Demystifying Autonomic Imbalancewith P&SMonitoring

Aaron I. Vinik, MD, PhD, FCP, MACP, FACE Murray Waitzer Endowed Chair for Diabetes Research

Professor of Medicine/Pathology/NeurobiologyDirector of Research & Neuroendocrine Unit

Eastern Virginia Medical SchoolThe Strelitz Diabetes Center

AACE May2018

A Simplified View of The PNSMotor Sensory Autonomic

Myelinated Myelinated Thinly myelinated

Un-myelinated

Thinly myelinated

Un-myelinated

A A/ A C C

Large

Muscle control

Touch, Vibration, Position

perception

Cold perception,

Pain

Warm perception,

Pain

Heart Rate, Blood Pressure,

Sweating, GIT,GUT, function

Small

Vinik, Ullal, Parson, Casellini Nature Clinical Practice 2; 1-13, 2006

The Autonomic Nervous System

3Vinik A et al, J Diabetes Invest, doi: 10.1111/jdi.12042, 2013

Clinical Manifestations of Small Fiber Neuropathies

• Cardiovascular– Tachycardia, orthostatic tachy‐ and bradycardia, cardiac denervation– Failure of hypoxia induced respiratory drive– Obstructive sleep apnea– Arrythmias and sudden death

• CNS– Depression, anxiety, panic syndrome

• Gastrointestinal– Gastroparesis, constipation, diarrhea

• Genitourinary– Erectile dysfunction Incontinence, Vaginal dryness

• Neurovascular– Dry skin, cold or hot feet due to poor or excessive blood flow, gustatory 

sweating, hyperhidrosis• Metabolic

– Hypoglycemia unawareness, hypoglycemia unresponsiveness, severe hypoglycemia, brittle diabetes

• Small fibers– Numbness, tingling, burning, superficial pain and allodynia

Case #1History

• R.K. is a 36 year old white, non-obese male, 5 ft 7 inches tall, weighing 142 lbs. with a 15 year history of insulin dependent diabetes mellitus (type1).

• His diabetes has been poorly controlled for many years on a regimen of a single dose of 35 units 70/30 insulin per day without regular blood glucose monitoring.

• He has had repeated admissions to hospitals for diabetic ketoacidosis and resisted attempts at intensification of treatment or improved monitoring.

Case # 1 History contd

• Over the past few weeks he had intensified his diabetes control and developed intractable burning pain in the feet which he described as a "dog gnawing at the bones" or like somebody who has a "toothache in the feet". It was unbearable for him to have his feet come in contact with the bed clothes and putting on his shoes and socks in the morning was close to or near impossible. The pain was worse at night and he was getting little sleep.

Case # 1 History contd

• He was constantly tired, felt weak, apathetic, lethargic, and was incapable of carrying out his normal daily activities.

• He had become significantly depressed by the pain and was not eating well.

• He felt bloated and full after eating only little bits of food, and he occasionally vomited and could taste food on his breath that he had eaten maybe a day or two before.

• His bowels had become irregular and varied from marked constipation to explosive diarrhea. These were sometimes so sudden and so forceful that he would soil himself.

Case # 1 contdExamination

• He was a lean asthenic individual with a resting blood pressure of 80/64 mmHg a heart rate of 96 beats/min. On standing his blood pressure fell to 50/40 mmHg, his heart rate did not change.

• There was background retinopathy. He did not have renal disease or clinical evidence of cardiovascular disease.

• He had clear evidence of mixed sensory motor polyneuropathy.

Case # 1 contdInvestigation

• Cholesterol was 132 mg/dL, triglycerides 101 mg/dL, and HbA1C 11.5 (normal < 6.05%)Urine protein 500mg, Cr 1.7, BUN 40mg/dl.

• Supine norepinephrine was 196 pg/ml and rose to 369 pg/ml after standing for 15 min.

• His resting cardiac ejection fraction was 61% and did not increase with maximal exercise.

• Gastroparesis was documented with a gastric emptying time of solid foods of 55 min (normal of < 17 min).

Case # 1 contdAutonomic function tests. 

• Resting heart rate was 100 beats/min. • The beat-to-beat heart rate variability was 12

beats/min between deep inspiration and expiration E:1 ratio was 1.01 (n>1.3).

• The Valsalva ratio was 1.06 (normal > 1.10). • Heart rate response to standing (the 30:15 ratio)

was 0.9 (normal > 1.0). • Orthostatic systolic pressure drop was 36 mm/Hg

(normal < 30mm/Hg) and he became quite dizzy.• TSP was 200, RMSSD 20 and SDNN 10• QTC was 480 ms

Know Autonomic Neuropathy and You Will Know the Whole of Medicine

Tests of Autonomic Function Parasympathetic• Resting heart rate• Beat to beat variation with 

deep breathing (E:I ratio)• 30:15 heart rate ratio with 

standing• Valsalva ratio• Spectral analysis of heart 

rate variation ,  high frequency power (HFP 0.15‐0.40 Hz)

Sympathetic• Resting heart rate• Spectral analysis of

heart rate variation , low frequency power 

(LFP<0.14 Hz)• Orthostasis BP• Hand grip BP• Cold pressor response• Sympathetic skin galvanic 

response (cholinergic)• Sudorimetry (cholinergic)

Sympathetic/parasympathetic balance=LFP/HFP

NeuropeptidergicCutaneous blood flowSkin bipsies for IENFSudorimetry

0.1 0.2 0.3 0.4 0.5 Hz

High-frequency (HF) band [0.15-0.4]Respiratory activity: parasympathetic

Low-frequency (LF) band [0.04-0.15 Hz]Baroreceptor activity: parasympathetic & sympathetic

Very low-frequency (VLF) band [0.003-0.04 Hz]Thermoregulatory activity: sympathetic

Spectral Analysis of Heart Rate Variability

Vinik and Ziegler. Circulation. 2007 Jan 23;115(3):387-97

The SDNN of all normal R-R intervals (sdNN), =S and PS action on HRV, The root-mean square of the difference of successive R-R intervals (RMSSD) : parasympathetic

Cardiovascular Autonomic NeuropathyCAN is often asymptomatic >>>>>Especially early

Low ejection fraction [Bullinga, et al.  J Card Fail. 2005][Fantoni, et al.  J Am Coll Cardiol. 2005]

Poor cardiac output [Fathizadeh, et al.  Crit Care Med. 2004]

Arrhythmias [Chen, et al.  J Cardiovasc Electrophysiol. 2006],[Copie, et al. Ann Noninvasive Electrocardiol. 2003]

Cardiomyopathies [Alter, et al.  Am Heart J.  2006][Debono and Cachia Auton Neurosci. 2006]

Poor circulation;incl. cardiac

[Nakamura, et al.  Neurosci Res.  2005][Manfrini, et al.  Eur Heart J.  2004]

Greater mortality [Vinik & Ziegler  Circulation. 2007]

Greater morbidity (reduced quality of life)

[Vinik, Maser, & Nakave US Endocrin. 2007]

CAN is the silent killer

16Mar18AIV/jc 14

Autonomic DeclineP&SMonitoring

• P&SMonitoring:  HRV & RA– P is measured as RFa = spectral analysis of RSA, based on the Fundamental Respiratory Frequency (FRF = 0.125Hz = 7.5 breathes per minute in figures) 

16Mar18AIV/jc 15

FRF=0.125Hz=7.5 breathes/min

Normal, Healthy, Resting Cardiogram

SlowermHR

Faster RSA

**

*

Time (sec)

Time (sec)

= Sympathetic number

= Parasympathetic number

Autonomic DeclineP&SMonitoring

Diabetes, the model of chronic disease• The six progressive stages of autonomic dysfunction:

16Mar18AIV/jc 16

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Stage 6

NomenclatureParasympathetic Withdrawal (PW)

Sympathetic Release (SR)

Sympathetic Decline (SD)

Sympathetic Withdrawal 

(SW)AAD or DAN CAN

Clinical feature↓ Response to deep breathing 

(DB)

↑ Sympathetic response to Valsalva, released as a reflex 

from DB

↓ Response to

Valsalva (V)

↓↓ Response with postural change (PC)

↓ Baseline (Bx) P‐ or S‐response 

↓↓ BxP‐response

Gray areas indicate normal:

Sympathetic (LFA)

Vaga

l (RF

A) A

NS

Decline

{DAN

Normal

{CAN

ref Lfa: 0.5 – 10ref Rfa: 0.5 – 10ref Lfa/Rfa: 0.4 – 3.0

A

Normal

Sympathetic (LFA)

Vaga

l (RF

A) A

NS

Decline

{DAN

{DAN

NormalNormal

{CAN

{CAN

ref Lfa: 0.5 – 10ref Rfa: 0.5 – 10ref Lfa/Rfa: 0.4 – 3.0

A

Normal

Persons More or Less likely to Have Bad Legacy and Events with Intensification of 

Treatment

Women: HR 1.21

(95% CI: 1.02- 1.43)

African American: HR 1.43

(95% CI: 1.20- 1.71)

Albumin:creatinine >300: HR 1.74

(95% CI:1.37-2.21)

BMI > 30: HR 0.65

(95% CI: 0.50-0.85)

Coronary Artery Disease

or calcification HR Risk =2-4 X :

Every 1 yr increase in age: HR 1.03

(95% CI: 1.02, 1.05)

Autonomic Nerve Dysfunction:

HR 4.43

Numb feet: HR 2.8

Long Duration >12-15 y of Diabetes:

Previous Hypoglycemic Event:HR 3.3

Orthostasis (SW)(Examples)

• Orthostatic Hypotension– Clinical:  SW plus 20 mmHg systolic and 10 mmHg diastolic BP decrease upon standing

– Pre‐clinical: SW plus any BP decrease upon standing• Orthostasis (Orthostatic Intolerance)

– SW plus normal BP change upon standing• Postural Tachycardia Syndrome (POTS)

– Clinical: SW plus 30 bpm increase in HR or HR > 120 bpm upon standing

– Pre‐clinical: SW plus excessive HR increase (>15%) upon standing

16Mar18AIV/jc 18

Severe Orthostasis• A 41-year old gentleman

presented with severe symptomatic orthostatic hypotension, polyarthritis, chronic dry eyes and mouth, difficulty swallowing, constipation, nausea, 27 pound weight loss, absence of sweating, nocturia, and erectile dysfunction.

• PHYSICAL EXAM – Severe orthostatic hypotension with no compensatory increase in pulse, dilated pupils, swan neck deformities in the fingers, and decreased prickling pain perception in lower extremities.

LAB STUDIES: Supine norepinephrine 66 pg/mLstanding 422 pg/mL.Epinephrine < 20 and Dopamine levels < 30 pg/mL pg/mL .(+) ANA (1:320) ESR 44 mm/hr); -dsDNA and Rheumatoid Factor.Negative – Anti-Hu, MAG IGM, GAD-65, C-ANCA, ASIALO-GM1 IGM, GD1a, GD1a IGM, GD1b IGM, and ANTI-RI (IFA), heavy metal screen, RPR, Lyme titer, Hepatitis C, HIV, Gastric parietal cell antibodies, adrenal cell antibodies, cortisol, ACTH, and aldosterone.Positive – (+) P-ANCA, GD1b IGG antibody positive titer 1:100, and….

POSITIVE ACETYLCHOLINE RECEPTOR BINDING ANTIBODY (0.1 nM/L)

Acetylcholine (ACh) System•ACh is produced by the enzyme choline acetyltransferase (ChAT) which uses acetyl coenzyme A (AcCoA) and choline as substrates for the formation of ACh.•Upon release, ACh binds to the post synaptic ACHR initiating a cascade of events at the ganglionic level including the release of catecholamines.•Blocking this receptor can result in severe orthostasis

Figure 1 – Baseline and Post Enbrel Quantitative Autonomic Function Tests Demonstrating Severe Reduction in Vagal Sympathetic Tone.  Note the Improvement in Deep Breathing and Valsalva Responses after Enbrel 

Treatment.

Bourcier, Vinik et al 2007

Orthostatic Hypotension (SW)45 y/o Female

• History:– Tilt positive 7 yrs prior; Dx:  Syncope– Pindolol on board,  ineffective therapy

• Bx Diagnosis (Dx) (before ANS testing):– SW (red circle in table, next side) and– Low BP upon standing (green circle, next side)

• Therapy: initiate Midodrine• Serial P&S testing (over a 4 month period):• Follow‐up P&S testing: SW (red circle, next side)

– Reversed Orthostasis with increasing BP upon standing

• P&S changes first then end‐organ changes– Patient reports more stable on therapy and no more dizziness

16Mar18AIV/jc 22

Case Study

Orthostatic Hypotension (SW)45 y/o Female

16Mar18AIV/jc 23

+ Vasopressor

Case Study

Postural Orthostatic Tachycardia (POTS) and Hyperhidrosis

WHAT DID WE DO?

Postural Orthostatic Tachycardia(POTS) 56 y/o Male

Sympathetic Withdrawal• Therapy Options

– Proper daily hydration (check diuretics)– Mechanical intervention, e.g., stockings– Volume building (check resting BP)– Vasopressors, e.g., Midodrine (check for supine HTN)

• Start low dose, consider weaning when reversed and stabilized (in a little as six months if detected early)

• Alpha‐Lipoic Acid titrated to maximum tolerance [Ziegler, 1997,2006; Murray, Submitted]

16Mar18AIV/jc 26

Kahn et al. J Am Coll Cardiol 1986;7:1303-9.

Maldistribution of Sympathetic Innervation in Cardiac Autonomic Neuropathy (MIBG)

MUGA MIBG Thallium

Maldistribution of Sympathetic Innervation in Cardiac Autonomic Neuropathy

CARDIAC INNERVATION STUDYN-13 Ammonia Blood Flow

Distal ShortAxis

Proximal ShortAxis

Vertical LongAxis

Horizontal LongAxis

Stevens et al University of Michigan

Relative Risk of Mortality from CAN

0                         1                         10                       100Vinik et al., Diabetes Care 26: 1553-79, 2003Maser et al Diabetes Care 26: 1895-1901,2003

Prevalence Rate Ratios and 95% CI from 15 Studies; p<0.0001; n=2900

Log Relative Risk

2.14 (1.83‐2.51)  Pooled data3.45 if > 2 abnormalities CAN 

Cardiac Denervation Syndrome

• Increased prevalence of –Painless myocardial infarction–Coronary artery spasm–Sudden death– Loss of diurnal rhythm of CAD– Loss of diurnal rhythm of blood pressure–Prolonged QTc interval

• Adrenergic supersensitivity or imbalance between sympathetic and parasympathetic may be a cause of sudden death

Causes of Death in Diabetic Autonomic Neuropathy

• Sudden unexplained• Cardiac arrhythmia• Silent myocardial infarction

–More likely to die of heart attack–Greater incidence of cardiac failure

• Aspiration pneumonia• Ulcers, amputations, gangrene• Chronic renal failure

00 1 2

0.2

3 4 5 6 7 8 9

0.4

0.6

0.8

1.0

Years

26.0%

57.1%

p=0.0014

Diabetic Cohort: Age 55‐74 yr (n=171)Mortality in Relation to QTc Interval Length

MONICA/KORA Survey 2 Augsburg

QTc 440 ms (n=150) QTc > 440 ms (n=21)

Survival proba

bility

Sudden death isn’t so bad. Anyone who has spent an evening with an insurance salesman knows this.

Woody Allen

Type II Diabetes ‐ 63 y/o Male

• Original Dx: Type II Diabetes, with CAN and Hypertension

• Rx History: Zocor

• Dx after ANS testing:– Diabetes & Hypertension– Sympathetic Withdrawal (SW:  Orthostasis) 

• Therapy: Add Carvedilol

• Serial P&S testing (over a 12 month period):– Relieved SW (Orthostasis) and high BP

• Patient reports relief of fatigue, dizziness, palpitations, andheadaches

Clinical P&S Applications

16Mar18AIV/jc 34

Type II Diabetes ‐ 63 y/o Male (continued)

• 1st P&S test:– Resting BP = 179/80, Dx w/ CAN– No real responses– Rx:  + Carvedilol

• 2nd P&S test (+ 3 months):– Resting BP 177/86– Some signs of a response– Rx:  no change

• 3rd P&S test (+ 3 months):– Resting BP = 152/84– As normal as can be hope for a 63y/o

Normal: 24y/o

Clinical P&S Applications

16Mar18AIV/jc 35

Autonomic Balance Achievable is” [Vinik & Murray, US Endocrine, 2008]

(ex.: 67 y/o Diabetic, Poorly Controlled)

8 Aug 9 CME/jc 36

Normal

ANS Follow-upANS

+Alpha, Beta-blocker(Carvedilol

6.25mg, bid)

A

• Sympathetic Excess (SE) responses to Beta‐blocker (Metoprolol)

• HR decreases as expected• SE decreases as expected• Patient feels better• Improved outcome documented

37

SE, β-blocker

N=57

Therapeutic Results(Single Agent Changes Only)

• Parasympathetic Excess (PE) responses to anti‐cholinergic (Amitriptyline)

• Both systolic and diastolic BP increase as expected

• PE decreases as expected• Patient feels better• Improved outcome documented

38

Orthostatic Bradycardia Syndrome(Single Agent Changes Only)

PE, Anti-Cholinergic

N=50

Orthostatic hypotension Dizziness and syncope Unexplained tachycardiaPresence of other organ manifestations of DAN

erectile dysfunction, gastroparesis, sleep apnea, depression, panic syndrome

Preoperative risk stratificationKnow your number-it may save your life!!!Use your number to predict your future

Indications for Cardiovascular Autonomic Testing

Sailing Close to the Wind

Me on my WindsurferAt Victoria Falls

SUDOSCAN a quick and simple method to measure nerve function

Degeneration of small C‐fiber innervating sweat glands as observed in diabetes.

(reproduced from Lauria et al.)

Application of a low voltage to electrodes on hands and feet to extract chlorides 

from the sweat.

Electrochemical reaction between the chlorides of the sweat and the 

stainless‐steel electrodes creates a flow of ions

Measurement of Electrochemical Sweat Conductances ,directly dependent from the glands capability to transfer chlorides and

reflecting small-C fiber status.

Vinik, et al. Current Diabetic Reports. Online 2013.

SUDOSCAN 

42

Symmetry

Conductances measured on hands and feet

Autonomic neuropathy

(LF HRV model)

Vinik, et al. Current Diabetic Reports. Online 2013.

Gibbons H and Freeman R. Brain 1-10, 2014

Risk of developing Insulin Neuritis

Never faster than 1%/month 

Reduction in A1c

Gibbons H and Freeman R. Brain 1-10, 2014

DANGER of TOO RAPID GLYCEMIC CONTROL

Treatment Algorithm: After Exclusion of Non‐Diabetic Etiologies and Stabilization 

of Glycemic Control

TCA/SNRI

Gabapentin/Pregabalin

Gabapentin/Pregabalin

AnxietyAutonomic activation

yes

noTCA contraindication

TCA/SNRI

TCA contraindicationno

yes

Tramadol, oxcarbazepine, opioids, topicals,

Treatment targetedat pain

comorbidity

Treatment combinations

Depression Inflammatory/demyelinating

IVIg, Steroids, Enbrel

Modified from Vinik J Clin Endocrinol 2010, Vinikai NEJM 2016, 374, 1455-1464.

Neuropathic pain

Sleepdisturbances

Gabapentin/Pregabalin

AnxiolyticClonidine

NEED for PATHOGENESIS-ORIENTED

PREVENTION and TREATMENT

Spectrum of Gastropathy in DiabetesIncreased rate of Gastric emptyingFailure of slowing

Gastricdysrythmias

Failure of fundic

relaxationBradygastriaTachygastria

Antral hypomotility

Gastroparesis

Brittle DiabetesNausea,dyspepsia

Early satietybloating

Nausea, vomiting,abdominal pain,succussion splash

PercentRadionuclideRemainingIn Stomach

Postprandial Time (min)

100

80

50

20 60 100 140

20 100

Solid Phase

Liquid Phase

Gastroparesis

Effects of Hyperglycemia

Early Rapid Emptying

50

80

100

Brain

Vagus

Intestine

Pancreas

Gastric Emptying

Food

Hypoglycemia Hyperglycemia

CCK, GLP-1, GIP, NOhIAPPGhrelin

Vagus

Intrinsic Pathway

Extrinsic Pathway

L cell

K cell

Factors Potentially Influencing Gastric Emptying in Diabetes

Test meal composition Aging Male sex Obesity Hyperglycemia Hyperinsulinemia ↔Hypoglycemia Autonomic Neuropathy

Whom to Suspect of Gastropathy

Patients with both type 1 and type 2 diabetes Evidence of distal symmetric polyneuropathy and 

autonomic neuropathy Brittle diabetes in a previously well‐controlled 

patient Symptoms of early satiety, bloating and a succussion 

splash (anorexia, nausea, vomiting, dyspepsia are nonspecific and herald other conditions)

Gastropathy: Diagnostic Challenges

• Clinically silent• Symptoms do not correspond with severity of gastropathy

• Symptoms are non‐specific and resemble many other conditions

Gastropathy: Diagnostic Pearls

• Liquid gastric emptying studies tell you that the Magenstrasse is Patent

• Solid Gastric emptying when the blood glucose is > 400 mg/dl is the most expensive way to do a blood glucose

TimeInsulin injectionat mealtime

Delayed emptying

Stomachemptying

Blo

od g

luco

se c

once

ntra

tion

Non‐Pharmacological Treatment of Gastropathy

Eat small amounts of food at frequent intervals Avoid high fat foods fries, dairy products and fatty meats

Avoid fibrous vegetables and fruits such as broccoli, cauliflower, cabbage, green beans, celery, apples, pears, citrus fruits, grapes and raisins

Eat digestible foods such as white breads, pasta, potatoes and rice

Avoid spicy and irritating foods such as pepper, chili sauce, hot peppers, onions and garlic.

The Effects of Gastropathy on Glycemic Control

Diabeticgastropathy

Delayed gastricemptying

Irregular delivery of nutrients/drugs

Insulin/glucosemismatch

Hyperglycemia

Clinical escape

Prokinetic Treatment of Diabetic Gastroparesis

Drug Mechanism of action Dose/day

Metoclopramide 5-HT4 receptor agonist 10 mg b.d.-q.i.d.

Dopamine D2 rec. antagonist p.o., i.v., s.c., i.m.

Domperidone Dopamine D2 receptor 10-20 mg b.d.-q.i.d.antagonist p.o.

Erythromycin Motilin receptor agonist 250-500 mg t.i.d. p.o.0.5-1 g t.i.d. i.v.

PresentationNausea,vomiting, bloating, satiety,brittle diabetes

Crisis managementiv fluids and electrolytes/ liquid diet/iv prokinetics

Withdraw drugse.g. opioids, tricyclic

antidepressants, anticholinergics, levodopa, Ca++ antagonists, octreotide

Exenatide, Pramlintide

Nutritional and psychiatric evaluation

treat eating disorders, e.g. anorexia nervosa,

bulimia,

Exclude functionale.g. hyperglycemia,

ketoacidosis, electrolyte imbalance

endocrine e.g. hypo and hyperthyroidism,

Addisons.

Solid phase gastric emptyingElectrogastrography

Psychiatric/behavioral therapy

Hygienic:Soups, crackers

starches, chicken fishNo fat

Prokinetics

Gastric PacingFeeding

jejunostomyuntil stomach

recovers

Specific Therapies for Autonomic Neuropathy

• Spironolactone– The addition of Spironolactone to enalapril, furosemide and digoxin 

in patients with heart failure improves sympathovagal balance» Korkmaz et al Am J Cardiol 86: (6) 649‐53

• ARIs/Antioxidants– Sorbinil improved resting and maximum cardiac output

» Pfeifer et al Diabetes Res Clin Practice 1990, 10: 91‐97– Epalrestat improves MIBG uptake and HRV in patients with mild 

abnormalities not advanced » Ikeda et al Diabetes Res Clin Practice 1999, 43: 193‐198

– Zenarestat restores peripheral small fibers» Greene Neurology 1999;53:580‐91

• Intensive Multifactorial Management– Control of BP, Lipids, HBA1c, use of Vit E and C and ACE‐inhibitors 

reduces AN by 68%» Gaede et al Lancet 353: 617‐622, 1999

Intensive Multifactorial Intervention in Type 2 Diabetes

Systolic BPDiastolic BPHbA1cTriglyceridesTCHDL‐CACE inhibitor regardless of BPAspirin in ischemiaVitamin C and E

<160 mmHg<95 mmHg<7.5%<2.2 mM<6.5 mM>0.9 mMNoYesNo

Treatment Goal Standard Intensive

<140 mmHg<85 mmHg<6.5%<1.7 mM<5.0 mM>1.1 mMYesYesYes

Gaede et al. Lancet 1999;353:617‐22. 

Intensive Multifactorial Intervention in Type 2 Diabetes

Gaede et al. Lancet 1999;353:617‐22. 

Complication Odds Ratio

Nephropathy

Autonomic Neuropathy

Retinopathy

0.27

0.32

0.45

AN:  Clinical Features, Diagnosis, and Treatment

Vinik AI, Vinik E, Chapter 28: Diabetic Neuropathies, AADE DeskRef 2016, p. 769‐806.

Recommendations• Screen all Type 2 diabetics at diagnosis• Screen all Type 1 diabetics after 5 years• Repeat on an annual basis if normal• Use HRV to diagnose the cause of ED,orthostasis,gastroparesis• If abnormal provide a staged management plan for prevention of 

complications of diabetes• Provide system specific recommendations for prevention and 

treatment of manifestations– ACE inhibitors– Beta blockers– Foot care

• Care with hygienic measures, eg, dietary fiber, exercise, and hypoglycemic therapy 

Vinik and Zola. In: Marteke VJ, Current Science. Chap 19; 159‐171;2000.

ACE Inhibitors

AGE BlockerBreaker NAAG‐ase 

inhibitors

Immunophilins

Antioxidants

Glycemic control

PKCInhibitor

Neuro-trophic agents

Aldose Reductase Inhibitors

Autonomic Neuropathy Prevention

Gut hormones and the regulation of energy homeostasisKevin G. Murphy and Stephen R. BloomNature 444, 854‐859 (December 2006)

Gastric Pacing in GastroparesisExperimental indication: intractable vomiting

Conclusions Gastroparesis

Due to moderate prokinetic effects, poor symptomatic responses and the presence of adverse effects, there is a clear need for new classes of prokinetics.

The relatively poor correlation between upper GI symptoms and disordered gastric emptying represents a major difficulty in the therapeutic approach.

Novel treatments such as botulinum toxin, ghrelin receptor and motilin agonists, and gastric electrical stimulation should be further evaluated in long-term controlled trials.