PBL 4 - Diabetes T2 Flashcards
What chemical process is measured by Hba1c level? (ii) What does
Hba1c reflect? [
Glycation of proteins (in this case: haemoglobin) [1/2]
(ii) Elevated glucose levels over an extended period of time OR poor control of
blood glucose [
Briefly state what are the mode of action of the drugs Metformin and
Sitagliptin? How are they used in the management of type 2 diabetes?
Metformin: inhibits hepatic gluconeogenesis – reducing blood glucose levels
Sitagliptin: inhibits the breakdown of GLP1 – this in turn increases insulin and
decreases glucagon secretion from the pancreas
) What tissue is the source of (i) Leptin (ii) GLP-1? What changes cause an
increase of each of these hormones?
(i) Leptin:
Source: Adipocytes (OR fat cells OR white adipose tissue, NOT fat) [1/2]
Level increased by an increase in adipose tissue (OR body fat mass) [1/2]
(ii) GLP-1:
Source: Intestinal L cells in mucosa of distal ileum & in colon [1/2]
Level increased by a glucose or fat rich meal
Why might using insulin as a therapy not work in this case?
Potential of insulin resistant tissues causing the type 2 diabetes – especially due to
the high weight.
What is a BMI of 28 classified as? What is the BMI range for someone
considered mildly obese? In the scenario, why does the GP take time to measure
Mr Creosote’s waistline?
28 = high end of overweight [1/2] mildly obese = BMI from 30 to 34.9 [1/2]
Waistline measurement is actually better correlated with T2D than BMI. [1]
Name four hormones triggering a feeling of satiety? [2]
CCK, insulin, leptin, PYY, GLP-1 – [1/2 for any of]
Risk factors for T2D
Obesity
Family history
Age
Ethnicity
Why does obesity increase risk of diabetes
Accumulation of lipids + their metabolites e.g. FFA cause chronic inflammation + altered adipokine levels –> CD 36 increasing its uptake into cells –> Excess in cells affects signalling pathways–> Insulin resistance
Hyperinsulinemia occurs to try and overcome the insulin resistance –> increases lipid synthesis –> exacerbates problem
Why do some people have insulin resistance but not develop diabetes
islet compensation e.g. increase in size/number
How to diagnose T2D
Glucose tolerance test
Values for fasting, random and HbA1c to diagnose T2D
Fasting - >7mmol/l
Random - >11mmol/l
HbA1c - >48mmol/l
Symptoms of T2D
Polyuria
Polyphagia
Thirst
Peripheral neuropathy
Complications of T2D
Neuropathies, nephropathies
iscaemic heart disease/stroke –> atherosclerosis, dyslipidaemia
Cause of T2D
Insufficient insulin production + insulin resistance
At the insulin receptor –> IRS is not longer phosphorylated by tyrosine –> Threonine/serine is phosphorylated instead –> No P13K/Akt activation
Impaired islet compensation
Effect of giving insulin to T2D patients
hyperglycemia –> glutotoxicity –> damages Beta cells –> even less insulin secreted hence insulin may be useful
- Insulin may not be effective if receptors faulty and saturated already.
- Can cause lipogenesis
Treatment of T2D
Metformin Sitaglipin Pioglitazone Sulfonylureas Obesity treatments
Metformin
Biguanide
Activation of AMPK
1) Suppresses hepatic gluconeogenesis
2) Increased peripheral uptake of glucose via GLUT
3) Increased GLP1 –> Stimulates insulin and inhibits glucagon + promotes satiety
Increases insulin sensitivity
Sitaglipin
Incretin
Inhibits DDP-4 –> normally breaks down GLP-1 –> Increase insulin secretion + suppresses glucagon release
Increase POMC and decrease AGRP/NPY
Pioglitazone
TZD
Stimulates PPARG
= Increases sensitivity for insulin uptake in muscles/adipocytes
2) reduce insulin resistance 3) decrease hepatic gluconeogenesis
4) Reduce level of glucose in blood
Sulfonylureas
Act to stimulate insulin release by inhibiting K+ channels.
Orlistat
Lipase inhibitor
Obesity medication
Phentermine
Orlistat
When surgery for overweight pts
Morbidly obese >40
or obese >30 with problem
Gastric banding - restrictive
Biliopancreatic diversion - absorptive
Centre for appetite regulation
Arcuate nucleus in hypothalamus
Orexigenic
NPY
AgRP
MHC
Ghrelin
Anorexigenic
POMC CART a-MSH (secreted by POMC) Insulin, leptin and CCK activate POMC neurones (without insulin it is not inhibited) GLP-1 and PYY
Genes affecting diabetes
GKRP
PPARG
GKRP
Glucokinase regulatory protein
- Protein produced that binds and moves glucokinase controlling activity and intracellular location based on insulin.
- In high levels of glucose, GKRP allows GK to enter cytoplasm and uptake glucose into hepatocytes to lower glucose.
PPARG
peroxisome proliferative-activated receptor gamma
• Receptor that regulates fatty acid storage and glucose metabolism
• Genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells
• PPARG is regulator of adipocyte differentiation
Ancanthosis Nigricans
Marker for hyperinsulinaemia
Dark patches of skin
Insulin binds and stimulates receptors (IGFL) on keratinocytes and dermal fibroblasts promoting its proliferation
Hb1Ac
- Measures glycosylation of haemoglobin, proportion of glycosylation can indicate level of glucose in the last 3 months since RBCs have life span of 120 days
