Diabetes and ageing 02/05 Flashcards
What is diabetes mellitus?
Dysregulated insulin secretion or insulin action that results in an inability to regulate blood glucose levels properly
Fasting: >7mM 2hrs after 75g glucose load: >11mM
What are the major forms of diabetes?
Type 1 diabetes (juvenile onset). 10% of all cases of diabetes. autoimmune destruction of pancreatic b-cells. progressive disorder. almost total destruction when clinical symptoms present
Type 2 diabetes. 90% of all cases of diabetes. many causes leading to similar pathology. insulin resistance in peripheral tissues OR β-cell dysfunction leading to impaired insulin secretion.
How is insulin secretion normally regulated by B-cells?
- Blood glucose rises, glucose enters the cell and undergoes metabolism by mitochondria.
- Increased production of ATP results in closure of ATP sensitive K+ channels.
- B-cells depolarise and voltage Ca2+ channels open.
- Exocytosis of insulin.
- Insulin binds to receptors on muscle, liver and adipose tissue to upregulate glucose transporters. (GLUT4 in adipose and muscle, GLUT2 in liver). Glucose enters cells.
- Reduced plasma glucose levels feedback to reduce insulin secretion from B-cells.
What are the causes of insulin resistance in type-2 diabetes?
- Obesity, especially increased visceral adiposity. Increased adiposity leads to increased adipokines such as TNF-a and IL-6.
- High levels of triglycerides or fatty acids (secondary to excess food intake).
Increased insulin resistance is a slow process, beggining several years before disease emergence. beta cells over compensate therefore blood glucose remain normal even though insulin resistance is occuring. Eventually they can no longer secrete enough insulin and blood glucose will be elevated.
How are ageing, obesity and T2D linked?
Ageing and obesity both increase the risk of T2D.
Testeosterone and oestrogen are known to increase lipolysis. These hormone levels fall with ageing, which may lead to increased weight gain with age.
How may TNF-a be implicated in T2D?
Knocking out TNF-a has been shown to increase GLUT4 expression
TNF-a regulates plasma insulin release - it actually increases fasting insulin levels.
TNF-a knock out show a better glucose tolerance. This may be related to increased insulin receptor sensitivity, perhaps because less insulin is being secreted
What are the main three causes of insulin resistance in T2D?
Increased visceral adiposity
Increased free fatty acid levels: dietary intake of saturated
fats
Decreased skeletal muscle mass (sarcopenia)
How do increased free fatty acids lead to insulin resistance?
They lead to increased phosphorylation of serine residues on IRS/1 via DAG, PKC and JNK, reducing insulin receptor signalling
How does sarcopenia result in insulin resistance?
Decreased skeletal muscle mass = sarcopenia
mitochondria in aged skeletal muscle produce less ATP and more ROS, promoting oxidative stress and insulin resistance
this reduces the rate of calorie use by the body and exacerbates the problems associated with increased adiposity
main reasons for why does B-cell productivity decline with age?
It is reduced due to three main factors:
Impaired β-cell stimulus-secretion coupling
Islet amyloid deposition and increased β-cell apoptosis
Protein mis-folding and ER stress
Reduced β-cell proliferation
What is the relationship between B-cell productivity and ROS production with ageing?
Generation of ROS by mitochondria is normally neutralised by SOD and catalse.
B-cells have much lower expression of these anti-oxidant enzymes, therefore they are far more suceptible to ROS damage. Damage acummulates with age.
They therefore produce less ATP.
ATP is required to block K+ channel, depolarising cell and leading to Ca2+ efflux, which triggers the release of insulin.
As they age, they theyfore produce less insulin.
Studies from mtDNA mutator mice (premature ageing model) have shown impaired Ca2+ oscillations in repsonse to glucose.
What is the relationship between islet cell functioning, ageing and amyloid deposition?
Misfolded proteins and amyloid deposition lead to apoptosis by two pathways:
-Amyloid deposition causes oxidative stress. Increased ROS production
- Protein misfolding causes endoplasmic reticular stress, leading to inflammatory signals
Protein misfolding and amyloid deposition increase with age, leading to increased b-cell apoptosis.
How is β-cell proliferation altered in ageing?
In younger mice, B-cells can respond to insulin resistance by proliferating.
Older mice express higher levels of cell cycle inhibitor P16ink4a - promoting cell cycle arresting and sensecence. B-cells cannot compensate for increased metabolic demand during obesity.
What are the molecular effects of hyperglycaemia?
**increased Generation of ROS
increased Glycation of proteins**
Increased DAG production leads to increased PKC activation - cellular dysfunction through growth factor production
Activation of the polyol pathway
What is protein glycation and why is it increased in diabetes?
Glycation is non-enzymatic attachment of sugars such as glucose and fructose to amino groups of cellular proteins e.g. haemoglobin, collagen, elastin
Early glycation products combine to form complex cross-linked structures termed advanced glycation end-products (AGE).
Hyperglycaemia can lead to increased maillard reaction due to increased glucose.
Breakdown products of AGEs are usually cleared from plasma, but impaired renal function in diabetes leads to their accumulation
