Carbohydrate handling in Feeding/Fasting states and Complications of diabetes

Question 1

In the general “dephsophorylated” state, what processes are inhibited?

Answer 1

• Insulin is the dephospho state (of the carbohydrate handling proteins)
  
  • Glycogenolysis
  • Gluconeogenesis
  • Ketogenesis
  • Lipolysis

Question 2

In the general “phospho” state, what processes are INCREASED?

Answer 2

• The general phospho state is indicative of high glucagon, low insulin, high catecholamines
  
  • Glycogenolysis
  • Gluconeogenesis
  • Ketogenesis
  • lipolysis

Question 3

How does the definition of diabetes help you think through the complications of chronic disease?

Answer 3

• 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)

Question 4

What are the big takeaways for management of Cardiovascular disease in diabetic patients?

Answer 4

• 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

Question 5

What does HTN have to do with diabetes and its complications?

Answer 5

• 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

Question 6

Why is metabolic syndrome considered a complication of diabetes?

Answer 6

• 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)

Question 7

What is the vascular wall response to diabetes?

Answer 7

• 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

Question 8

Describe what is going on in the inflammation and decreased fibrinolysis process in diabetes

Answer 8

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

Question 9

Describe what is going on with vascular smooth muscle in the response to diabetes

Answer 9

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

Question 10

How does diabetes affect the vascular endothelial cells?

Answer 10

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

Question 11

What is one more “easy” way, to decrease the burden of disease in diabetic patients?

Answer 11

• 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

Question 12

The pylol pathway plays what specific role in disease associated with hyperglycemia?

Answer 12

• 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

Question 13

How does non-enzymatic glycosylation play a role in hyperglycemia-associated disease?

Answer 13

• 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

Question 14

Hyperglycemia can lead to elevated levels of active protein kinase C. How does PKC lead to increasing burden of disease?

Answer 14

• 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

Question 15

Hyperglycemia sets the stage for oxidative and carbonyl stress how?

Answer 15

• 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

Question 16

Explain why retinopathy is a complication of diabetes

Answer 16

• Diabetes is the LEADING cause of blindness in the US
  
  • Historically - by 10 years of disease duration, 90% of individuals have some sort of retinopathy going on
  • Most retinopathy begins with pericyte dropout and loss of autoregulation of blood flow to the retinal capillary bed
  • Subsequently, there is capilary dropout, basement membrane thickening, and leackage of intravascular fluids leading to soft and hard exudates
  • This abnormal blood flow is believed to create hypoxic stress and stimulate local production of cytokines and growth factors (VEGF) which stimulate neovascularization and proliferative retinopathy

Question 17

What does CSME mean in the context of diabetes?

Answer 17

• ocular manifestations of disease

* CSME = clinically significant macular edema

Question 18

What are the 6 stages of retinopathy in ascending order of severity?

Answer 18

• Early pre-proliferative
	• Mild proliferative
	• Severe proliferative
	• Early proliferative
	• Neovascularization disc/elsewhere
	• Macular edema
		○ This is why annual ophthalmologic exams are important to permit ID of individuals with progressive retinopathy

Question 19

Why is early intervention in diabetic retinopathy such a good idea?

Answer 19

• RCTs in large multi-center studies show that early intervention at this stage with pantretinal photocoagulation can prevent or decrease visual loss
• (in the mild or moderate proliferative stage is where the intervention with laser is appropriate)
• Remember the other ocular manifestations of diabetes are:
○ Macular edema, corneal ulceration, glaucoma, cataracts

Question 20

What are the current guidelines for retinopathy treatment?

Answer 20

• First line
○ Focal or modified ETDRS grid photocoagulation for focal or diffuse CSME
○ Intravitreal pharmacotherapies +/- photocoagulation for more advanced, diffuse CSME
• Persistent or recurrent CSME
○ Visual acuity here is less than 20/40
○ Repeat photocoagulation
○ Intravitreal triamcinolone acetonide or intravitreal antivascular endothelial growth factor (VEGF) agent
○ PKC inhibitors (only in research right now)
• CSME refractory to photocoagulation and intravitreal pharmacotherapies
○ Consider pars plana vitrectomy
○ No traction: use PPV with internal limiting membrane peeling
○ Taut posterior hyaloid face or vitreomacular traction syndrome
§ Use PPV and ILM peeling in this case

Question 21

What is up with diabetic nephropathy?

Answer 21

• Diabetes is the leading cause of renal failure and dialysis and transplant nationwide
  
  • Even when managed well diabetes can still lead to CKD and kidney failure
  • b/c of hyperfiltration (osmotic load of hyperglycemis)
  • b/c of intrarenal and peripheral hypertension
  • b/c of direct hyperglycemic injury
  • The end result is basement membrane thickening that leads to abnormal funciton of the basement membrane
  • There is also the result of mesangial proliferation and eventual glomerular destruction
  • Aggressive control of both glucose levels and hypertension with ACEIs and Beta blockers slows the progression of nephropathy in DM

Question 22

What’s going on in diabetic neuropathy?

Answer 22

• 50% of diabetes patients present with complaints of neuopathy
• The etiology is complex
○ Neuronal attempts at survival, regeneration and maintenance of normal healthy function in a neurotoxic environment
• Neurotoxic environment
○ Hyperglycemia, hyperosmolarity, increased polyol flux, advanced glycosylation end products (AGEs), oxidant stress, hypoxia, neural antibodies and neurotrophin deficiency
• Diverse and complex clinical picture
○ Distal symmetric polyneuropathy
○ Mononeuritis multiplex
○ Autonomic neuropathy
○ Sensorimotor neuropathy
○ Mixtures of the above

Question 23

Why foot trauma in diabetics?

Answer 23

• Both poor blood flow and neuropathy lead to lack of sensation in foot
  
  • High incidence of mechanical trauma and infectious complications leading to amputation and hospitilization
  • PREVENTABLE with better hygiene and footwear

Question 24

What are the 4 categories of diabetic neuropathy?

Answer 24

• Distal symmetric polyneuropathy
○ Stocking glove distribution, can be painless or painful
○ Superficial pain or paresthesias involve the c-fibers
○ Deep seeded gnawing pain involves the delta fibers
• Autonomic neuropathy (worry when you see this b/c of high risk of cardiovascular death)
○ Gastorparesis
○ Sexual dysfunction
○ Orthostatic hypotension/inappropriate heart rate response
○ Hypoglycemic unawareness
• Mononeuritis multiplex
○ Vascular occlusion to single nerve distribution
○ Can recover in time
• Diabetic amyotrophy
○ Profound neuromuscular wasting syndrome