Pathophysiology / insulin resistance
15 important questions on Pathophysiology / insulin resistance
How do you diagnose Diabetes? And what are the cut of points?
- normal
- diabetes
- imparied glycose tolerance
- impaired fasting glycaemia
The blood glucose regulation (hyperglycaemia hyperinsulinemia)
euglycaemia causes the alvleesklier to produce insulin, which will decrease the hepatic glucose output from the liver and increase the peripheral glucose uptake
genetic and environmental factors can influence insulin action (I resistance) and insulin secretion (Beta-cell failure)
How does insulin stimulate glucose uptake (GLUT4)?
glucose can go through the membrane, but this will go quicker whit a transporter (GLUT4).
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There is also a insulin-independent way for glucose uptake, namely
when physical exercise takes place, AMPK, ROS, NO, CaMK are released and activate AS160, which activates the GLUT4
What is the resistance towards action of insulin:
Reduced glucose disposal peripheral tissues
- oxidative and non-oxidative glucose disposal
- Muscle: impaired glucose uptake (-> IGT)
- Liver: increased glucose output (EGO/HGP) (->IFG)
- Adipose tissue: reduced anti-lipolytic effect (->FFA)
- Pancreas: impaired suppression glucagon (paracrine)
But also protein anabolism, growth, vascular function
What is the role of insulin resistance in health and disease?
- Diabetes mellitus
- Obesity
- Cardiovascular disease
- Metabolic syndrome
- Prolonged fasting / starvation
- Pregnancy
- Lipodystrophy
- Peri-operative (surgery)
- Drug treatment (corticosteroids)
What do you know about pregnancy and insulin sensitivity
- to regulate energy metabolism
- Maternal IR leads to more use to fats than carbohydrates for energy by mother and spared carbohydrates for fetus
Hyperglykemia -> gestational diabetes
- Macrosomia
- obstetric complications
Hormones
Lows grade inflammation (TNFa)
What is (generalised) lipodystrophy?
- (partial) absence of AT (=adipose tissue) in certain regions
- Severe insulin resistant
- Familial (genetic): rare
- Acquired
- autoimmune/inflammatory
- Antiretroviral medication (HIV)
What are the pathogenesis/physiologies of type 2 diabetes?
- Genetics
- 'Thrifty geno/phenotype'
- Perfusion SM
- Glucagon
- Hyperglycaemia (glucotoxicity)/hyperinsulinemia
Lipocentric view
- FFA
- Ectopic lipids
- Inflammation/adipokines
What is the role of adipose tissue and lipotoxicity
the hypertrophic dysfunctional adipose tissue
- hypertrophy (due to caloric overload)
- Insulin resistant antilipolytic effect --> FFA increases
- Inadequate proliferation / differentiation, ER stress
- Inflammatory response (JNK, IKK/NF-kB), CRP, ROS
- Cytokine secretion (TNFa, IL, MCP-1)
- paracrine (IL's), endocrine (TNFa)
- Macrophage infiltration
- Adipokines (leptin/adiponectin)
Cause (?): AT Hypoxia
Give two examples of adipokines
- Elevated on obesity
- Reduces appitite
- leptin resistance
- 'starvation signal'
Adiponectin
- adipose tissue hormone
- inversely associated with obesity
- adioponectin receptor
- adipocyte differentiation, insulin action, anti-inflammatory
Lipid induced insulin resistance: ectopic lipids & lipotoxicity
the higher the lipids in the muscle cell the lower the insulin sensitivity.
insulin signaling is subrest
Intra Hepatic lipids (IHL) (=)
Why do lipids accumulate?
- diet
- adipose tissue dysfunction
and/or
reduced utilisation
On what does a decreased transcription of metabolic and mitochondrial genes have influence on?
- Decreased oxidative phosphorylation
- Decreased lipid oxidation
- Accumulation of lipid in skeletal muscle
Which all result in insulin resistance obesity and diabetes.
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