood can show endogenous production of insulin by pancreas hence indicate pancreatic function.
What is the incretin effect?
Glucose absorbed via the intestines leads to higher insulin levels than when glucose directly infused into blood.
Eg Glucagon like Peptide 1 (GLP1), secreted in response to nutrients in blood from L cells.
STIMULATES INSULIN PRODUCTION AND INHIBITS GLUCAGON
Why do incretins have short half life?
Rapidly degenerated by dipeptidyl pepridase-4 enzymes (DPPG4)
What is the insulin receptor?
Tyrosine kinase receptor, two alpha units where the insulin binds and two beta cytoplasmic domains which are crossphosphorylated allowing phosphorylation of cell protein substrates hence triggering a cellular signal.
What does the metabolic arm of the insulin pathway do?
Decreases hepatic glucose output
Increases uptake of glucose in muscles
Decreases proteolysis, lipolysis and ketogenesis
What is involved in the mitogenic arm of the insulin pathway?
Regulates:
Lipoproteins Smooth muscle hypertrophy Ovarian function Clotting Energy expenditure Growth and proliferation
Where is GLUT4 mostly expressed?
Muscle and adipose tissue
Inserted into the membrane via vesicles in response to insulin, leads to massive increase in glucose uptake
In regards to proteins, what stimulates protein synthesis?
Insulin
Growth hormone
IGF1
In regards to proteins, what inhibits protein synthesis?
Insufficient insulin
Cortisol
What inhibits amino acids from entering the krebs cycle?
Insulin
What promotes hepatic glucose output?
Glucagon stimulates uptake of gluconeogenic amino acids into the liver
Glucagon promotes proteolysis
Glucagon, catecholamines and cortisol increase HGO
Which store of energy is used up first?
Glycogen in muscle and liver
Then protein
Then fat
What are omental adipocytes?
Adipocytes around the waste, have endocrine capacity. Higher central adiposity more likely to develop diabetes and heart disease.
How does insulin promote lipogenesis?
Insulin promotes lipoprotein lipase to produce glycerol and non esterified fatty acids (NEFAs). Insulin then promotes the recombining of these to form TAGs. Also promoting conversion of glucose into NEFAs by producing acetyl coA.
What promotes lipolysis To glycerol and NEFAs?
Low insulin Glucagon Growth hormone Catecholamines Cortisol
Why can’t our brain use fatty acids?
Our brain made of farts hence enzymes would degrade brain fats too.
Insulin usually inhibits ketone body formation, why do t1 diabetics have ketones in blood?
As they are insulin deficient
Where is the main store of glycogen?
Liver, for hepatic glucose output
Can muscle release glucose from glycogen?
No, there is no glucose output from muscles.
In fasted state, there is low insulin to glucagon ratio what does this mean?
Glucose levels should be roughly normal
Increased Lipolysis therefore increased NEFAs
Increased proteolysis but amino acid conc low as used for gluconeogenesis
Muscles use lipids
Increased ketogenesis if prolonged
What happens in fed state?
High insulin to glucagon ratio HGO stops Glycogenesis increases Increased protein synthesis Increased lipogenesis Decreases gluconeogenesis
Presentation of T1DM
Insulin deficiency Weight loss Hyperglycaemia Glycosuria Polyuria + polydipsia Ketonuria
Ketoacidosis leads to kaussmals respiration, deep laboured breathing to try and increase blood pH.
Subcutaneous Insulin induced hypoglycaemia is usually fine, why?
Glucagon detects low blood sugar and has its effects, HGO increases.
intramuscular injection of glucagon needed if severe hypoglycaemia.
In T2DM why is there no ketoacidosis or weight loss?
Insulin resistance, enough insulin still produced to prevent lipolysis and ketogenesis. But not enough insulin to reduce glucose levels in blood.
Describe the mitogenic and the metabolic pathway of insulin
The mitogenic pathway is triggered by binding of insulin: it triggered the ras MAPK pathway which causes growth and proliferation. This pathway is also responsible for controlling High BP and abnormal dyslipidemia.
Metabolic pathway is the PI3K-Akt Pathway giving rise to metabolic actions.
Insulin resistance in T2DM occurs in which pathway?
Metabolic, glucose not absorbed and remains high in blood.
This causes compensatory hyperinsulinaemia which overstimulates mitogenic arm. This cause proatherogenic, high bp and prothrombotic effects.
Polycystic ovary syndrome may occur.
What is insulin resistance associated with?
- High triglyceride and low HD/high LDL
- fasting glucose above 6mM
- High waist circumference
- hypertension
This leads to adipocytokines being released which cause beta cell dysfunction and inflammatory mediators being released.
Presentation of T2DM
Insulin resistance Obesity Dyslipidemia Later insulin deficiency Hyperglycaemia
Who does type 2 diabetes have more complications?
As there are cardiovascular effects too due to dyslipidemia
Controlling diet for diabetes
Reduce calorie intake Reduce fat Reduce simple carbs Increase slow release complex carbs Increase fibre Decrease sodium
