Carbohydrate handling in Feeding/Fasting states and Complications of diabetes Flashcards
In the general “dephsophorylated” state, what processes are inhibited?
- Insulin is the dephospho state (of the carbohydrate handling proteins)
- Glycogenolysis
- Gluconeogenesis
- Ketogenesis
- Lipolysis
In the general “phospho” state, what processes are INCREASED?
- The general phospho state is indicative of high glucagon, low insulin, high catecholamines
- Glycogenolysis
- Gluconeogenesis
- Ketogenesis
- lipolysis
How does the definition of diabetes help you think through the complications of chronic disease?
• Definition - glucose handling that results in chronically high blood glucose, enough to cause microvascular damage
• In pre-diabetes, that is not yet microvascular damage but more macrovascular damage
• This looks like increased athersclerosis build-up and pre-disposition for peripheral artery disease or coronary artery disease (CAD)
• As diabetes progresses and the sugars are high enough to mess with the MICROVASCULAR system then you have other more classic diabetes complications
○ Retinopathy
○ Nephropathy
○ Neuropathy
○ Amputation (microvascular/macrovascular)
What are the big takeaways for management of Cardiovascular disease in diabetic patients?
- 77% of all hospitalizations and 80% of all mortality in diabetes are secondary to cardiovascular disease
- Essentially, diabetes is such a risk factor that is risk EQUIVALENT
- It is very important to aggressively treat other risk factors for CVD and any symptoms of CVD as serious
- LOWER LIPDS
- MANAGE HTN
- CONTROL GLUCOSE EARLY
What does HTN have to do with diabetes and its complications?
- HTN contributes to all microvascular and macrovascular complications of diabetes
- Tons of prospective RCT evidence to support aggressive treatment of HTN in patients with diabetes
- HTN is super common in T2DM but uncommon in T1DM (prior to onset of renal disease
- T1DM will lose the circadian rhythm of their native blood pressure control
Why is metabolic syndrome considered a complication of diabetes?
• Metabolic syndrome and insulin resistance should be thought of as nearly the same thing
• Hyperinsulinemia is associated with the metabolic syndrome
• Constellation:
○ Insulin resistance, visceral adiposity, hypertension, dyslipidemia, type 2 diabetes, glucose intolerance
• It’s clear this syndrome contributes significant risk to disease burden
• Insulin also acts as a direct growth factor, making changes directly to the vessel wall
○ (so think of metabolic syndrome as contributing to the vascular wall response to diabetes)
What is the vascular wall response to diabetes?
• Abnormal endothelial cell function
○ Abnormal clotting factor production - decreased tPA and increased PAI-1
○ Inflammation due to expression of adhesion molecules - aggregation of platelets and leukocytes
○ Decreased endothelium dependent vasomotion
○ Increased cytokine and chemokine production
• Abnormal vascular smooth muscle cell function
○ Enhanced vascular smooth muscle proliferation and migration
○ Increased production of matrix proteins, cytokines and growth factors
○ Altered contractile function
• Inflammation and decreased fibrinolysis
○ Platelet adhesion and activation
○ Monocyte adhesion and macrophage activation and invasion into sub-intimal space
○ Increased expresion of cytokines and chemokines of invading monocytes
○ Foam cell formation and activation of metalloproteinases
Describe what is going on in the inflammation and decreased fibrinolysis process in diabetes
Part of the vascular response to diabetes
• Inflammation and decreased fibrinolysis
○ Platelet adhesion and activation
○ Monocyte adhesion and macrophage activation and invasion into sub-intimal space
○ Increased expresion of cytokines and chemokines of invading monocytes
○ Foam cell formation and activation of metalloproteinases
Describe what is going on with vascular smooth muscle in the response to diabetes
Part of the vascular response to diabetes
• Abnormal vascular smooth muscle cell function
○ Enhanced vascular smooth muscle proliferation and migration
○ Increased production of matrix proteins, cytokines and growth factors
○ Altered contractile function
How does diabetes affect the vascular endothelial cells?
Part of the vascular response to diabetes
• Abnormal endothelial cell function
○ Abnormal clotting factor production - decreased tPA and increased PAI-1
○ Inflammation due to expression of adhesion molecules - aggregation of platelets and leukocytes
○ Decreased endothelium dependent vasomotion
○ Increased cytokine and chemokine production
What is one more “easy” way, to decrease the burden of disease in diabetic patients?
• Aggressively treat their cardivascular risk and burden
• Use beta blockers and antihypertensives
• Use lipid lowering agents
○ These have great outcomes in this patient population
• Establish glycemic control EARLY on in the disease process, as this has great benefits years later
The pylol pathway plays what specific role in disease associated with hyperglycemia?
- Hyperglycemia leads to an influx of glucose into cells, and this can be metabolized by aldose reductase to sorbitol and fructose
- ENZYME - aldose reductase
- PRODUCTS - sorbitol and fructose
- These products are osmotic and oxidative mediators of damage
- Inhibition of aldose reductase is under investigation for effectiveness in disease progression
How does non-enzymatic glycosylation play a role in hyperglycemia-associated disease?
• The main takeaway here is that AGEs play a well-established role in the development of diabetic complications and have been rigorously studied in nephropathy, vasculopathy and retinopathy
• AGE = advanced glycosylation end product
• In a hyperglycemic state, there is NON-ENZYMATIC glycosylation of primary amino groups on proteins
○ Though this is reversible, in chronic hyperglycemia, the reaction is shifted to the glycosylation state
• Subsequent reduction and amadori rearrangements result in the irreversible formation of AGES
• These abnormally cross-linked proteins interfere with basement membrane function and in the vasculature can squelch nitric oxide and impair vasodilation
• AGEs also bind AGE cellular receptors and this can lead to abnormal cellular function of vascular endothelial cells, vascular smooth muscle cells and production of mesangial matrix proteins such as type IV collagen by renal mesangial cells
• Intracellular AGEs can crosslink and disrupt DNA function and repair
Hyperglycemia can lead to elevated levels of active protein kinase C. How does PKC lead to increasing burden of disease?
• Hyperglycemia –> PKC beta and delta isoform activation
• Leads to the productino of the extracellular matrix proteins collagen and fibronectin by renal and vascular cells
• Essentially this results in basement membrane THICKENING
• In endothelial cells PKC elevations promote increased expression of ICAMs
○ This promotes platelet aggregation AND monocyte adhesion and invasion
• The endothelial cells also increase their expression of plasminogen inhibitor activator-1 (PAI-1), VEGF
• Leads to defective production of vasodilating factor, NO
Hyperglycemia sets the stage for oxidative and carbonyl stress how?
• Cellular damage from intra and extracellular oxidative burden can start a downward cycle
• Intracellular oxidative damage can lead to the activation of shunting pathways in glucose handling
• Glucose can go to pylol, which is deleterious to the cell
• F6P can go to glucosamine
• Glyceraldehyde 3 phosphate can go directly to DAG production and increased PKC activation (leads to basement membrane thickening)
○ Or can go to methylglyoxal which is made eventually into AGEs
• The downward cycle means more damage leads to more damage