Biochemistry of Diabetes and Insulin Flashcards
Is insulin anabolic or catabolic? Explain.
Anabolic
Promotes synthesis of lipids, proteins and glycogen.
What hormones “take over” in diabetes?
Glucagon (liver only), adrenaline and cortisol
What substances are mobilised from muscle and fat respectively in diabetes?
Muscie: lactate and AAs
Adipose: glycerol
What is insulin resistance?
Decreased sensitivity of target cells to normal circulating insulin levels due to impaired insulin signalling.
What are the BSL levels of people with insulin resistance like?
Hyperglycaemia even in the presence of high plasma insulin levels
What are the factors needed to develop insulin resistance?
Obesity genes or obesity, insulin resistance genes + environmental factors
What is the early-stage response of the body to insulin resistance?
Increased insulin made by beta-cells and adequate compensatory response.
Beta-cell mass increases and function enhances
Compensatory hyperinsulinaemia and maintenance of normal glucose tolerance
How do we transition from insulin resistance to T2DM?
Eventually increased demand for insulin causes beta cells to fail to compensate + insulin resistance causes hyperglycaemia and this causes glucolipotoxicity to beta cells.
Does everyone with insulin resistance eventually get DM?
No
What type of receptor is the insulin receptor?
Tyrosine kinase receptor
What are the rapid and long-term effects of activating the insulin receptor?
Rapid: glucose uptake, enzyme activation
Long-term: enzyme synthesis, cell growth
What is the negative control mechanism for insulin receptors?
Downstream kinases are activated and phosphorylate IRS proteins on serine residues, preventing propagation of the insulin signal.
What impairs insulin signalling?
- Genetic variations
2. Excess nutrients and IR induces (cytokines, ROS etc.) that stop signalling
Which important GLUT receptor is insulin-independent and where is it located?
GLUT2 in the liver
How does insulin resistance affect lipid metabolism?
Increased plasma FFA
Increased plasma TAGs and VLDL
:. Predisposes to hypertriglyceridaemia and NA fatty liver
How does abdominal visceral fat predispose to CVD?
Causes insulin resistance AND affects lipid levels, increasing bad cholesterols
What are the main features of the metabolic syndrome?
CENTRAL OBESITY
- Raised TAGs <1.7
- Reduced HDL-C
- Raised BP >130
- Raised fasting BGL >5.6 or T2DM
What is adiposopathy and how does it occur?
Dysfunctional adipose tissue! Low-grade chronic inflammation of expanded adipocytes.
As tissue expansion occurs so does necrosis as the vascular network can’t keep up with growth
What are the risk factors for adiposopathy?
Caused by adiposity, genetic predisposition and sedentary lifestyle
What are the effects of adiposopathy?
Increased FFA release Abnormal cytokines (adipokines) Adipose tissue is endocrine tissue! Adiposopathy causes metabolic disturbances including insulin resistance.
How to these lipid issues cause damage in non-adipose tissue?
Excess FFAs are taken up and lipid storage occurs in droplets near mitochondria, causing lipotoxic effects
Cause beta-cell failure and fatty liver also.
Don’t need to know proposed mechanisms!
How go biguanides work?
Inhibit hepatic gluconeogenesis
Activate AMPK to increase insulin sensitivity.
How do sulphonylureas/meglitinides work?
Bind to pancreatic SUR1 receptor to increase insulin secretion
Close K channel to promote insulin release (:. can cause a hypo!)
How do thiazolidinediones/glitazones work?
Bind to PPAR-gamma to promote peripheral FFA uptake
Sensitise cells to insulin
Increase glucose utilisation
How do alpha-glucosidase inhibitors work?
Slow down digestion and absorption of some carbs (starch!)
What normally happens re glucagon after a meal?
Glucose prompts action of beta-cells which in turn inhibit alpha-cells so glucagon is not produced
What happens with decreased sensitivity of alpha cells to insulin/decreased insulin?
Glucagon is not adequately suppressed and so is oversecreted
