V. Complications of Diabetes Mellitus

Question 1

Leading cause of death in people with both T1DM and T2DM diabetes

Answer 1

Accelerated cardiovascular disease

Question 2

TRUE or FALSE: In contrast to the beneficial effects of glycemic reduction on microvascular complications, a meta-analysis of RCTs shows reduction in MI rates but limited benefits of intensive glucose-lowering treatment on all-cause mortality and deaths from CV causes.

Answer 2

TRUE

Question 3

TRUE or FALSE: Chronic, unresolved systemic inflammation is a cardiovascular risk factor independent of traditional lipid and nonlipid risk factors.

Answer 3

TRUE

Chronic inflammation also contributes to chronic kidney disease.

Question 4

Study that assessed for reduction in CV mortality in those given inhibition of IL1beta with canakinumab to reduce hsCRP concentrations

Answer 4

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

Question 5

The single upstream hyperglycemia-induced process that activates all the pathogenic mechanisms of the complications of diabetes

Answer 5

Mitochondrial overproduction of superoxide

Question 6

4 hyperglycemia-induced pathogenic mechanisms that are activated by overproduction of ROS

Answer 6

1. Increased aldose reductase (AKR1B1) substrate conversion
2. Increased O-GlcNAcylation
3. Activation of protein kinase C
4. Increased AGE formation

Question 7

TRUE or FALSE: The amount of ROS production is more relevant compared to its location.

Answer 7

FALSE

ROS production at too high a level, for too long, or at an inappropriate subcellular location, leads to impaired cellular function and diabetic tissue pathology.

ROS from mitochondrial complex I - high percentage of irreversible overoxidations of cysteine thiols
ROS from mitochondrial complex III - reversible oxidation of cysteine thiols, consistent with their function as redox switches in critical signaling pathways

Question 8

Consequence of increased aldose reductase (AKR1B1) substrate conversion

Answer 8

Glucose –> sorbitol –> fructose (through sorbitol dehydrogenase, using NAD+ as cofactor)

Polyol pathway - implicated in the pathogenesis of severe diabetic complications

Question 9

Consequence of increased O-GlcNAcylation

Answer 9

The hexosamine pathways causes reversible post-translational modification of intracellular protein serine and threonine residues by N-acetylglucosamine

Question 10

Consequence of activation of protein kinase C

Answer 10

Nine of the 15 PKC isoforms are activated by a lipid second messenger, diacylglycerol, as well as intracellular ROS

Hyperglycemia primarily activates the beta and delta isoforms of PKC

Has multiple consequences: blood flow abnormalities, vascular permeability, angiogenesis, capillary occlusion, vascular occlusion, proinflammatory gene expression, T-cell activation

Question 11

Consequence of increased AGE formation

Answer 11

First, AGE modification of intracellular proteins changes their function.

Second, AGE modification of extracellular matrix components alters their interaction with other matrix components and with integrin matrix receptors.

Third, intracellular methylglyoxal increases expression of both the pattern recognition receptor for AGEs (RAGEs) and its major endogenous ligands, the proinflammatory S110 calgranulins.

Question 12

What is the precursor of AGEs that accounts for the majority of hyperglycemia-induced increase in AGE adducts in diabetic tissues?

Answer 12

Methylglyoxal

Formed by the nonenzymatic fragmentation of the glycolytic intermediate triose phosphate

Detoxified by the enzyme glyoxalase I, together with glyoxalase II and a catalytic amount of glutathione, reducing this highly reactive alpha-oxoaldehyde to D-lactate

Question 13

Increased soluble epoxide hydrolase binds to specific epoxides such as epoxyeicosatrienoic acids (EETs) and rapidly converts them to less active or inactive dihydroiols. Why is this detrimental?

Answer 13

In cell and animal modes, EETs have major anti-inflammatory activity.

Question 14

Upregulation of soluble epoxide hydrolase (sEH) also decreases levels of this arachidonic acid-derived inflammation stop signal

Answer 14

Lipoxin A4 (a PMN stop signal that limits further recruitment)

Question 15

TRUE or FALSE: Increased pyruvate kinase M2 activity has also been implicated in the pathogenesis of the complications of diabetes.

Answer 15

FALSE

Reduced pyruvate kinase M2 activity

Question 16

TRUE or FALSE: Patients with T1DM are not insulin resistant.

Answer 16

FALSE

Patients with T1DM are also insulin resistant, with insulin sensitivity reduced by about 50%.

Question 17

Insulin resistance increases ___ oxidation, causing mitochondrial overproduction of ___.

Answer 17

Insulin resistance increases FATTY ACID oxidation, causing mitochondrial overproduction of ROS.

Overproduction of ROS leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of endothelial nitric oxide synthase. This will thereby convert eNOS to a superoxide-producing enzyme.

Question 18

TRUE or FALSE: At the level of the vessel wall, insulin has both antiatherogenic and proatherogenic effects.

Answer 18

TRUE

Question 19

TRUE or FALSE: Insulin resistance selectively inhibits only the IRS/PI3K/Akt pathway (eNOS) but not the proatherogenic pathways (PDGF-induced VSMC proliferation and endothelial and VSMC production of the thrombolysis inhibitor PAI1), thereby reducing insulin’s antiatherosclerotic action and contributing to the acceleration of atherosclerosis and other cardiovascular pathologies of diabetes.

Answer 19

TRUE

Insulin resistance also increases macrophage ROS, which drive chronic inflammation and accelerate their progression to unstable rupture-prone plaques.

Question 20

Diabetes reduces:
a. Activity of Nuclear Erythroid-Related Factor 2 (Nrf2)
b. NLR Family Pyrin Domain Containing 3 Inflammasome (NRLP3)
c. Nuclear factor of activated T cells (NFAT)
d. Neutrophil extracellular traps (NETs)

Answer 20

A

• Diabetes REDUCES activity of Nuclear Erythroid-Related Factor 2 (Nrf2), master regulator of antioxidant gene expression
• Diabetes ACTIVATES NLR Family Pyrin Domain Containing 3 (NRLP3) Inflammasome, which underlies many chronic inflammatory states
• Diabetes ACTIVATES the transcription factor - nuclear factor of activated T cells (NFAT), which plays a role in the development of DM retinopathy, nephropathy, atherosclerosis, and cardiomyopathy
• Diabetes INCREASES neutrophil extracellular traps (NETs), priming macrophages for inflammation

Question 21

How does diabetes cause nonresolving inflammation?

Answer 21

Diabetes causes defective specialized proresolving mediators (SPM) biosynthesis downstream of their fatty acid precursors.. Reduced SPMs and increased leukotrienes (LTs) promotes instability of atherosclerotic plaques. When the SPM:LT ratio is low, resolution of inflammation is impaired, leading to sustained inflammatory monocyte influx, platelet aggregation, proinflammatory macrophage polarization, impaired efferocytosis, large necrotic cores, and thin fibrous caps.

Question 22

TRUE or FALSE: Diabetes alters mitochondrial dynamics, fusion, fission, biogenesis, and mitophagy, which together maintain optimal cellular bioenergetics and ROS homeostasis.

Answer 22

TRUE

Diabetes induces increased mitochondrial fission in kidney, coronary artery, and myocardium.

Question 23

TRUE or FALSE: No associations remained significant regarding candidate gene polymorphisms and the risk of diabetic complications.

Answer 23

TRUE

Question 24

The best understood noncoding RNAs with respect to diabetic complications
a. piwi-interacting RNAs (piRNAs)
b. endogenous small interfering RNAs (siRNAs)
c. intron-derived microRNAs (miRNAs)

Answer 24

C

Which regulate several key biologic pathways and cellular functions involved in diabetic complications

High DNA repair machinery; Low miR200 –> Fixing of DNA errors leading to normal cell cycle and growth

Low DNA repair machinery; High miR200 –> Accumulation of DNA errors; inflammation leading to apoptosis

Question 25

Likely explanation for the long-term metabolic memory in the DCCT-EDIC study

Answer 25

Treatment-related epigenetic causes (those that change DNA or RNA structure and function, but do not change DNA-RNA sequence)

Question 26

What factor induces long-lasting activating epigenetic changes in the proximal promoter of the NFKB subunit p65 in endothelial cells?

Answer 26

Transient hyperglycemia, at a level sufficient to increase mitochondrial ROS production

Question 27

TRUE or FALSE: Diabetic retinopathy eventually afflicts virtually all patients with diabetes mellitus.

Answer 27

TRUE

Question 28

TRUE or FALSE: Early intensive treatment of hyperglycemia delays the onset and progression of diabetic retinopathy in T1DM.

Answer 28

TRUE (although might not prevent it completely)

Question 29

TRUE or FALSE: There is a higher risk of more frequent and severe ocular complications in T2DM than T1DM.

Answer 29

FALSE

There is a higher risk of more frequent and severe ocular complications in T1DM than T2DM.

Question 30

TRUE or FALSE: T2DM accounts for a higher fraction of patients with vision loss compared to T1DM.

Answer 30

TRUE (since T2DM accounts for 90-05% of the diabetic population in the US)

Question 31

3 earliest histologic effects of diabetes mellitus in the eye

Answer 31

1. Loss of retinal vascular pericytes (supporting cells for retinal endothelial cells)
2. Thickening of vascular endothelium basement membrane
3. Alterations in retinal blood flow

Question 32

Potent inducer of angiogenic growth factors in the eye

Answer 32

Retinal ischemia (caused by increasing sclerosis and endothelial cell loss –> narrowing of retinal vessels –> decreased vascular perfusion –> ultimately, obliteration of the capillaries and small vessels)

Question 33

Cause of neovascular glaucoma

Answer 33

Uncontrolled anterior segment neovascularization –> Fibrovascular proliferation in the angle of the eye

Question 34

TRUE of proliferating blood vessels in the eye:
a. Vitreous hemorrhage clear spontaneously without intervention
b. All retinal neovascularization, given sufficient time, eventually becomes quiescent
c. Progressive fibrosis of the new vessel complexes can lead to tractional retinal detachment and retinal tears
d. All of the above

Answer 34

D

Question 35

Vision loss can follow if this part of the eye is affected

Answer 35

Fovea

Question 36

Most significant known risk factor for the onset and progression of diabetic retinopathy

Answer 36

Lack of appropriate glycemic control

Question 37

Risk factors for onset and progression of diabetic retinopathy

Answer 37

Lack of appropriate glycemic control
Duration of diabetes
Age of onset of diabetes
Presence of renal disease
Hypertension
Elevated serum lipid levels

Question 38

This risk factor is associated with PDR and is an established risk factor for the development of macular edema

Answer 38

Hypertension

Question 39

This risk factor is association with extravasated lipid in the retina (hard exudates) and vision loss

Answer 39

Elevated serum lipid levels

Question 40

Match the term to the definition of clinical eye findings:

Terms:
- Cotton-wool spot
- Hard exudate
- Microaneurysm

Definitions:
a. Lipid accumulation within the retina as a result of increased vasopermeability
b. A gray or white area lesion in the nerve fiber layer of the retina resulting from stasis of axoplasmic flow caused by microinfarcts of the retinal nerve fiber layer
c. An early vascular abnormality consisting of an outpouching of the retinal microvasculature

Answer 40

• Cotton-wool spot - B
• Hard exudate - A
• Microanuerysm - C

Others:
- Rubeosis iridis - neovascularization of the iris (first observed at the pupillary border), usually as a result of extensive retinal ischemia
- No light perception

Question 41

Differentiate the following intraretinal hemorrhages based on their location:
Flame-shaped hemorrhages and Dot-blot hemorrhages

Answer 41

Flame-shaped hemorrhages - occur in inner retina closer to the vitreous

Dot-blot hemorrhages - occur deeper in the retina

Question 42

2 signs of severe retinal hypoxia

Answer 42

1. Venous caliber abnormalities, also known as venous beading
2. Featureless retina (appear free of nonproliferative lesions), which occurs in extensive vascular loss

Question 43

Most common cause of vision loss from diabetes

Answer 43

Macular disease and macular edema

Question 44

Macular edema is more likely to occur in patients with: T1DM or T2DM?

Answer 44

T2DM

Question 45

Match the study to the scope:
- Diabetes Control and Complications Trial (DCCT)
- Diabetic Retinopathy Study (DRS)
- Diabetic Retinopathy Vitrectomy Study (DRVS)
- Early Treatment Diabetic Retinopathy Study (ETDRS)

a. A multicenter, randomized clinical trial designed to address whether intensive insulin therapy could prevent or slow the progression of systemic complications of diabetes mellitus
b. A multicenter, randomized clinical trial that addressed at what stage of retinopathy scatter (panretinal) photocoagulation was indicated, whether focal photocoagulation was effective for preventing moderate vision loss due to clinically significant macular edema, and whether aspirin therapy altered the progression of diabetic retinopathy
c. The first multicenter, randomized clinical trial to demonstrate the value of scatter (panretinal) photocoagulation in reducing the risk of vision loss among patients with all levels of diabetic retinopathy
d. A multicenter clinical trial evaluating early vitrectomy for patients with very advanced diabetic retinopathy or nonresolving vitreous hemorrhage

Answer 45

DCCT - A
DRS - C
DRVS - D
ETDRS - B

Question 46

Match the term with the definition:
- Center-involved (or central-involved) diabetic macular edema (ciDME)
- Clinically significant macular edema (CSME)

a. Abnormal thickening of the central retina (usually 1 mm in diameter central retinal subfield) due to increased vascular permeability
b. Thickening of the retina in the macular region of sufficient extent and location to threaten central visual function

Answer 46

ciDME - A
CSME - B

Question 47

Match the term with the definition:
- Neovascularization at the disc (NVD)
- Neovascularization elsewhere (NVE)

a. Retinal neovascularization that is located more than 1500 um away from the optic disc
b. Retinal neovascularization occuring at or within 1500 um of the optic disc

Answer 47

NVD - B
NVE - A

Question 48

TRUE of clinically significant macular edema (CSME):
a. Exists if there is retinal thickening more than 500 um from the fovea
b. Diagnosed through fluorescein angiography
c. Can be present even when vision is 20/20 or better
d. Was not used as a threshold to determine need for laser treatment

Answer 48

CSME:
- Exists if there is retinal thickening at or within 500 um of the fovea, hard exudates at or within 500 um of the fovea with adjacent retinal thickening, or an area or areas of retinal thickening one disc area or more in size, any part of which is within 1500 um of the fovea
- A clinical diagnosis that is not dependent on visual acuity or results of ancillary testing such as fluorescein angiography
- Can be present even when vision is 20/20 or better
- Used in the ETDRS as a threshold to determine need for laser treatment

Question 49

TRUE of center-involved (or central-involved) diabetic macular edema (ciDME)
a. Highly associated with short-term and long-term visual acuity outcomes
b. Commonly used as a threshold for treatment in diabetic retinopathy
c. Both
d. Neither

Answer 49

C

If the center of the macula is not involved, there is often not a compelling reason to treat

Question 50

Describe the following simplified classification of diabetic retinopathy:
- No apparent retinopathy
- Mild NPDR
- Moderate NPDR
- Severe NPDR
- PDR

Answer 50

No apparent retinopathy - no abnormalities

Mild NPDR - microaneurysms only

Moderate NPDR - more than microaneurysms but less than severe NPDR

Severe NPDR - any of the following: >20 intraretinal hemorrhages in each of the four retinal quadrants, definite venous beading in two or more retinal quadrants, prominent intraretinal microvascular abnormalities in one or more retinal quadrants, and no PDR

PDR - one or more of retinal neovascularization, vitreous hemorrhage, or preretinal hemorrhage

Question 51

Describe the following simplified classification of diabetic macular edema:
- Macular edema apparently absent
- Macular edema apparently present
- Mild macular edema
- Moderate macular edema
- Severe macular edema

Answer 51

Macular edema apparently absent - no apparent retinal thickening or hard exudates in the posterior pole

Macular edema apparently present - some apparent retinal thickening or hard exudates in the posterior pole

Mild macular edema - some retinal thickening or hard exudates in the posterior pole but distant from the center of the macula

Moderate macular edema - retinal thickening or hard exudates approaching the center of the macula but not involving the center (considered by ETDRS as CSME)

Severe macular edema - retinal thickening or hard exudates involving the center of the macula (considered by ETDRS as CSME)

Question 52

Mononeuropathies of the third, fourth, or sixth cranial nerves can arise in association with diabetes. Which among these is the least likely associated with diabetes and warrants workup for other causes?

Answer 52

Mononeuropathy of the fourth cranial nerve

Question 53

TRUE about diabetes-induced mononeuropathy:
a. May be the initial presenting sign of new-onset diabetes
b. Usually permanent
c. Once resolved, cannot recur

Answer 53

A

• May be the initial presenting sign of new-onset diabetes
• Usually self-limited and should resolve spontaneously in 2 to 6 months
• Palsies can recur or subsequently develop in the contralateral eye

Question 54

Primary therapy for neovascular glaucoma and provides durable regression of neovascularization

Answer 54

Scatter (panretinal) laser photocoagulation

Question 55

Treatment for DME and PDR but effect is often transient, and there is frequently recurrence of neovascularization unless injections are given on a monthly basis

Answer 55

Intravitreal administration of VEGF inhibitors (such as afibercept, bevacizumab, and ranibizumab)

Question 56

TRUE or FALSE: The cornea of the diabetic person is more susceptible to injury and slower to heal after injury than is the nondiabetic cornea.

Answer 56

TRUE

Question 57

TRUE regarding cataracts EXCEPT:
a. Can occur earlier in life and progress more rapidly in the presence of diabetes
b. Risk factors in earlier onset diabetes: duration of diabetes, retinopathy status, diuretic use, and HbA1c levels
c. Risk factors in later onset diabetes: age of the patient, lower intraocular pressure, smoking, and lower diastolic BP
d. Simultaneous kidney and pancreas transplantation can lower the risk of cataracts

Answer 57

D

Diabetic patients undergoing simultaneous kidney and pancreas transplantation are at increased risk of developing all types of cataracts, independent of the use of corticosteroids after transplantation

Question 58

Species that can cause fatal orbital infection in diabetic patients

Answer 58

Fungal infection - Mucorales phycomycosis

Question 59

Recommendations regarding initial ophthalmic examination in diabetic patients

Answer 59

For T1DM - For age >=10 years, refer to eye care provider if 1) pregnant, 2) beginning 5 years after diagnosis
(If age is <10 years, initial ophthalmic exam not yet required)

For T2DM - refer to eyecare provider immediately after diagnosis

Followed by annual retinal evaluation, or as per diabetic retinopathy level

Question 60

TRUE or FALSE: Initial ophthalmic examination in diabetic patients usually involve examination of undilated pupils only.

Answer 60

FALSE

Dilated ophthalmic examination is superior to undilated evaluation because only 50% of eyes are correctly classified as to presence and severity of retinopathy through undilated pupils.

Question 61

At what level of diabetic retinopathy should patients be referred from an optometrist or regular opthalmologist to an opthalmologist experienced in the management of diabetic retinopathy?

Answer 61

At least by the time moderate DR or DME is present

Question 62

Term used to refer to proliferative diabetic retinopathy of defined extent, location, or clinical findings that is particularly associated with severe vision loss

Answer 62

High-risk characteristic proliferative diabetic retinopathy (HRC-PDR)

Question 63

2 phases of life that can accelerate retinopathy progression

Answer 63

Puberty and pregnancy

Question 64

Recommendations regarding comprehensive eye examination in patients with diabetes who are planning pregnancy

Answer 64

• Within 1 year prior to conception
• In the first trimester of pregnancy
• If NO DR or DME - every 3 months
• If with DME and CSME - focal/grid laser photocoagulation probably indicated (but first-line for ciDME is intravitreous VEGF inhibitors)
• If with DME but no CSME - consider focal/grid laser photocoagulation
• If with HRC PDR - panretinal photocoagulation probably indicated
• If with severe NPDR or worse (but not HRC PDR) - consider panretinal photocoagulation

Question 65

TRUE or FALSE: Women who develop gestational diabetes should undergo comprehensive eye examination during the first trimester.

Answer 65

FALSE

They are not at increased risk of developing diabetic retinopathy

Question 66

Definitions of:
- Severe vision loss
- Moderate vision loss
- Legal blindness

Answer 66

Severe vision loss - best corrected acuity of 5/200 or worse on 2 consecutive visits 4 months apart

Moderate vision loss - at least doubling the visual angle; e.g., 20/40 reduced to 20/80

Legal blindness - 20/200 or worse

Question 67

Treatment considered appropriate for all patients with high-risk PDR

Answer 67

Prompt scatter photocoagulation

Question 68

2 situations that will prompt to consider novel therapies instead of photocoagulation in DR or DME

Answer 68

On need for retreatment, further laser apparently futile or there is no retina left to treat

Question 69

Scatter photocoagulation exerts its benefit by

Answer 69

Increasing oxygen delivery to the inner retina, decreasing viable hypoxic growth factor-producing cells, and increasing the relative perfusion per area of viable retina

Question 70

Effective first-line alternative to scatter photocoagulation in carefully selected patients with PDR

Answer 70

Anti-VEGF treatment with aflibercept or ranibizumab

Not ideal if compliance is expected to be a problem

Question 71

Method to 1) clinically evaluate, 2) objectively assess for diabetic macular edema

Answer 71

Best evaluated clinically by dilated examination using slit-lamp biomicroscopy or stereo fundus photography

OCT to objectively quantify retinal thickening and is currently the objective method of choice

Question 72

Current first-line therapy for most eyes with center-involved DME and DME-related visual impairment of 20/32 or worse

Answer 72

Intravitreous injections of VEGF ibhibitors

In eyes with baseline vision of 20/50 or worse, aflibercept provided visual gains superior to those of bevacizumab and ranibizumab

Question 73

Alternative to intravitreous VEGF inhibitors for some patients with DME without center involvement or in eyes with good vision or in patients who cannot tolerate a regimen of intravitreal injections

Answer 73

Focal laser photocoagulation

Question 74

Test used if macular laser is planned, in order to guide focal treatment of microaneurysm that are leaking fluid into the retina and identify areas of macular capillary nonperfusion that might benefit from grid laser treatment

Answer 74

Fluorescein angiography

Contraindicated in patients with known allergy to fluorescein dye or during pregnancy

Question 75

Frequency of follow-up evaluation after focal laser treatment

Answer 75

Generally occurs after 3 months

Question 76

TRUE or FALSE: Currently, intravitreal steroid alone is not the preferred primary therapy for DME or a recommended adjuvant therapy in eyes that have not responded successfully to anti-VEGF therapy.

Answer 76

FALSE

It may have a role in patients with DME who cannot receive anti-VEGF agents or who are pseudophakic before treatment

Question 77

Systemic disorder that exacerbates the development and progression of diabetic retinopathy and should therefore be rigorously controlled

Answer 77

Elevated blood pressure

Target BP should most likely be maintained as low as safely possible (no threshold for any renal endpoint in patients with diabetes; lowest achievable blood pressure is associated with the best clinical outcomes)

Question 78

TRUE or FALSE: Dialysis can improve macular edema in diabetic patients with renal failure.

Answer 78

TRUE

Question 79

TRUE or FALSE: Rapidly progressive retinopathy, especially in a patients with a long history of diabetes where retinopathy previously has been stable, should suggest the need for renal evaluation.

Answer 79

TRUE

The presence and severity of diabetic retinopathy are indicators of the risk of gross proteinuria, and conversely, proteinuria predicts PDR.

Question 80

Blood parameter that is believed to be an independent risk factor for development of high-risk PDR and severe vision loss, and should therefore receive appropriate management

Answer 80

Low hematocrit and hemoglobin

Question 81

TRUE or FALSE: Nephropathy appears to be more common in T2DM and majority of diabetic patients on RRT have T2DM.

Answer 81

FALSE

Although nephropathy appears to be more common in T1DM, because of the large and increasing number of persons with T2DM, more than 80% of diabetic patients in renal replacement programs have T2DM.

Question 82

Diabetic nephropathy is characterized clinically as a triad of ___.

Answer 82

Hypertension, proteinuria, and ultimately renal replacement

Question 83

5 stages in the natural history of nephropathy in T1D

Answer 83

1. Hyperfiltration - considered to occur as a result of concomitant renal hypertrophy and glomerular hypertension
2. Silent - no evidence of albuminuria but with significant structural changes
3. Microalbuminuria - urinary albumin excretion rate of 20-200 ug per minute or 30-300 mg per 24 hrs
4. Macroalbuminuria (or overt nephropathy) - urinary albumin excretion rate greater than 300 mg per 24 hrs (200 ug/minute)
5. Renal impairment - requires the institution of renal replacement therapy

Question 84

2 main factors of the hyperfiltration phase of diabetic nephropathy

Answer 84

1. Renal hypertrophy - associated with specific growth factors such as the growth hormone/insulin-like growth hormone (IGF1) system and transforming growth factor beta (TGFB), as well as tubular hypertrophy, and increased salt reabsorption
2. Increase in effective renal plasma flow, increased intraglomerular capillary pressure reflecting relative efferent versus afferent arteriolar vasoconstriction with activation of RAS, and reduced synthesis of the vasodilator nitric oxide

Question 85

Cause of increased kidney weight in diabetes

Answer 85

Tubular hypertrophy explains the increased kidney weight in diabetes because tubules make up more than 90% of the kidney weight

Question 86

Class of drugs that influences tubuloglomerular feedback and has been shown to reduce intraglomerular pressure via effects on afferent arteriolar dilation

Also has been shown to have strong renoprotective effects even in the absence of glucose lowering

Answer 86

SGLT2 inhibitors

Question 87

Significance of the silent stage of diabetic nephropathy

Answer 87

Critical that we detect those who are the potential progressors and could be candidates for early prevention and treatment strategies

Question 88

Give examples of structural changes in the silent stage of diabetic nephropathy

Answer 88

Prominent glomerular abnormalities: Basement membrane thickening, mesangial expansion

Loss of glomerular cells known as podocytes

Question 89

TRUE about the stage 3: microalbuminuria of diabetic nephropathy:
a. Blood pressure decreases
b. Nocturnal dip in blood pressure is maintained
c. Renal function may be increased
d. Can be transient and can reverse

Answer 89

D

Stage 3: microalbuminuria
- Often develops 5 to 15 years after the initial diagnosis of T1DM
- Systolic and diastolic blood pressure are increased
- Nocturnal dip in blood pressure seen in normal persons is often lost
- Renal function may be increased, normal, or reduced
- In many patients with T1DM, can be transient and can reverse in normoalbuminuria, therefore screening is recommended

Question 90

Test used for screening for microalbuminuria and recommended frequency

Answer 90

The original studies used 24-hour or overnight urine sampling methods. However, a spot urine albumin:creatinine ratio in an early-morning urine specimen has been validated and appears to be a practical option for routine clinical practice.

Screening of diabetic patients for nephropathy is now recommended to include at least twice-annual measurements of urinary albumin concentrations in T1DM patients.

Question 91

Stage 4: Macroalbuminuria usually occurs after __ to __ years of diabetes (T1DM).

Answer 91

10 to 15 years

There are at least 2 peaks of incidence of overt nephropathy.

Question 92

TRUE about Stage 5: Uremia of diabetic nephropathy:
a. Renal lesions of diabetes often recur in the transplanted kidney
b. Pancreas transplantation can lead to resolution of many diabetes-related renal lesions such as mesangial expansion
c. Both
d. Neither

Answer 92

C

Reversal is often not apparent until after 10 years of euglycemia

Question 93

TRUE about the natural history of nephropathy in T2D EXCEPT:
a. Hyperfiltration does not occur in T2DM
b. Microalbuminuria occurs in T2DM
c. Renal impairment with progressive decline in GFR can occur in the absence of proteinuria
d. The risk of end-stage renal disease in patients with T2DM and renal impairment is similar in the presence or absence of microalbuminuria

Answer 93

A

Hyperfiltration does occur in T2DM (but less commonly observed).

Question 94

These measurements should be performed on a yearly basis at a minimum since the risk of end-stage renal disease is similar in the presence of absence of microalbuminuria.

Answer 94

Serum creatinine and determination of estimated GFR

Question 95

Metabolic factor that occurs at an acclerated rate in diabetic patients and is a prominent phenomenon in the kidney.

Answer 95

Advanced glycation

Question 96

Agents that appear to be very powerful antiproteinuric agents at all stages of renal disease

Answer 96

RAS inhibitors

Interruption of the renin-angiotensin system appears to be an excellent approach not only for reducing blood pressure but also for correcting many of the cellular, biochemical, hemodynamic, and structural abnormalities seen in the diabetic kidney.

ACE inhibitors have renoprotective actions beyond their antihypertensive effects for primary prevention

Question 97

Why is dual RAS inhibition not recommended?

Answer 97

Increased risks of hyperkalemia and acute kidney injury, as was also seen with RAS blockade with a combination of a renin inhibitor and an ARB

Question 98

Differentiate Kimmelstiel-Wilson lesion and Armani-Ebstein lesion

Answer 98

Kimmelstiel-Wilson lesion - glomerulopathy (nodules of pink hyaline material form in regions of glomerular capillary loops in the glomerulus)

Armani-Ebstein lesion - tubulopathy (sub-nuclear vacuolation of the proximal tubules)

Question 99

TRUE or FALSE: Renal function and prognosis correlate better with structural lesions in the glomeruli than in the tubules.

Answer 99

FALSE

Renal function and prognosis correlate better with structural lesions in the tubules and cortical interstitium than with classic glomerular changes of diabetic nephropathy.

Question 100

TRUE or FALSE: Diabetic patients have a higher risk of renal artery stenosis but these lesions are often of no hemodynamic significance.

Answer 100

TRUE

Renal artery stenosis in diabetes:
- Often of no hemodynamic significance
- If with hemodynamically significant stenosis, interventions such as surgery or angioplasty may be considered
- Some patients have bilateral artery stenosis that, on commencement of an agents such as an ACE inhibitor, can lead to acute renal failure

Question 101

Clinical manifestations of renal papillary necrosis

Answer 101

Flank pain, hematuria, and fever

Urinalysis: Red and white blood cells, bacteria, and papillary fragments

Can develop ureteric obstruction as a result of the fragments

Papillary necrosis can be prevented by blockade of the renin-angiotensin system

Question 102

Manifestation of renal tubular acidosis in diabetes

Answer 102

Hyperkalemia and hyperchloremic metabolic acidosis (type 4)

Renal tubular acidosis in diabetes
- Type 4
- Hyperkalemia and hyperchloremic metabolic acidosis
- Manifestation of hyporeninemic hypoaldosteronism associated with diabetes
- A major risk is development of life-threatening hyperkalemia

Question 103

Measures to prevent contrast-induced nephropathy in diabetes

Answer 103

Use low-osmolality, nonionic, or gadolinium-based contrast media

Patient should be well hydrated

N-acetylcysteine shows promise to protect against CIN

Metformin should be discontinued before contrast procedures to prevent life-threatening lactic acidosis

Question 104

2 major cornerstones for preventing and treating diabetic nephropathy

Answer 104

Blood pressure and glycemic control

Question 105

Immediate management for:
Microalbuminuria
Clinical proteinuria
Azotemia (serum crea >2.0 mg/dL)

Answer 105

Microalbuminuria:
- Treat hypertension
- Strive for euglycemia
- Reduce hyperlipidemia

Clinical proteinuria and Azotemia
- Same +
- Extract edena
- Correct anemia

Question 106

Treatment objectives for:
Microalbuminuria
Clinical proteinuria
Azotemia (serum crea >2.0 mg/dL)

Answer 106

Microalbuminuria
- BP <135/75 mm Hg (ACE inhibitor)
- HbA1c <7%
- LDL chol <100 mg/dL (statin)

Clinical proteinuria
- Same +
- Attain dry weight: diuretics
- Hct >35%: erythropoietin
- Educate patient re: regimen applied

Azotemia:
- Same +
- Prepare patient for uremia regimen
- Inventory potential kidney donors
- Create access for HD or PD
- Tissue type
- Consider dietary protein restriction

Question 107

TRUE or FALSE: Aggressive management of hypertension and lipid lowering are clearly more important than glycemic control in reducing cardiovascular events and slowing renal disease progression at this stage of relatively advanced disease.

Answer 107

TRUE

Although some studies suggest that poor glycemic control can accelerate the loss of renal function in diabetic nephropathy

Question 108

Name the drug in the following trials on glycemic control in diabetic kidney disease:
ADVANCE
VADT
SAVOR
CARME-LINA

Answer 108

Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)

Veterans Administration Diabetes Trial (VADT) - no particular drug

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)

Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARME-LINA)

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)

Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6)

EMPA-REG

CANVAS

Question 109

3 drugs to be used with caution in diabetic kidney disease and why

Answer 109

SU - hypoglycemia

Metformin - lactic acidosis

TZDs - used with caution in patients with advanced nephropathy who have or are at risk of heart failure, although renal impairment per se is not a contraindication for this class of drugs

Question 110

Name the drug in the following trials on diabetic kidney disease:
RENAAL
IDNT
DETAIL
ONTARGET
IRMA2
AVOID
ALTITUDE
ARTS-DN
FIELD
TREAT
ASCEND
BEAM

Answer 110

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL)

Irbesartan in Diabetic Nephropathy Trial (IDNT)

Diabetics Exposed to Telmisartan and Enalapril (DETAIL)

ONgoing Telmisartan Alone and combination with Ramipril Global Endpoint Trial (ONTARGET)

Irbesartan Microalbuminuria Type 2 (IRMA2)

Air Versus Oxygen in Myocardial Infarction (AVOID) - aliskiren appeared to have additional effect on albuminuria when administered with losartan

Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) - failed to demonstrate superior cardiovascular or renal protection

Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) - finerenone

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) - erythropoietin analogue darbepoetin

A Study of Cardiovascular Events iN Diabetes (ASCEND) - one of the drugs studied was avosentan

Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM)

Heart Protection Study - simvastatin appeared to retard the decline in renal function

Question 111

First-line treatment for blood pressure reduction in T2DM patients with overt proteinuria

Answer 111

ARBs

Question 112

Protein diet that has been shown to retard the progression of renal disease

Answer 112

Low-protein diet (0.75 g/kg/day)

However, the expected benefits that can be achieved through protein restriction in patients with diabetic nephropathy are at best modest in comparison with adequate blood pressure control and blockade of renin-angiotensin system.

Question 113

TRUE or FALSE: Lipid-lowering treatment should be considered in most diabetic patients.

Answer 113

TRUE

Because cardiovascular disease is so prominent in diabetic patients, it should be considered in most patients independent of its putative renoprotective actions.

Question 114

Drug class that can be safely used in diabetic uremic patients

Answer 114

DPP4 inhibitors

Question 115

Drugs that should be avoided in diabetic uremic patients

Answer 115

NSAIDs and COX2 inhibitors

Their use is associated with inadequate blood pressure control, often as a result of reduced efficacy of antihypertensive drug therapy

Question 116

Drug that slows the rate of reduction of eGFR in patients with stage 2 to 4 heart failure with reduced ejection fraction and, interestingly, is also associated with modest glucose-lowering effects

Answer 116

Sacubitril/valsartan

Question 117

Which among the 3 options for end-stage renal disease has:
a. Complete rehabilitation
b. Same death rate as nondiabetic patients
c. Highest morbidity during first year
d. Highest survival to second decade
e. Most expensive over long run

Answer 117

a. KT (common as long as graft functions)

b. KT (PD and HD have much higher death rate than for nondiabetic patients)

c. KT

d. KT (1 in 5; PD - almost never; HD - <5%)

e. PD (pancreas plus kidney engraftment most expensive, but after first year, KT alone is lowest cost option; HD is less expensive than KT in first year, then subsequent years more expensive)

Question 118

Most common complication of T1DM and T2DM

Answer 118

Diabetic neuropathies

Question 119

Most common diabetic neuropathy

Answer 119

Distal symmetric polyneuropathy (DSPN)

Question 120

TRUE or FALSE: Distal symmetric polyneuropathy (DSPN) also occurs in patients with prediabetes and the metabolic syndrome.

Answer 120

TRUE

Question 121

Most common involvement in DSPN

Answer 121

Mixed small and large fiber neuropathy

Question 122

TRUE or FALSE: Foot ulcers are a strong predictor of early mortality in diabetic patients.

Answer 122

TRUE

Question 123

Type of nerve fiber that is first damaged in diabetes

Answer 123

Small fiber damage usually precedes large fiber damage in diabetes, and frequently presents as burning pain, although patients also report tingling and prickly sensation.

Small fibers - relay thermal sensation and pain, and also regulate microvascular blood flow

Large fibers - relay vibratory, proprioception, and tactile sensation

Question 124

Define DPSN

Answer 124

An international consensus meeting defined DPSN as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes”.

Question 125

What are the positive and negative symptoms of DPSN and which fibers do these involve?

Answer 125

Positive symptoms - small fibers - pain, hyperalgesia, allodynia; often exacerbated at night and are manifested in the feet more than the hands

Negative symptoms - large fibers - patient presenting with a numb, insensate foot; poor balance with frank falling is a common presenting symptom in diabetic patients with a large fiber predominant DSPN.

Question 126

What are considered atypical symptoms for DSPN secondary to diabetes, and hence, an alternative diagnosis to DSPN must be pursued if these are present

Answer 126

• Motor greater than sensory symptoms
• Reportable asymmetry
• Rapid and aggressive clinical course

Question 127

Simple bedside approaches to examination for diabetic neuropathy

Answer 127

1. Differentiate between sharp and dull end of the safety pin on the dorsum of the toe
2. If he can perceive a cotton wisp in the same anatomic location
3. Cool tuning fork is placed on the cheek, then the same instrument is placed on the great toe, and the patient is asked to report on perceiving the same cool temperature in both anatomic locations or not
4. Measure time in seconds that a patient can perceive vibration sensation on the great toe after a 128-Hz vibrating tuning fork is placed on the dorsum of the great toe
5. Proprioception is assessed by minor movements of the first metatarsophalangeal joint of the great toe
6. Ankle reflexes are an essential part of assessing large fiber function

Question 128

What does the glove and stocking distribution of DSPN reflect?

Answer 128

It reflects nerve fiber length, when sensory loss reaches the midcalves, patients begin to perceive symmetric sensory loss of the fingertips

Question 129

TRUE of the Semmes-Weinstein 10-g filament EXCEPT:
a. Used to assess touch pressure, a large fiber function,
b. Can be used to assess as a screening tool for DPSN
d. Recommended that a three-site test be done involving the plantar aspects of the great toe, the third metatarsal, and the fifth metatarsal
d. Generally held that this is sufficiently sensitive to diagnose DSPN

Answer 129

D

Generally held that this is NOT sufficiently sensitive to diagnose DSPN

Question 130

The American Academy of Neurology recommends doing these tests in all patients suspected of having DPSN (3)

Answer 130

1. Serum protein electrophoresis with immunofixation
2. Vitamin B12 level
3. Thyroid function tests

Question 131

How are the 3 classifications of diabetic DSPN defined?
Possible, Probable, and Confirmed DSPN

Answer 131

Possible DSPN - presence of symptoms or signs of DSPN (even just 1)

Probable DSPN - presence of a combination of symptoms and signs of neuropathy, including any 2 or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes (2 or more of positive, negative, or ankle reflexes)

Confirmed DSPN - presence of an abnormality of nerve conduction and a symptom or sign of neuropathy

Question 132

What is Subclinical DSPN

Answer 132

Presence of no signs or symptoms of neuropathy are confirmed with abnormal nerve condution or a validated measure of small fiber neuropathy

Question 133

Grading of small fiber neuropathy
Possible, probable, and definite

Answer 133

Possible - presence of length-dependent symptoms and/or clinical signs of small fiber damage

Probable - presence of length-dependent symptoms, clinical signs of small fiber damage, and normal sural nerve conduction

Definite - presence of length-dependent symptoms, clinical signs of small fiber damage, normal sural nerve conduction, and altered intraepidermal nerve fiber density at the ankle and/or abnormal thermal thresholds at the foot

Question 134

TRUE or FALSE: In DSPN, electrophysiologic testing or nerve conduction studies along with a referral to neurologist is normally not needed, unless the patient has either atypical symptoms or signs.

Answer 134

TRUE

Skin biopsy may also be utilized when no clear objective evidence of small or large fiber dysfunction is present on examination

Question 135

Neuropathy scale with highest sensitivity at 98

Answer 135

Modified Toronto Clinical Neuropathy Score (mTCNS)

Sp 97

Question 136

ADA recommendations for prevention of DSPN

Answer 136

T1D - tight glucose control targeting near-normal glycemia

T2D - intensive glucose control alone is modestly effective and patient-centered goals should be targeted; lifestyle interventions

Prediabetes/metabolic syndrome - lifestyle interventions (must target dyslipidemia, hypertension, obesity, and low hip:waist ratios)

*Glucose control has a significant effect on DSPN onset and progression in T1DM but no effect or a modest 3-5% effect at best on DSPN in T2DM.

Question 137

TRUE or FALSE: Intensive glucose control is helpful in the treatment of painful neuropathy.

Answer 137

FALSE

In contrast, aggressive glucose control over a short period of time can result in debilitating pain syndromes in both T1DM and T2DM patients. These pain syndromes are known as treatment-induced neuropathies.

Question 138

Rate of HbA1c reduction in order to avoid treatment-induced neuropathies

Answer 138

Rate of less than 1% per month

Question 139

3 FDA-approved drugs for treatment of painful DSPN

Answer 139

Better evidence: duloxetine and pregabalin
Weaker evidence: tapentadol (discouraged due to current opioid epidemic)

ADA recommendations: pregabalin, duloxetine, gabapentin

Question 140

3 classes of therapies that appear effective in the treatment of DSPN

Answer 140

Voltage-gated alpha2 delta ligands: Pregabalin, gabapentin
*Pregabalin initial dose 25-75 mg, 1-3x/day; Effective 300-600 mg/day

Serotonin-norepinephrine reuptake inhibitors: Duloxetine, venlafaxine
*Duloxetine initial 20-30 mg/day; Effective 60-120 mg/day

Secondary amine tricyclic antidepressants: Amitriptyline, nortriptyline, desipramine

*May add tramadol or tapentadol only when the above agents are not effective

Question 141

Recommended by ADA and AAN as a non-pharmacologic adjunct to treatment of painful neuropathy

Answer 141

There is emerging literature that coupling pain treatment with an exercise regimen provides even greater symptom relief.

Question 142

Other treatment measures for painful neuropathy according to the AAN guidelines

Answer 142

Alpha-lipoic acid
Capsaicin cream
Local lidocaine
Transelectric stimulation (TENS)

Question 143

TRUE or FALSE: Opioids don’t have a role in acute DSPN but are beneficial for chronic DSPN.

Answer 143

FALSE

There is no role for opioids in the treatment of chronic painful DSPN, and limited use, if at all, in acute painful DSPN, possibly for the pain experienced with treatment-induced neuropathy.

Question 144

Differentiate mononeuritis from entrapment syndromes in terms of:
Onset
Number of nerves affected
Common nerves affected
Progression
Treatment

Answer 144

MONONEURITIS:
Onset - sudden
Number of nerves affected - usually single
Common nerves affected - C3, C6, C7, ulnar, median, peroneal
Progression - not progressive
Treatment - symptomatic (resolves spontaneously)
(Diagnosis confirmed by neuroimaging)

ENTRAPMENT
Onset - gradual
Number of nerves affected - single nerves
Common nerves affected - median, ulnar, peroneal, medial and lateral plantar
Progression - progressive
Treatment - rest, splints, diuretics, steroid injections, surgery for paralysis
(Diagnosis confirmed by nerve conduction studies or ultrasound)

Question 145

TRUE of cranial mononeuropathies in diabetes
a. Occur primarily in the younger population
b. Onset is usually chronic
c. Frequently requires surgical treatment
d. Neuroimaging is frequently required to confirm diagnosis

Answer 145

D

Cranial mononeuropathies
- Occur primarily in the older population
- Onset is usually acute, associated with pain
- Course is self-limited, resolving within 6 to 8 weeks
- Generally believed to be secondary to vascular insufficiency
- Most common: Mononeuropathy of the third cranial nerve
- Neuroimaging is frequently required to confirm that the symptoms and signs are due solely to diabetes

Question 146

Most common entrapment site in diabetic patients

Answer 146

Median nerve (carpal tunnel syndrome)

Question 147

TRUE of diabetic polyradiculoneuropathies:
a. Primarily affects older female T2DM patients
b. Onset is more commonly chronic
c. Usually begins unilaterally
d. General course of treatment involves IV immunoglobulin

Answer 147

C

Diabetic polyradiculoneuropathies
- Also known as proximal motor neuropathy, diabetic amyotrophy, diabetic femoral neuropathy, and diabetic radiculoplexus neuropathy
- Primarily affects older T2DM male patients
- Onset is more commonly abrupt, presenting with excruciating pain in the thighs and hips or buttocks, followed by significant weakness of the proximal muscles of the lower limbs
- Begins unilaterally, but frequently spreads bilaterally, and coexists with DSPN
- Usually clinically resolve with time, and general course of treatment is supportive
- Use of IV gammaglobulin is reported to accelerate the resolution of symptoms, but must be used with caution in diabetic patients because of the greater risk of inducing renal failure

Question 148

Clinically the most important of the autonomic neuropathies

Answer 148

Cardiac autonomic neuropathy

Because of its association with early cardiac arrhythmia, silent myocardial infarctions, and early mortality

Question 149

Early and late signs of cardiac autonomic neuropathy

Answer 149

Early: Abnormal heart rate variability, either with deep breathing or upon standing

Late: Resting tachycardia with a HR above 100 bpm and orthostatic hypotension (reduction of >20 mm Hg SBP or >10 mm Hg DBP when going from a lying to a standing position)

Question 150

ADA recommendations for cardiac autonomic neuropathy screening and diagnosis

Answer 150

Screen:
- In patients with microvascular and neuropathic complications
- In patients with hypoglycemia unawareness

Exclude other comorbidites or drug effects/interactions that could mimic cardiovascular autonomic neuropathy

Question 151

ADA recommendations for the prevention of cardiac autonomic neuropathy

Answer 151

T1D: Optimize glucose control
T2DM and Prediabetes: Multifactorial approach targeting glycemia among other risk factors

Question 152

Forms of GI autonomic neuropathy and which is the best studied

Answer 152

Gastroparesis (more prevalent in T1DM; if non-pharma interventions (multiple small meals, low fat and fiber) not successful, may give metoclopramide but not longer than 5 consecutive days due to risk of EPS)
Esophageal dysmotility
Constipation
Diarrhea

Question 153

How to screen for gastroparesis in people with diabes

Answer 153

Screen those with diabetic neuropathy, retinopathy, and/or nephropathy by assessing for symptoms of unexpected glycemic variability, early satiety, bloating, nausea, and vomiting. Exlude other causes such as opioids, GLP1RAs, and organic outlet obstruction before performing specialized tests for gastroparesis

Question 154

Specialized tests for gastroparesis

Answer 154

Scintigraphy of digestible solids at 15-min intervals for 4 h after food intake
13C-octanoic acid breath test

Question 155

First-line therapy for erectile dysfunction

Answer 155

Phosphodiesterase type 5 inhibitiors - sildenafil, tadalafil, vardenafil

Question 156

Symptoms of bladder and lower urinary tract dysfunction in patients with diabetes

Answer 156

Frequent urination with urinary urgency, nocturia, and a weak urinary stream

Question 157

Definition of hypoglycemia unawareness

Answer 157

Defined as the presence of neuroglycopenic symptoms (hunger, altered mental status, confusion, perioral paresthesia, difficulty speaking, diffuse weakness, and syncope) prior to or in the absence of autonomic warning symptoms (diaphoresis, tremulousness, pallor, palpitations, and generalized anxiety)

Question 158

TRUE about hypoglycemia unawareness EXCEPT:
a. Recurrent hypoglycemic episodes increase the plasma glucose level that serves as the setpoint for activating the counterregulatory response in both T1DM and T2DM patients
b. Severe hypoglycemia with life-threatening neuroglycopenic symptoms is more common in T1DM patients
c. There is a strong association between recurrent hypoglycemia and an increase in fatal cardiac arrhythmias
d. Personalized insulin treatment with appropriate glycemic targets is the cornerstone of treatment

Answer 158

A

Hypoglycemia unawareness
- Recurrent hypoglycemic episodes decrease the plasma glucose level that serves as the setpoint for activating the counterregulatory response in both T1DM and T2DM patients
- Severe hypoglycemia with life-threatening neuroglycopenic symptoms is more common in T1DM patients with hypoglycemia unawareness
- There is a strong association between recurrent hypoglycemia and an increase in fatal cardiac arrhythmias
- Personalized insulin treatment with appropriate glycemic targets is the cornerstone of treatment

Question 159

Clinically the most important of the autonomic neuropathies

Answer 159

Cardiac autonomic neuropathy

Because of its association with early cardiac arrhythmia, silent myocardial infarctions, and early mortality

Question 160

Early and late signs of cardiac autonomic neuropathy

Answer 160

Early: Abnormal heart rate variability, either with deep breathing or upon standing

Late: Resting tachycardia with a HR above 100 bpm and orthostatic hypotension (reduction of >20 mm Hg SBP or >10 mm Hg DBP when going from a lying to a standing position)

Question 161

ADA recommendations for cardiac autonomic neuropathy screening and diagnosis

Answer 161

Screen:
- In patients with microvascular and neuropathic complications
- In patients with hypoglycemia unawareness

Exclude other comorbidites or drug effects/interactions that could mimic cardiovascular autonomic neuropathy

Question 162

ADA recommendations for the prevention of cardiac autonomic neuropathy

Answer 162

T1D: Optimize glucose control
T2DM and Prediabetes: Multifactorial approach targeting glycemia among other risk factors

Question 163

Forms of GI autonomic neuropathy and which is the best studied

Answer 163

Gastroparesis (more prevalent in T1DM; if non-pharma interventions (multiple small meals, low fat and fiber) not successful, may give metoclopramide but not longer than 5 consecutive days due to risk of EPS)
Esophageal dysmotility
Constipation
Diarrhea

Question 164

How to screen for gastroparesis in people with diabetes

Answer 164

Screen those with diabetic neuropathy, retinopathy, and/or nephropathy by assessing for symptoms of unexpected glycemic variability, early satiety, bloating, nausea, and vomiting. Exlude other causes such as opioids, GLP1RAs, and organic outlet obstruction before performing specialized tests for gastroparesis

Question 165

Specialized tests for gastroparesis

Answer 165

Scintigraphy of digestible solids at 15-min intervals for 4 h after food intake
13C-octanoic acid breath test

Question 166

Diabetes drug that has been shown to be effective in reducing cardiovascular events

Answer 166

Metformin (UKPDS)

Little data was available to support other therapeutic approaches or specific agents

Question 167

Symptoms of bladder and lower urinary tract dysfunction in patients with diabetes

Answer 167

Frequent urination with urinary urgency, nocturia, and a weak urinary stream

Question 168

Definition of hypoglycemia unawareness

Answer 168

Defined as the presence of neuroglycopenic symptoms (hunger, altered mental status, confusion, perioral paresthesia, difficulty speaking, diffuse weakness, and syncope) prior to or in the absence of autonomic warning symptoms (diaphoresis, tremulousness, pallor, palpitations, and generalized anxiety)

Question 169

TRUE about hypoglycemia unawareness EXCEPT:
a. Recurrent hypoglycemic episodes increase the plasma glucose level that serves as the setpoint for activating the counterregulatory response in both T1DM and T2DM patients
b. Severe hypoglycemia with life-threatening neuroglycopenic symptoms is more common in T1DM patients
c. here is a strong association between recurrent hypoglycemia and an increase in fatal cardiac arrhythmias
d. Personalized insulin treatment with appopriate glycemic targets is the cornerstone of treatment

Answer 169

A

Hypoglycemia unawareness
- Recurrent hypoglycemic episodes decrease the plasma glucose level that serves as the setpoint for activating the counterregulatory response in both T1DM and T2DM patients
- Severe hypoglycemia with life-threatening neuroglycopenic symptoms is more common in T1DM patients with hypoglycemia unawareness
- There is a strong association between recurrent hypoglycemia and an increase in fatal cardiac arrhythmias
- Personalized insulin treatment with appopriate glycemic targets is the cornerstone of treatment

Question 170

Laboratory finding that is a strong predictor of the development of coronary heart disease

Answer 170

Persistent proteinuria

Proteinuria is a marker of generalized vascular damage that predisposes to atherosclerosis and coronary events.

Question 171

TRUE or FALSE: Women with diabetes have a cardiovascular mortality rate as high as that of diabetic men.

Answer 171

TRUE

In women, diabetes eliminates the cardioprotective effects of the premenopausal period.

Question 172

TRUE or FALSE: Hyperinsulinemia has been shown to independently predict cardiovascular risk.

Answer 172

TRUE

Question 173

Mechanisms that are hypothesized to be responsible for worse outcomes of acute coronary syndromes in patients with diabetes

Answer 173

• Increased risk of heart failure due to maladaptive remodeling of the left ventricle
• Increased risk of sudden death due to sympathovagal imbalance as a consequence of autonomic neuropathy
• Increased likelihood of early reinfarction due to impaired fibrinolysis
• Extensive underlying atherosclerosis
• Changes in myocardial cell metabolism, including a shift from glucose oxidation to FFA oxidation, with less generation of ATP at any level of oxygen consumption
• Associated cardiomyopathy

Question 174

What diabetes test provides the best index of risk of mortality associated with impaired glucose tolerance?

Answer 174

Oral glucose tolerance test

Question 175

Criteria of the metabolic syndrome according to the NCEP guidelines

Answer 175

3 of the following 5 risk factors:
- Abdominal obesity (waist circumference >40 inches (>101.6 cm) in men and >35 inches (88.9 cm) in women)
- Plasma triglycerides 150 mg/dL or higher
- Plasma HDL cholesterol <40 mg/dL in men, <50 mg/dL in women
- Blood pressure 130/85 mmHg or higher
- Fasting plasma glucose 110 mg/dL or higher

Question 176

PARADIGM-HF showed that the combination of these two agents proved superior to the ACE inhibitor enalapril in patients with reduced ejection fraction (<=40%), significantly reducing cardiovascular death or hospitalization for heart failure.

Answer 176

ARB (valsartan) and neprilysin inhibitor (sacubitril)

Question 177

Diabetes drug that has been shown to be effective in reducing cardiovascular events

Answer 177

Metformin (UKPDS)

Little data was available to support other therapeutic approaches or specific agents

Question 178

Studies with these 2 drug classes provided landmark data showing decreased cardiovascular events with glucose-lowering therapy

Answer 178

GLP1-RA (liraglutide, semaglutide, and albiglutide; but not lixisenatide or extended-release exenatide)
SGLT2i (empagliflozin and canagliflozin)

Also improved renal outcomes

Question 179

Characteristic features of dyslipidemia in people with diabetes

Answer 179

• LDL particles in diabetes are smaller and more dense than normal LDL, and more prone to oxidation
• HDL cholesterol levels are decreased
• Reduced lipoprotein lipase activity leads to an accumulation of triglyceride-rich lipoprotein in the plasma

Question 180

TRUE or FALSE: Statins are associated with an increase in new-onset diabetes.

Answer 180

TRUE

The modest increase in diabetes in response to statin treatment is markedly offset by major decreases in cardiovascular events. Concerns over increased conversion to diabetes should not be a factor in the decision to use statins.

Question 181

Reason why niacin has limited use despite its ability to lower HDL levels

Answer 181

Lack of proven efficacy combined with its side effects of increasing insulin resistance and relatively poor tolerability

Question 182

TRUE or FALS: Patients with significant dyslipidemia are recommended to receive combination statin-fibrate therapy for further risk reduction on the basis of T2DM alone.

Answer 182

FALSE

(Fibrates lower triglyerides and raise HDL)

Question 183

Recommendations of JNC 8, AHA/ACC regarding target blood pressure

Answer 183

JNC 8: Adults >18 y old and <60 y old or any adult with diabetes or CKD, SBP/DBP treatment initiation threshold and target of 140/90 mm Hg

AHA/ACC: Lower DBP treatment initiation threshold and target to 85 mm Hg for diabetic adults

Question 184

Mechanisms that are hypothesized to be responsible for worse outcomes of acute coronary syndromes in patients with diabetes

Answer 184

• Increased risk of heart failure due to maladaptive remodeling of the left ventricle
• Increased risk of sudden death due to sympathovagal imbalance as a consequence of autonomic neuropathy
• Increased likelihood of early reinfarction due to impaired fibrinolysis
• Extensive underlying atherosclerosis
• Changes in myocardial cell metabolism, including a shift from glucose oxidation to FFA oxidation, with less generation of ATP at any level of oxygen consumption
• Associated cardiomyopathy

Question 185

Drug class that dramatically reduce the mortality rate after a myocardial infarction in patients with diabetes, ostensibly through their effects to reduce infarct size and limit ventricular remodeling

Answer 185

ACE inhibitors

Question 186

Drug that has been a cornerstone of therapy for the primary or secondary prevention of acute coronary syndrome in patients with T1DM and T2DM who do not have contraindications to its use

Answer 186

Aspirin

Antiplatelet therapy with the antagonist of the P2Y12 subclass of ADP receptor clopidogrel also benefits patients with diabetes

Question 187

PARADIGM-HF showed that the combination of these two agents proved superior to the ACE inhibitor enalapril in patients with reduced ejection fraction (<=40%), significantly reducing cardiovascular death or hospitalization for heart failure.

Answer 187

ARB (valsartan) and neprilysin inhibitor (sacubitril)

Question 188

More than 80% of amputations are preceded by ___.

Answer 188

Foot ulcers

Question 189

Triad of component causes of diabetic foot ulcerations

Answer 189

Neuropathy, deformity, and trauma

A combination of 2 or more risk factors promotes diabetic foot ulceration.
All 3 components of neuropathy - sensory, motor, autonomic, can contribute to foot ulceration.

• Sympathetic autonomic neuropathy affecting the lower limbs results in reduced sweating, dry skin, and development of cracks and fissures.
• Small muscle wasting in the feet
• Motor neuropathy, with imbalance of the flexor and extensor muscles in the foot, commonly results in foot deformity, with prominent metatarsal heads and clawing of the toes.
• Minor injury and subsequent infection increase the demand for blood supply beyond the circulatory capacity, and ischemic ulceration and risk of amputation develop.

Question 190

TRUE or FALSE: Absence of symptoms of neuropathy does not exclude the diagnosis and must never be equated with a lack of foot ulcer risk.

Answer 190

TRUE

Question 191

Presence of ___ is a highly significant marker for foot ulcer risk.

Answer 191

Plantar callus

Question 192

May be the simplest and most reliable indicator of significant ischemia that can be elicited at the bedside

Answer 192

Presence or absence of a dorsalis pedis or posterior tibial pulse

The use of the toe-brachial index together with Doppler waveforms of distal arteries can be useful (Dopper-derived ankle pressure can be misleadingly high in patients with long-standing diabetes)

Question 193

Recommended frequency of screening for neuropathy and foot examination

Answer 193

At a minimum, such screening should be carried out annually

Question 194

Strongest predictors of future foot ulceration

Answer 194

Sensory neuropathy with clinical evidence of peripheral arterial disease

Question 195

Risk factors for ulceration to check in a diabetic patient

Answer 195

Peripheral neuropathy
Peripheral vascular disease
Foot deformity
Edema
Past ulcer history
Other complications

Table 37.21 Key Components of the Comprehensive Diabetic Foot Examination, page 1521

Question 196

Diagnosis and treatment for Wagner Grades 1,2; UT Grades 1c, 1d

Answer 196

Neuroischemic ulcers

TCCs are not usually recommended, although removable casts and pneumatic cast boots (Aircast) may be used in cases without infection.

Antibiotic therapy is required for most neuroischemic ulcers.

Investigation of the circulation is indicated and, if required, arteriography with appropriate subsequent surgical management or angioplasty.

Question 197

In general, diabetic foot ulcer has high likelihood of healing if the following 3 conditions are satisfied

Answer 197

• Arterial inflow is adequate
• Infection is treated appropriately
• Pressure is removed from the wound and the immediate surrounding area

Question 198

Most common cause of nonhealing neuropathic foot ulcers

Answer 198

Failure to remove pressure from the wound and immediate surrounding area

Question 199

Wagner Diabetic Foot Ulcer Classification SyStem

Answer 199

Grade 0 - No ulcer, but high-risk (e.g., deformity, callus, insensitivity)
1 - Superficial full-thickness ulcer
2 - Deeper ulcer, penetrating tendons, but no bone involvement
3 - Deeper ulcer with bone involvement, osteitis
4 - Partial gangrene (e.g., toes, forefoot)
5 - Gangrene of whole foot

Question 200

University of Texas Wound Classification System

Answer 200

Grade 0 - Preulcer or postulcer lesion; no skin break
1 - Superficial ulcer
2 - Deep ulcer to tendon or capsule
3- Wound penetrating bone or joint

Stage A - No other factor
B - + Infection
C - + Ischemia
D - + Infection and ischemia

Question 201

Common infectious organisms in foot ulcers:
a. Gram-positive cocci
b. Gram-negative rods
c. Anaerobes
d. All of the above

Answer 201

D

Most infections are polymicrobial.
Topical applications are usually unhelpful, and if clinical infection is present, then it must be treated urgently with antibiotics.

Question 202

The most difficult ulcer to heal

Answer 202

Neuroischemic ulcer

Appropriate noninvasive investigation and arteriography are indicated for patients with a nonhealing diabetic foot ulcer if there is any question about the vascular status.

Question 203

TRUE or FALSE: Inappropriate wound debridement contributes to slow healing or nonhealing of a diabetic foot ulcer.

Answer 203

TRUE

Question 204

Most important feature in the management of neuropathic foot ulcers that occur under weightbearing areas such as the metatarsal heads and greater toe

Answer 204

Provision of adequate pressure relief

Question 205

Management of the acute phase of Charcot foot includes:
a. TCC
b. Antibiotics
c. Arterioplasty
d. Pregabalin

Answer 205

A

Early intervention with immobilization, usually with TCC, may halt progression that, in untreated state, can lead to marked foot deformity and require local or major amputations.

There is little evidence to support use of any pharmacologic treatment in the management of this condition.

Question 206

Diagnosis and treatment for Wagner Grades 1,2; UT Grades 1ab, 1b, 2a, 2b

Answer 206

Neuropathic foot ulcer without osteomyelitis

Adequate pressure relief (TCC) with regular removal of cast

Antibiotics are not indicated unless there are clear clinical signs of infection, including prominent discharge, local erythema, and cellulitis.

Question 207

Diagnosis and treatment for Wagner Grade 3; UT Grades 3b, 3d

Answer 207

Osteomyelitis

Plain radiographs are indicated for any nonhealing foot ulcer, although radiographic changes may be delayed. In difficult cases, further investigation, such as MRI, bone scans, or an indium-111 labeled WBC scan can be useful in diagnosing bone infection.

Treatment is traditionally surgical and involves resection of the infected bone.

Successful long-term treatment can occasionally be effective with antibiotics. Staphylococcus aureus is the most common infective bacteria - clincamycin or flucloxacillin (~90 days)

Question 208

Diagnosis and treatment for Wagner Grades 4,5

Answer 208

Gangrene

Localized areas of gangrene, especially in toes, that are without cellulitis, spreading infection, or discharge can occasionally be left to spontaneously auto-amputate.

The presence of more extensive gangrene requires urgent hospital admission; treatment of infection, often with multiple antibiotics; glycemic control, usually with intravenous insulin; and detailed vascular assessment.

Question 209

Most common cause of a Charcot foot in the Western world

Answer 209

Diabetes

Question 210

Permissive features for the development of Charcot Neuroarthropathy

Answer 210

Presence of severe peripheral neuropathy and autonomic dysfunction with increased blood flow to the foot.

The peripheral circulation is usually intact. Repetitive trauma results in increased blood flow through the bone, increased osteoclastic activity, and bone remodeling.

Question 211

These features in a foot must be considered to be a Charcot foot until proved otherwise

Answer 211

A unilateral swollen, hot foot without an ulcer in a patient with neuropathy

Question 212

Key features of Charcot neuropathy

Answer 212

No signs of trauma
Shortened first ray (first metatarsal bone)
Gapping
Pain, swelling, redness in the midfoot
Bony fragmentation
Bony consolidation, osteosclerosis, fusion of joints

Question 213

Test for diagnosis of a Charcot foot

Answer 213

Plain radiograph and a high index of suspicion

May be normal early in disease, so alternatives include three-phase bisphosphonate bone scans (increased bone uptake), 111In-labeled bone scans (will be negative in the absence of infection), and FDG-PET-CT (if osteomyelitis is suspected)

Question 214

Imaging test that has the highest sensitivity for distinguishing Charcot arthropathy from osteomyelitis

Answer 214

FDG-PET-CT

Question 215

Management of the acute phase of Charcot foot includes:
a. TCC
b. Antibiotics
c. Arterioplasty
d. Pregabalin

Answer 215

A

Early intervention with immobilization, usually with TCC, may halt progression that, in untreated state, can lead to marked foot deformity and require local or major amputations.

There is little evidence to support use of any pharmacologic treatment in the management of this condition.

Question 216

Adjunct treatments for foot ulcers that have been proven effective
a. Tissue-engineered skin (e.g., Apligraf, Dermagraft) and platelet-derived growth factors
b. Negative-pressure wound therapy (NPWT) or vacuum-assited close which may stimulate development of granulation tissue
c. Achillles tendon lengthening procedure
d. Canagliflozin
e. None of the above

Answer 216

E

The nonsurgical approach of prescribing footwear designed to reduce pressure on the metatarsal heads is preferable.

The use of canagliflozin should probably be avoided in patients with distal neuropathy or peripheral arterial disease or with a history of foot disease. Although this does not appear to be a class effect, use of other SGLT2 inhibitors should be used with caution in the abovementioned groups.