week 10 Flashcards
What causes type 1 diabetes?
loss of insulin production. The pancreas produces little to no insulin
What causes type 2 diabetes?
insulin resistance; insuffcient secretion of insulin.
Pancreatic beta cells cannot release sufficent insulin to compensate.
What causes hyperglycemia ?
loss of insulin-stimulated glucose uptake.
Loss of insulin repression of gluconeogenesis and glycogen breakdown.
What causes dislipidaemia?
Loss of insulin repression of lipolysis.
How is type 1 diabetes managed?
insulin injections, diet and exercise control
How is type 2 diabetes managed?
oral medications or insulin injections, diet and exercise control.
What is gestational diabetes? When does it develop?
2nd trimester develops and dissapears after child is born. Cause not clear but thought to be due to various hormonal changes which can block the action of insulin.
In a fasting glucose test what figures are deemed as pre-diabetic and diabetic?
pre-diabetic ; 5.5 - 6.9 mmol/l
diabetic ; over 7 mmol/l
What figure indicates diabetes in a random glucose test?
over 11 mmol/l
What HbA1c values indicate type 2 diabetes?
Over 48 mmol/mol
at 42-47 there is a risk of developing type 2 diabetes
HbA1c formation
forms as a result of a slow and irreversible reaction between hemoglobin A (HbA) and glucose.
Values give a measure of average blood glucose levels of the previous 3-4 months.
Complications of diabetes
hpyerglycaemia, vascular damage.
Acute symptoms of diabetes
dehydration, nausea and vomiting, increased fatigue, polydipsia, polyuria, polyphagia, weight loss, infections, poor wound healing, blurry vision.
Why does polyuria occur in untreated diabetes?
the amount of glucose filtered by the kidney, exceeds maximal capacity for reabsorption resulting in glucose entering urine and drawing H2O with it by osmotic diuresis.
Why is fatigue and hunger experienced in diabetes?
caused by cells that do not get energy due to glucose not being taken in.
Why is poor wound healing experienced by untreated diabetics?
damage to blood vessels limit flow of oxygen and nutrients needed for repair.
Process of Diabetic ketoacidosis (DKA)
Occurs in low insulin environments when glucose is unable to enter cells. Absence of insulin enhances free fatty acids (FFA) release from adipocytes. FFAs converted to ketones by the liver, which can serve as an energy source. Ketones cause the pH of the blood to become acidic. Liver continues to synthesize glucose; therefore, the blood glucose rises. High glucose in the urine takes water and solutes such as potassium and sodium with it- dehydration.
Is DKA life threatening?
life threatening in type 1
metabolic changes in type 2 are not usually severe enough to cause DKA.
How can DKA be treated?
fluid replacement, insulin and mineral replacement.
microvascular damage included in chronic complications of diabetes
damage to small blood vessels (capillaries) e.g. nephropathy, retinopathy, neuropathy
macrovascular damage included in chronic complications of diabetes
damage to larger blood vessels (arteries and veins) e.g. stroke and cardiovascular disease
Increased uptake and metabolism of glucose leads to an __ in ATP:ADP ratio. This leads to __ which then leads to __ . Resulting in __.
(regulation of insulin secretion by blood glucose)
increase.
Leads to a closure of ATP-sensitive K+ channels and membranes depolarization.
Leads to opening of voltage gated Ca2+ channels
Resulting in increase in cytosolic Ca2+ - promotes secretion of insulin.
How does insulin repress gluconeogenesis?
insulin stimulated AKT phosphorylates, and inhibits the transcription factor FoxO1.
The expression of gluconeogenic genes such as glucose 6 phosphate is supressed.
What impact does insulin have on;
glucose uptake
glycolysis
glycogen synthesis
fatty acid synthesis
protein syntheis
proteolysis
glycogen breakdown
lipolysis
increase
increase
increase
increase
increase
decrease
decrease
decrease
Insulin signaling
- Binding of insulin to the insulin receptor (IR) leads to receptor auto-phosphorylation.
- Phosphorylated residues on the IR acts as binding sites for insulin receptor substrate (IRS) proteins.
- IR phosphorylates 4 tyrosine residues in IRS proteins.
- The lipid kinase, phosphoinositide 3-kinase binds to phosphorylated residues on IRS proteins, and then converts PIP2 to PIP3.
- Binding to PIP3 activates PDK1, which then phosphorylates and activates kinases such as PKB/Akt.
- Activated PKB/Akt can then diffuse through the cell and activate processes such as glucose transport and glycogen synthesis.
How does insulin stimulate glucose uptake into muscle and adipocytes?
The glucose transporter GLUT4 is contained inside the cell in storage vesicles.
The protein AS160 acts to retain these vesicles in the cell.
Activated PKB phosphorylates AS160 and inactivates it
This allows GLUT4 vesicles to fuse with the plasma membrane, leading to increased levels of the glucose transporter at the cell surface.
Type 1 diabetes causes the auto-immune destruction of beta cells.
TRUE or FALSE
true
Why is obesity a major factor associated with insulin resistance?
amount of triglycerides exceeds the storage capacity of adipose cells. as a result, the fat accumulates in tissues such as the liver and muscle.
Excess fat leads to increase DAG and ceramide in the cytoplasm of cells.
Metformin, how does it work? Side effects?
glucose-lowering agent that works by stopping glucose production in the liver - a biguanide that does not cause weight gain or hypoglycemia.
Side effects; nausea, vomiting, reduced appetite, vitamin b12 deficiency.
How may metformin cause a b12 deficiency?
metformin reduces intestinal absorption of vitamin b12
Sulfonylureas’, how do they work? Side effects? Give example.
Stimulate insulin secretion from pancreatic beta cells - bind to ATP-gated K+ channels, causing channel closure and membrane depolarization.
Examples; gliclazide, glipizide, glimepiride and tolbutamide.
Side effects; increased risk of hypoglycemia and weight gain.
Meglitinides, how do they work? Side effects? Give example.
similar mechanism of action as sulfonylureas but rapid onset and short duration.
stimulate insulin secretion by binding to subunits in the beta-cell membrane
examples; repaglinide and nateglinide
taken before meals
Glitazones, how do they work? side effects? give examples.
lower HbA1c levels, insulin sensitizers and increase insulin sensitivity by stimulating expression of insulin-sensitizing genes.
Pioglitazone
Water retention and weight gain.
Gliptins, how do they work? side effects? examples.
DPP4 inhibitors and so block incretin degradation, insulin release is increased and glucagon release is reduced. Used alongside metformin.
sitagliptin
SGLT2 inhibitors, how do they work? side effects? give example
inhibit the glucose transporter SGLT2, which functions in the kidney to mediate glucose reabsorption. Block sodium.
Take 4-6 weeks for response, also reduce cholesterol.
Empagliflozin.
How do sulphonylureas’ cause increased risk of hypoglycemia?
will increase insulin releases from pancreatic beta cells, irrespective of what the blood glucose is; thus, if it is already low the the sulfonylurea can potentially lower it even further.
Diabetes medications causing weight gain
Sulphonylureas, glitazones, meglitinides
diabetes medication not associated with weight gain
metformin, SGLT2 inhibitors, gliptins
diabetes medication associated with hypoglycaemia
sulphonylureas, metglitinides
In a hypoglycaemic state; what will blood glucose levels be? What are the symptoms?
below 4mmol
sweaty, hungry, cold, pounding heartbeat, tingling lips
Management of hypoglycaemia
eat/drink sugary thing followed up by a longer acting carbohydrate
metformin logP and pKa
logP -1.2
pKa 12.4
What makes metformin orally available?
the mechanism which takes it into cells - intrinsic factors make it orally available
sulfonylureas logP and pKa
logP 2-4
pKa 5-6
