Pathophysiology of Diabetes Complications

Question 1

What are the major chronic complications of diabetes mellitus?

Answer 1

Macrovascular: Accelerated coronary, cerebrovascular, and peripheral vascular disease (“premature aging,” atherosclerosis blocks arteries supplying the heart, brain, and extremities)

Microvascular: renal disease (abnormal structure and function of the glomerulus causing filtration of large proteins such as albumin -> proteinuria, may lead to kidney failure); retinopathy; neuropathy

Foot ulcers (contributing factors include neuropathy, impaired blood flow causing poor wound healing, and susceptibility to infection; gangrene may develop and require amputation)

Erectile dysfunction (contributing factors are neurologic and vascular)

Increased susceptibility to infections (impaired immune system responses)

Cataracts (‘premature aging’)

Complications may already be present at the dx of Type 2 Diabetes

Question 2

Describe cardiovascular disease and how it relates to a complication of diabetes.

Answer 2

macrovascular complication

CVD is a major cause of mortality and morbidity for patients with diabetes

type 2 diabetes an independent risk factor for CVD and it’s common coexisting conditions are also risk factors for CVD

Question 3

How might dyslipidemia increase CVD risk in patients with diabetes?

Answer 3

dyslipidemia in type 2 diabetes and in the ‘metabolic syndrome’ is characterized by decreased plasma HDL cholesterol and increased triglycerides with smaller more dense LDL particles (abnormal) that are ‘atherogenic’ - benefit from tx with statin

Question 4

How does hypertension relate to diabetes complications?

Answer 4

Hypertension present as part of metabolic syndrome and a major risk factor for CVD as well as microvascular complications (retinopathy and nephropathy)

• pt with diabetes advised to keep BP < 140/90

Question 5

Describe what hyperglycemia can affect the vascular system

Answer 5

Hyperglycemia and other metabolic abnormalities in diabetes can lead to dysfunction of the vascular endothelium, which in healthy individuals promotes relaxation of vascular smooth muscle (mediated by endothelial cell secretion of nitric oxide)

Endothelial dysfunction may play a role in development of CVD in pt with type 2 diabetes

Question 6

What is diabetic nephropathy?

Answer 6

Microvascular complication of diabetes

leading cause of end-stage renal disease (ESRD)

Question 7

What is the glomerular filtration rate (GFR) and how can it be tested by creatinine clearance?

Answer 7

GFR is a measure of kidney function

Serum creatinine can be used to calculate an estimated GFR (eGFR) - as GFR decreases, creatinine clearance decreases and serum creatinine rises

rate of creatinine formation is usually constant because creatinine is formed from metabolism of muscle creatine

Question 8

What is the blood urea nitrogen (BUN) and what can the ratio of BUN to creatinine be used for?

Answer 8

Blood urea nitrogen (BUN) is increased in patients with kidney dysfunction

ratio of BUN to creatinine can be used to differentiate between renal dysfunction (BUN and creatinine both increased) vs. prerenal azotemia (excess urea in the blood)

in prerenal azotemia (often caused by dehydration), there is a disproportionate increase in BUN relative to serum creatinine (more urea is reabsorbed by kidney tubules in dehydration, while reabsorption of creatinine remains minimal)

Question 9

How does diabetic nephropathy progress?

Answer 9

In the earliest stage of diabetic nephropathy, there is an abnormally high blood pressure within glomerular capillaries -> hyperfiltration

these hemodynamic changes initially raise GFR, they gradually cause glomerular damage and irreversible changes in glomerular structure (increased extracellular matrix, glomerular basement membrane thickening, mesangial expansion, fibrosis, sclerosis)

in some cases, mesangial sclerosis appears as acellular periodic acid-schiff (PAS) stain-positive nodules (called Kimmelstiel-Wilson nodules)

Question 10

What is glomerulosclerosis?

Answer 10

Loss of podocytes -> abnormal filtration

Basement membrane thickening

Increase extracellular matrix (mesangial expansion)

Fibrosis

Question 11

Compare healthy renal glomeruli to unhealthy.

Answer 11

Renal glomeruli usually filter small molecules such as glucose, but do not filter large molecules such as plasma proteins

albumin usually most abundant circulating protein and healthy persons excrete less than 30mg of urinary albumin each day

as the kidneys become damaged by diabetes, ‘leakage’ of larger molecules such as albumin occurs

Question 12

What 3 glomerular structures does a molecule need to pass through to be filtered by the kidney?

Answer 12

Glomerular Filtration Barrier (GFB), which allows for selective filtration of molecules depending on their size and charge

1. Fenestrated endothelium
2. Glomerular basement membrane
3. The slit diaphragm formed by proteins extending from foot processes of podocytes

Question 13

What are podocytes and how does their injury relate to diabetes?

Answer 13

Podocytes (glomerular visceral epithelial cells) express specific proteins (nephrin) that are anchored to portions of the plasma membrane and are involved in podocyte cell-signaling and form importnat part of GFB by forming a zipper-like structure

normally produce the majority of the molecules making up glomerular basement membrane

podocytes communicate with endothelial and mesangial cells and normally secrete vascular endothelial growth factor (VEGF) which maintains (paracrine) the normal permeability of the glomerular fenestrated endothelium

Injury: may cause disruption of foot process cytoarchitecture, with decreased anchoring of foot processes to GBM and fusion of foot processes

Rearrangement of slit diaphragm proteins can lead to changes in filtration with increasd filtration of proteins such as albumin (proteinuria = increased protein excretion in the urine)

Question 14

How does increased glucose uptake and metabolism in patients with diabetes affect the kidney?

Answer 14

Hyperglycemia -> increased glucose uptake and metabolism in kidney cells (kidney cells not dependent on insulin for glucose uptake, instead use GLUT2 transporter)

Increased metabolism -> generation of ROS and altered cell signaling within glomerular mesangial cells and podocytes

Question 15

How does glycation of proteins affect gomerular cells in patients with diabetes?

Answer 15

glycation of proteins (extracellular and intracellular) -> generation of advanced glycation end products (AGE) which bind to their receptor (RAGE) on glomerular cell

changes in glomerular cell signaling and gene expression -> increased generation of pro-inflammatory chemokines and mediators such as TNF-alpha

Question 16

What happens to podocytes in diabetic nephropathy?

Answer 16

Disruption of the podocyte structure and function and/or loss of glomerular podocytes may allow abnormal filtration of albumin

Question 17

How are mesangial cells affected in diabetic nephropathy?

Answer 17

Mesangial cell function is altered -> mesangial cell proliferation, accumulation of mesangial matrix with changed composition, generation of chemokines, altered ‘cross-talk’ with endothelial cells and podocytes, and changes in regulation of intraglomerular capillary flow

Question 18

How is glomerular filtration affected by diabetic nephropathy?

Answer 18

GM is thickened; its composition and and filtration characteristics may be abnormal as a result of disrupted glomerular cell functions (podocytes and endothelial cells produce components of GBM, mesangial cells participate in normal GBM turnover)

The structural and functional integrity of the glomerular filtration barrier is compromised -> excrete gradually increasing quantiites of albumin in the urine (albuminuria)

Question 19

Compare excreting albumin in healthy persons to those with diabetic nephropathy.

Answer 19

healthy persons: very little albumin excreted in urine (<30mg/d) and can only be detected w/ sensitive assays

early stage of diabetic nephropathy: persistent excretion of small quantities of albumin (30-299mg/d)

Question 20

How can albuminuria be measured?

Answer 20

Microalbuminuria = 30-299 mg/24hrs

can be measured using urine microalbumin test, but is cumbersome to collect urine continuously for 24hrs

the albumin-to-creatinine ratio (ACR) is used to screen patients for early stage of diabetic nephropathy by estimating daily albumin excretion

Question 21

How do you measure the urinary albumin excretion rate (AER) by measuring the albumin-to-creatinine ratio (ACR)?

Answer 21

1. quantify urinary albumin in a ‘spot’ urine sample
2. measure albumin and creatinine
3. calculate the albumin-to-creatinine ratio (ACR)

[normal ACR is < 30 mg albumin/g creatinine]

an equation can be used to estimate the 24hr albumin excretion rate (AER): ACR (mg albumin/g creatinine) = approx the AER (mg albumin/24hr)

Question 22

What happens as diabetic nephropathy worsens and how can that be detected?

Answer 22

More albumin and other plasma proteins are excreted in the urine

Albuminuria >300mg/day (macroalbuminuria) can be detected on a routine urinalysis dipstick

if enough protein is lost in the urine (>3.5g/24hr), pt may be dx with nephrotic syndrome and loss of plasma proteins may lead to development of edema

Question 23

What are the American Diabetes Association Guidelines for screening for diabetic nephropathy?

Answer 23

Measure urine albumin-to-creatinine ratio annually in patients with:

1. Type 1 diabetes for 5 years or longer
2. Type 2 diabetes starting at the time of diagnosis

Question 24

What is the benefit of optimal glycemic control for type 1 and type 2 diabetes?

Answer 24

optimal glycemic control can delay the onset of diabetic nephropathy and can delay its progression to end stage renal disease

Question 25

How is hypertension another risk factor for development of renal complications in diabetes?

Answer 25

HTN usually develops during the microalbuminuric stage of diabetic nephropathy

treatment with antihypertensives may delay the progression of renal disease

recommended BP goal for patients with diabetes is < 140/90

Question 26

Why might a patient with diabetes be treated with angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs)?

Answer 26

delays the progression of diabetic nephropathy

these drugs are considered anti-HTN agents, they are prescribed for normotensive patients with diabetes because of their effect on slowing the progression of diabetic nephropathy

may produce beneficial effects by altering glomerular hemodynamics and paracrine signaling within the glomerulus

interfere with renin-angiotensin system and decrease aldosterone secretion, they may cause hyperkalemia

risk of acute renal failure increases if patients become dehydrated or if they use NSAIDs

Question 27

What happens in later stages of diabetic nephropathy?

Answer 27

causes a decrease in both creatinine clearance and GFR and eventually patients develop azotemia and chronic kidney disease (CKD)

leading cause of end stage renal disease (ESRD)

kidney is an important site of insulin degradation, so as renal function declines, patients with nephropathy may experience a more prolonged duration of insulin action

• patients may develop hypoglycemia and insulin dose may need to be reduced

Question 28

How can you summarize diabetic nephropathy?

Answer 28

Earliest stage is characterized by persistent microalbuminuria: 30-300mg albumin/24hrs (microalbuminuria) or albumin to creatinine ratio (ACR) = 30-300mg albumin/g creatinine

GFR may be high initially, but decreases over a period of years. Measurement of serum creatinine allows calculation of an estimated GFR (eGFR) - < 30 should be referred to nephrologist

Hypertension usually develops during microalbuminuric stage and accelerates renal damage from diabetes

Question 29

What is the treatment of diabetic nephropathy?

Answer 29

Goal: prevention and/or delay of prorgression

Intensive diabetes management (euglycemia; near normoglycemia)

Lower blood pressure to near normal

• inhibit renin-angiotensin-aldosterone system (RAAS or RAS) with: angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), monitor GFR/creatiinine clearance in patients taking ACE inhibitors or ARBs
• ACE inhibitors or ARBs slow the progression of diabetic nephropathy whether or not the patient is hypertension

Protein restriction is usually initiated once creatinine clearance begins to decline

Question 30

What can prevent or delay the onset of diabetic retinopathy?

Answer 30

Near normoglycemia prevents and/or delays the onset of diabetic retinopathy and slows progression of diabetic retinopathy

Question 31

What are the two types of diabetic retinopathy?

Answer 31

Nonproliferative

(more severe) proliferative

Question 32

What happens in nonproliferative retinopathy?

Answer 32

occurs earlier

characterized by alterations in the retinal microvasculature

vascular endothelial growth factor (VEGF) is overexpressed by retinal cells (possibly as a response to retinal ischemia and hypoxia) -> excess VEGF on retinal endothelial cells disrupts the blood-retinal barrier -> increased vascular permeability and accumulation of fluid in the interstitial space

if retinal edema occurs in the macula, vision may be impaired

• macular edema is the leading cause of decreased visual acuity in patients with nonproliferative retinopathy

Question 33

What is fluorescein angiography used for and what’s a possible treatment for diabetic retinopathy?

Answer 33

Fluorescein angiography = IV injection of fluorescein dye while taking photos of the retina that can visualize retinal blood vessels and detect macular edema

Intraocular injection of antibodies against VEGF has been shown to improve macular edema and vision in several studies

Question 34

What happens as nonproliferative retinopathy progresses?

Answer 34

excess VEGF stimulates neovascularization (begins the proliferative diabetic retinopathy)

new retinal vessels form and may rupture easily -> vitreous hemorrhage, fibrosis, and retinal detachment

laser photocoagulation surgery is beneficial in reducing the risk of further visual loss, but generally not beneficial in reversing already diminished visual acuity

Question 35

How does high blood pressure affect diabetic retinopathy?

Answer 35

high blood pressure is an established risk factor for the development of macular edema and hypertension hastens development of PDR

lowering BP can prevent development and/or decrease the rate of its progression

Question 36

Why is it important to have ophthalmologists screen patients for diabetic retinopathy?

Answer 36

patients with PDR or macular edema may be asymptomatic

that way therapies can be instituted prior to more severe and/or permanent visual loss

Question 37

Why is neuropathy important for the diagnosis of type 2 diabetes?

Answer 37

In patients with type 2 diabetes, who may remain undiagnosed for many years, neuropathy may be the presenting symptom

Question 38

What are the most common mononeuropathies?

Answer 38

asymmetric mononeuropathies

most commonly affecting extraocular muscles innervated by the 3rd and 6th cranial nerves

may present with diplopia (double vision)

Question 39

What is the most common form of diabetic neuropathy?

Answer 39

bilateral symmetrical sensory neuropathy affecting the ability to sense touch, pain, vibration, position, and temperature in the lower and sometimes upper extremities

severity of diabetic peripheral neuropathy is greatest in neurons with long axons -> ‘stocking-glove’ distribution pattern in which distal portions of the extremities are affected prior to proximal positions

lower extremities are affected earlier than upper extremities

sensory neuropathy more common than motor neuropathy

Question 40

How can diabetic sensory neuropathy be measured?

Answer 40

vibration sense = tuning fork

touch = touching skin with nylon filament

tendon reflexes may be diminished in lower extremities in patients with diabetic peripheral neuropathy - Achilles reflex is typically the first to be affected

Question 41

What happens in the distal symmetrical polyneuropathy that affects the achilles reflex?

Answer 41

primarily a loss of axons, which can be documented as a decrease in the number of nerve fibers on skin biopsy or as abnormaliites on electrophysiologic testing (decreased amplitude of neural signal, decreased nerve conduction velocity)

patients may note parasthesias or dysesthesias

as the neuropathy worsens, more severe sensory deficits develop and the patient is at risk for traumatic injury

Question 42

Why are foot problems prominent in diabetics?

Answer 42

major cause of nontraumatic amputations

neuropathy most important risk factor for developing foot problems

without sensory feedback, patients may not feel pain when they fracture bones in the feet (charcot joints)

Risk factors for foot problems: neuropathy, ischemia, infection

Question 43

What is autonomic neuropathy?

Answer 43

can cause gastroperesis (delayed gastric emptying), diabetic diarrhea, neurogenic bladder, erectile dysfunction, and impared cardiovascular responses such as orthostatic hypotension

Question 44

What is the effect of intensive glycemic control in the diabetes control and complications trial?

Answer 44

degree of blood glucose control was correlated with the development and/or progression of microvascular complications (retinopathy, nephropathy, and neuropathy)

improved control of blood glucose reduced the risk of clinically meaningful retinopathy, nephropathy, and neuropathy

patients with diabetes who maintain a HbA1c below 7% will reduce their risk for developing complications