Type II Diabetes Mellitus Flashcards
In a diabetes diagnosis, _____ > 6.5%
HbA1c
Races at a higher risk for T2DM?
Indigenous, Hispanic, African ancestry
Autoimmune disease => pancreatic beta cell destruction, usually onset is in childhood but sometimes in early adulthood
Type 1 diabetes
Combination of peripheral resistance to insulin action and an inadequate secretory response by beta cells
Type 2 diabetes
Single-gene disorders or secondary to infection or pancreatic destruction by other means
Monogenic and secondary causes
Is type 1 or type 2 diabetes more common?
Type 2
Monozygotic twin concordance T2DM vs T1DM?
T2DM - 70-90%
T1DM - 30-50%
Each gene implicated in T2DM has the ability to increase the relative risk of expressing diabetes by what percentage?
5%
Notable genes implicated in T2DM?
- TCF7L2 gene
- PPAR receptor
- IRS gene
Transcription factor that works on a wide variety of genes including the Wnt pathway genes?
TCF7L2
Transcription factor/nuclear receptor that binds FFAs and/or PGs?
PPAR receptor
Most important environmental risk factor?
Obesity (esp. central obesity)
Two step pathophysiology of T2DM?
- Impaired insulin action (sensitivity)
- Impaired insulin secretion
What happens with impaired insulin action?
Insulin resistance and abnormal fat and skeletal muscle metabolism
What is impaired insulin secretion usually accompanied by?
Imbalance in insulin/glucagon activity ratio => increased glucagon action
Pathophysiologic pearl?
To progress to overt T2DM, you need impaired insulin secretion, which seems to arise after a long history of insulin resistance
What are the 3 aspects of developing insulin resistance?
- Increased FFAs and adipocyte endocrine dysfunction
- Reduction of incretins
- INS-R desensitization
How does lack of insulin result in increased FFAs?
Results in excessive activity of lipoprotein lipase
What incretins are released by the GI tract in response to a meal?
GIP and GLP-1
What does incretin release do in a healthy person? (3)
- Decrease gastric emptying (satiety)
- Increase insulin release
- Reduce glucagon secretion
Non-esterified fatty acids increase _______, and more are released from ________ than peripheral fat
Insulin resistance; central fat
What process are NEFAs released from adipose tissue through?
Lipolysis
When is NEFA release normally stimulated?
When energy demand is high (fasting, exercise)
What hormones stimulate NEFA release?
Glucagon and adrenaline
What does increased intracellular [NEFA] cause?
Serine phosphorylation of insulin receptor (inactivates it)
What are adipokines and what do they do?
Protein hormones from fat cells
- Increase sensitivity of insulin receptor
- Increase enzymes that ox NEFAs
Increased NEFA oxidation is mediated by what?
AMP-K = protein kinase activated by metformin
Anti-hyperglycaemic adipokines? (2)
- Leptin
- Adiponectin
Hyperglycaemic adipokines? (2)
- Resistin
- Retinol-binding-protein 4
Pancreatic pathology: Reduction in the number and size of islets and leukocytic infiltrates in the islets (T-cells, mostly)?
Type 1
Pancreatic pathology: Reduction in islet cell mass as well as amyloid deposition around beta cells?
Type 2
What type of diabetes involves inflammation and reduction in islet size?
Type 1
What are advanced glycation end products (AGEs)?
Metabolic products of glucose non-enzymatically linked to amino groups of intra-and extracellular proteins
What do AGEs bind to?
R-AGE on macrophages, T-cells, smooth muscle cells and endothelial cells
What does R-AGE binding lead to? (4)
- Release of pro-inflam cytokines
- Generation of ROS
- Increased procoagulant activity
- Prolif of vasc smooth muscle cells and ECM
AGEs cause cross-linking of matrix proteins and render them resistant to what?
Proteolysis
In the end, what do AGEs contribute to? (4)
- Decreased large artery elasticity
- Narrowing of smaller arteries
- Atherosclerotic plaques
- Increased susceptibility to coagulation
Activation of what pathway by hyperglycemia leads to deposition of excess matrix, secretion of pro-inflammatory cytokines, and increased susceptibility to coagulation?
Protein kinase C
Endothelial dysfunction predisposes to what?
Atherosclerosis
What is a hallmark of diabetic macrovascular disease?
Accelerated atherosclerosis involving aorta and large and medium-sized arteries
Most common cause of death in diabetics?
MI caused by atherosclerosis of the coronary arteries
Vascular lesion associated with HTN more prevalent and more severe in diabetics?
Hyaline arteriolosclerosis
What does amorphous, hyaline thickening of wall of arteries cause?
Narrowing of the lumen
Diffuse thickening of basement membranes?
Diabetic microangiopathy
Where is diabetic microangiopathy prominent? (5)
- Capillaries of skin
- Skeletal muscle
- Retina
- Renal glomeruli
- Renal medulla
What does diabetic neuropathy cause the loss of?
- Pain sensation
- Loss of vibration, proprioception, fine touch
What are some features of autonomic neuropathy? (3)
- Orthostatic hypotension
- Incomplete bladder emptying = recurrent infection
- Sexual dysfunction
Some chronic diabetics develop hyper-osmolar non-ketotic crises (HONK) - what does this result in? (3)
- Severe dehydration
- Impaired level of consciousness
- Hyper-osmolarity
What is an early sign of insulin resistance in some?
Acanthosis nigricans
