Acute and Chronic Complications of Diabetes

Dr. Amel Arnaout

Objectives1. Explain the pathophysiology of diabetic ketoacidosis.  

2. Describe the major symptoms, signs and laboratory findings in

diabetic ketoacidosis.  

3. Discuss the principles of management for DKA.  

4. Describe the pathogenesis of microvascular disease in diabetes.  

5. Discuss the mechanisms and clinical effects of macrovascular

disease in diabetes mellitus.  

6. Describe the mechanisms & clinical effects of microvascular

disease in diabetes mellitus.  

7. Recognize hypoglycemia as an important complication of

diabetes mellitus.

Lecture OutlineAcute Complications

1. Diabetes Ketoacidosis2. Hyperosmotic State3. Hypoglycemia

Chronic Complications1. Microvascular2. Macrovascular

Diabetic ketoacidosis

Diagnostic criteriaHyperglycemia

Glucose >11.1 mmol/l; usually > 15 mmol/l

Metabolic acidosis (increased anion gap)pH < 7.35decreased bicarbonate <15 (best estimation

with venous)

Positive serum ketonesUrine ketones: may be absent in early stages

PrecipitantsInsulin deficiency

new diagnosis OmissionInadequate dosePump failure

Excess counter-regulatory hormones

GHCatecholaminesGlucagonCortisol (stress, infection, MI)

Four “I’s”Insulin DeficiencyIschemiaInfectionIntra-abdominal

process

(30 – 45%)

PathophysiologyInsulin deficiency

↓Decreased peripheral glucose

utilization↓

Increased glucose production↓

Increased ketogenesis

Increased lipolysis in adipocytes↓

Increasead free fatty acids for ketone production

↓Increased glycerol for gluconeogenesis

Excess counter-regulatory hormones

↑↑ insulin resistance

↑↑ ketone production

Increased lipolysis results in the production of acetylCoA from fatty acids which

Acetyl-CoA acts as the substrate for hepatic synthesis of ketone bodies

ACETOACETATE

BETA-HYDROXYBUTYRATE

ACETONE

Wallace T , Matthews D QJM 2004;97:773-780

QJM vol. 97 no. 12 © Association of Physicians 2004; all rights reserved.

Type 1Diabetes

Consequences of DKAHyperglycemiaosmotic diuresis

dehydrationloss of K+, Na+,

HCO3- in urine

hyperosmolar statefree water drawn

into blood hyponatremia, cerebral dehydration decreased level of consciousness

Acidosiscompensatory

respiratory alkalosis

K+ shift but total body K is

low

Calculations for Diagnosis

serum osmolality2 (Na + K) + glucose + BUN

serum Na+for each 10mM ↑in glucose>10, Na+ ↓ by 3

E.g. Glucose 40mmol and Na 130, Na really 139

anion gapNa – (Cl + HCO3)

compensation for metabolic acidosisfor each 1 mmol drop in HCO3, PCO2 should

↓by 1mmHg

Goals of Treatment1. Replace volume loss

2. Stop ketone production

3. Replace K+ loss

4. Lower serum glucose

5. Correct acidosis

Treatment

DKA

CDA Guidelines 2013-Management of Hyperglycemia Emergencies

Hyperosmolar Hyperglycemic State(HHS)

Hyperosmolar non-ketotic state1. Severe hyperglycemia

2. Dehydration

3. Serum hyperosmolality

4. *Lack of significant ketosisit takes less insulin to prevent ketosis than it

does to stop hyperglycemiaif there is some insulin around ketosis will not

occur

Precipitants

1. Stressor - ↑insulin resistance

2. Relative insulin deficiency

3. ↑glucose production, ↓utilization

4. ↓renal excretion of glucose (2˚ to renal disease, aging kidneys)unable to undergo osmotic diuresis : can’t get rid of

glucose through urine, therefore very hyperglycemic

NO KETOSIS

Goals of Treatment -HHS

Summary

METABOLICPRECIPITATING CAUSE OF DKA/HHS

OTHER COMPLICATIONS OF DKA/HHS

• ECFV contraction• Potassium deficit• Metabolic acidosis

caused by ketosis• Hyperosmolality

(water deficit leading to increased corrected sodium concentration plus hyperglycemia)

• New diagnosis of diabetes

• Insulin omission• Infection• Myocardial

infarction• (ECG changes may

reflect hyperkalemia ; A small increase in troponin may occur without overt ischemia )

• Thyrotoxicosis • Drugs

(e.g.antibiotics, steroids)

• Abdominal disease

• Hyper/hypokalemia• ECFV overexpansion• Cerebral edema• Hypoglycemia• Pulmonary emboli• Aspiration• Hypocalcemia (if

phosphate used)• Stroke• Acute renal failure• Deep vein

thrombosis

Hypoglycemia

Hypoglycemia

HYPOGLYCEMIA is defined by:

1.The development of autonomic or neuroglycopenic symptoms

2.Low plasma glucose level (<4.0 mmol/L for patients treated with insulin or an insulin secretagogue)

3.Symptoms responding to the administration of carbohydrate

Hypoglycemia

NON-DIABETIC

Insulin excess insulinoma, postprandial hypoglycemia

Non- insulin mediated Adrenal insufficiency Severe liver disease Malignancy

May be factitious Exogenous insulinOral agents

DIABETIC

Excess InsulinMiscalculation of doseMixed-up insulin

Inadequate oral intakeOverestimate appetiteIllness (nausea/vomiting)gastroparesis

ExerciseIncreased insulin

sensitivityIncreased glucose

utilization

Response to HypoglycemiaADRENERGIC

diaphoresis, tremulous, palpitations etc.

NEUROGLYCOPENICconfused, loss of consciousness,

seizure

HYPOGLYCEMIA UNAWARENESSLack of adrenergic signalsUnaware of hypoglycemia until ↓

LOCRisk of severe reactions that are

unpredictableLoss of drivers license

Risk factors for severe hypoglycemia

Canadian Diabetes Association Guidelines 2013: Hypoglycemia

Prior episode of severe hypoglycemiaCurrent low A1C (<6.0%)Hypoglycemia unawarenessLong duration of insulin therapyAutonomic neuropathyLow economic statusFood insecurityLow health literacyCognitive impairmentAdolescencePreschool-age children unable to detect and/or

treat mild hypoglycemia on their own

Treatment Mild – Moderate Hypoglycemia

15 g glucose in the form of glucose tablets

15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water

175 mL (3/4 cup) of juice or regular soft drink

6 LifeSavers (1 = 2.5 g carbohydrate)

15 mL (1 tablespoon) of honey

Canadian Diabetes Association Guidelines 2013: Hypoglycemia

Diabetes Complications

MACROVASCULAR MICROVASCULAR

Stroke

Heart disease and hypertension

Foot problems

Renal disease

Neuropathy

Foot problems

Diabetes: Chronic Complications

Peripheral vascular disease

Diabetic eye disease(retinopathy and cataracts)

Mechanisms for chronic complications

MICROVASCULAR• Clearly related to blood glucose, but also genetics• Glucose control lowers risk

MACROVASCULAR• Not as clearly related to blood glucose• Other risks

Hypertension Lipids Hyperinsulinemia/insulin resistance Hypercoagulable state etc. Smoking

• Glucose control may lower risk but blood pressure and lipid control also important

Does lowering blood sugar reduce or prevent

complications?

Landmark trialsDiabetes control and complications Trial (DCCT)

Type 1 diabetes (n=1441)

Intensive insulin management (<7% HbA1C) on prevention or progression of microvascular complications

NEJM 1993;329:977-986

Outcomes54-76% reduction

in retinopathy

39-54% reduction in nephropathy

60% reduction in neuropathy

UK Prevention of diabetes study (UKPDS)Type 2 diabetes (n=3867)

Intensive glycemic control (<7% HbA1C)) versus conventional treatment

Outcomes: macrovascular microvascular reduction

www.dtu.ox.ac.uk/ukpds

Risk Reduction in UKPDS with Intensive glucose control

12% for any diabetes related endpointp=0.029

25% for microvascular endpoints p=<0.01

16% for myocardial infarctionp=0.052

24% for cataract extractionp=0.046

21% for retinopathy at twelve yearsp=0.015

33% for albuminuria at twelve years p=<0.01

How does hyperglycemia cause complications?

Mechanisms1. Glucose Metabolic effectsEg. Polyol pathway, glycation of proteins

2. Growth factors/cytokinesEg. Transforming growth factor β, IGF-1, VEGF etc

3. Hemodynamic effectsEg. Nitric oxide, endothelium changes

4. Intracellular effectsEg. Protein kinases

From JAMA 2002;288:2582

Copyright restrictions may apply.

Sheetz, M. J. et al. JAMA 2002;288:2579-2588.

Aldose Reductase Pathway Theory

Glycosylation of protein Non-enzymatic glycosylation

Interaction of glucose with amino groups on proteins ( eg HbA1c) - reversible

Advanced glycosylationlonger-term exposure; correlates with level

of glycemiairreversible changes forms advanced

glycosylation end products (AGE)form cross-links, interact with receptors,

modify cell functions, accumulate, attract macrophages

Copyright restrictions may apply.

Sheetz, M. J. et al. JAMA 2002;288:2579-2588.

Advanced Glycation Endproduct (AGE) Pathway Theory

Increased levels of AGE occurs with:agingsmokingdiabetesrenal disease (AGE accumulate as GFR declines)

AGE crosslinked proteins:Recognized by macrophages that phagocytoze the

crosslinked AGE Induce leaky endotheliumPotent chemotaxic agentPromote growth factor release to make new blood

vessels.Quench nitric oxide

Glycosylation of protein

Reactive Oxygen Intermediate Pathway Theory

Hyperglycemia may increase oxidative stress through both enzymatic and nonenzymatic processes

Increased oxidant stress: reduces nitric oxide levelsdamages cellular proteinspromotes leukocyte adhesion

to the endothelium while inhibiting its barrier function.

Protein Kinase C (PKC)

Alters transcription of genes for:

fibronectintype IV collagencontractile

proteins ECM proteins in

endothelial cells and neurons

Diabetic NephropathyMost common cause of renal failure in North

America

Progressive increase in proteinuria in people with longstanding diabetes followed by declining function that leads to ESRD.

If diagnosed early, progression to end stage renal disease can be stopped

May occur at presentation in type 2 diabetes, not before 5 yrs in type 1 diabetes

Risk Factors

Long duration of diabetes

Poor glycemic control

Hypertension

Male gender

Obesity

Smoking

Structural Changes in glomerulus•Increased ECM•Basement membrane thickening•Mesangial expansion•Fibrosis

Changes lead to leaky filtration membrane• increased filtration of protein• damage to renal tubules and loss of nephrons

Five Stages of Kidney Disease

Stage 1:

•Hyperfiltration -↑ GFR occurs. Kidneys increase in size

Stage 2: •Glomeruli begin to show damage•Microalbuminurea occurs. (Earliest clinical sign of nephropathy)

Stage 3: •eGFR 30-60 ml/min •Albumin excretion > 300 mg/day•Blood pressure rises.

Five Stages of Kidney Disease (con’t.)

Stage 4: •GFR decreases to less than 30 ml/min•large amounts of protein pass into the urine•high blood pressure almost always occurs. •Levels of creatinine and urea-nitrogen in the blood rise further.

Stage 5: •End stage renal disease (ESRD). GFR is less than 15 ml/min.•Average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. •The average length of time to progress to Stage 5, kidney failure, is 23 years.

Screening for nephropathyTimed urine

24 hour urine for creatinine clearance, microalbumin, total protein

Gold Standard but cumbersome and not always performed correctly

Random urine albumin/creatinine ratioTest of choiceRequired to be persistently elevatedAt least 2 or 3 urine samples over time

Preventing Development or Progression of Diabetic Nephropathy

Glycemic control

Blood pressureACE inhibitors/ angiotensin receptor blockersEffects of ACEi/ARB reduce risk independent of

effect on BP

Protein restrictionOnly in advanced disease with significant

proteinuria

Diabetic Nephropathy

Test When Normal Range

Blood Pressure1

Each office visit <130/80 mm/Hg

Urinary Albumin1

Type 2: Annually beginning at diagnosis Type 1: Annually, 5-years post-diagnosis

<2.0 mg/mmol (ACR) <30 mg /day (24UFA)

CDA Guidelines 2013

Diabetic RetinopathyThe most common cause of new cases of legal

blindness in people of working age.

Associated with significant morbidity (i.e. falls, hip fractures and 4-fold increase in mortality).

Linked to duration and severity of hyperglycemia

Stagesbackground (non-proliferative)pre-proliferativeproliferative

Background (non-proliferative)Microaneurysms and hemorrhages

↑capillary permeabilityRetinal edema leads to hard exudates (composed of

lipoproteins)

Pre-proliferativeDilated, irregular veinsIntraretinal microvascular changes

small loops of fine vessels danger of burstingHemorrhagic infarct seen as large blot hemorrhageUp to 50% develop proliferative retinopathy

Proliferative Retinal ischemia stimulates proliferation

stimulates vessel growth in retina new vessel do not have the same support and easily

bleeds into surrounding areas Retinal detachment and blindness

Diabetic Retinopathy

Diabetic Neuropathies

1. Polyneuropathy (peripheral, symmetric)May be sensory

and/or motorMay involve small

fibers, large fibers or both

May be chronic (common) or acute (rare)

Longest fibres affected first – “glove and stocking”

Diabetic Neuropathy

2. Mononeuropathyaffects single nerve; less

commoninfarct of nerve (vascular

problem) reversible

3. Entrapment neuropathies (e.g. carpal tunnel syndrome)

4. Autonomic neuropathy

CardiovascularResting sinus tachycardia (fixed heart

rate) Exercise intolerance, “denervated

heart” Orthostatic hypotension

Gastrointestinal Autonomic gastropathy and delayed

gastric emptying Diabetic diarrhea (is uncommon,

usually intermittent)

Genitourinary Erectile impotence Bladder dysfunction (e.g. urinary

retention)

Hammer toesHallux valgusSubluxed MTPRocker bottoms

Diabetic Neuropathies

Pathological Abnormalities Axonal loss Paranodal and Segmental demyelination

Functional Abnormalities: Reduced nerve conduction velocity

(sensory and motor)

Effects on nerves related to fibre length Most distal portions of nerves affected earliest

(distal polyneuropathy)

Macrovascular diseasediabetes ↑ risk of heart disease,

cerebrovascular disease must look at all risk factors

lipidsblood pressuresmokingfamily historyetc

Coronary artery diseaseleading cause of death in Type 2 DMhigh incidence in Type 1 DMoccurs at younger agefrequency of coronary events doubleddeath rate per event doubledcoronary bypass surgery very difficult

(extensive narrowing and occlusions of coronary arteries)

Vascular diseases

Increased frequency of severe peripheral vascular disease with multiple lesions, especially in lower part of body

Ischemic ulcers and amputations in lower extremities occur more frequent than in non-diabetic individuals

“Stroke” (CVA) is more frequent than in non-diabetic individuals

UlcersVascular and neuropathic complications

put people at riskcommon place: balls of feetsubluxation of joints press on joints

deformity skin breakdown can’t feel trauma to the feetcan’t heal properly due to poor vascular

supplydue to neuropathy and peripheral

vascular disease