COMPLICATIONS OF DIABETES

MELLITUS

A metabolic disorder of various etiologies, characterized by chronic hyperglycemia due to insulin deficiency and/or insulin resistance as well as increased hepatic glucose output.

Type 1 Type 2 Other causes

(Genetic defect of β cell function, genetic defects of insulin action, disease of exocrine pancreas, endocrinopathies, drug/chemical-induced, infections and uncommon forms)

Gestational DM

ACUTE CHRONIC

• Diabetic Ketoacidosis• Hyperglycemic

Hyperosmolar State• Hypoglycemia

• Microvascular- Retinopathy- Nephropathy- Neuropathy

• Macrovascular- Accelerated

arteriosclerosis- Myocardial infarction- Stroke- Lower extremity gangrene

COMPLICATIONS OF DIABETES MELLITUS

-Diabetic Foot Ulcer-Infections

CHRONIC COMPLICATIONS OF DIABETES MELLITUS

HCO3-

HypertriglyceridemiaResembles

Pancreatitis

Reduced insulin:glucagon ratio↓

↑Lipolysis↓

↑fatty acid↓

Excess acetyl CoA↓

↑ Ketogenesis↓

↑Beta hydroxy butyrate (toxic to body)↓

Induce nausea/vomiting

Ketonemia

Ketonuria

Reduce HCO3-

Metabolic acidosis

Kussmaulrespiration (to compensate)-‘air hunger’

↑Acetone

Fruity smell in the breath

Absolute insulin deficiency/Increase counter

regulatory hormones↓

↑Catabolism of carbohydrate, fats and proteins

↓Hyperglycemia

↓Osmotic diuresis

↓Polyuria and nocturia (loss of

electrolytes + fluid)↓

Dehydration↓

Thirst center↓

Polydipsia

Nausea and vomiting

Impairs renal

excretion of H+ and ketone

AggravateacidosisAffect pH

dependent enzyme

Increased chylomicrons in the blood (>1000mg/L)

Obstruct capillaries

Local ischemia and acidemia

Local damage expose TG to pancreatic lipases

TG → Fatty acids

Further local injury + ↑ inflammatory mediators and free radicals

Resembles Pancreatitis

↓

↓

↓

↓

↓

↓

Tachycardia Dehydration/hypotension Tachypnea Abdominal tenderness (resembles

pancreatitis/surgical abdomen) Lethargy/ Reduce alertness (obtundation) Cerebral edema Coma

severe ketoacidosis + histotoxic action of the ketone bodies + disturbances in water and electrolyte balance → reduced oxidative metabolism of the central nervous system →diabetic coma

Hyperglycemia: Test with dipstick, confirm with venous blood glucose level

Ketonemia: test plasma with Ketostix. Finger prick sample for β-hydroxybutyrate

Ketouria: measure urine ketone levels Acidosis: measure

- pH of arterial blood- bicarbonate in venous blood

Arterial blood gas Urinalysis

Symptoms of hyperglycemia from history Pulse: >100bpm/ <60bpm Systolic BP <90 mmHg Glasgow Coma Score <12/abnormal ‘Alert,

Voice,Pain, Unresponsive’ scale (AVPU) O2 saturation <92% on air (If normal

respiratory function)

Replace fluid losses Replace electrolyte losses Restore acid-base balance Replace deficient insulin Monitor blood glucose closely Treat underlying cause

• Usually occur in Type 2 DM• Caused by relative insulin deficiency and inadequate

fluid intake • Involved mostly elderly patients

Hyperglycemia DehydrationDecreased

consciousness

Ketosis

Dehydration Stupor/Coma Confusion

ABSENCE OF KETOACIDOSISNo nausea, vomiting and Kussmaul respiration(delays the seeking of medical attention

marked increase in plasma osmolarity(reaches 340mOsm/L (280-295mOsm/L)

↓Profound cellular dehydration

↓severe loss of intracellular fluid in the brain cells

↓Coma

Plasma osmolality = (2(Na+ + K+) + glucose + urea) all in mmol/L

Due to insulin treatment for both Type 1 and Type 2 DM

Due to improper dosing with exogenous insulin or by induction of endogenous insulin

Exercise, fasting, low glucose intake

Hypoglycemia

Low insulin, High Counter regulatory hormone

X Restore blood glucose level

↓

↓

↓ Insulin treatment

Hypoglycemia

↓

Release of glucagon

sweating Confusion Irritability Headaches Abnormal behaviour Motor incoordination Coma Weakness Convulsion

Rapid oral/IV glucose IM glucagon

1.Coronary heart disease2.Peripheral arterial disease3.Cerebrovascular disease

Also called ischemic heart disease. Caused by a hardening or thickening of the

walls of the blood vessels that go to the heart.

Blood supplies oxygen and other materials to the heart for normal functioning. If the blood vessels to the heart become narrowed or blocked by fatty deposits, the blood supply is reduced or cut off, resulting in a heart attack.

Diabetes mellitus – metabolic disorder

Endothelial injury

Increase production of advanced glycation end products (AGEs)

Make the platelets ‘sticker’

Increase coagulation potential

Abnormal clot formation (thrombosis)

Pathogenesis :

Increase permeability and adhesion of molecules ;

monocyte,leukocyte,platelet,lipids (LDL)

Oxidized LDL attracts macrophages and monocytes to the site

Smooth muscle emigration from media to intima

Lipids engulf by cells foam cells, smooth muscle cells proliferate

Collagen and other ECM deposition

Coronary heart disease

Atheroslerotic plaque

Accumulation of lipid intracellularly & extracellularly

Reduction of blood flow

Anaerobic metabolism

Decreased blood supply to the myocardium, decreased oxygen supply

Myocardial ischemia myocardial necrosis

Inflammatory response

Hyperthermia/fever

Acidosis

Decreased myocardial contractility low cardiac

output

Sympathetic stimulation

Tachycardia Decreased perfusion of oxygenated blood to other organs

Dyspnea, fatigue and body weakness

Decreased systemic circulation

Redirection of blood from skin major organs

Pathophysiology :

Chest pain

Pallor

Signs and symptoms : Chest pain – usually a feeling of

squeezing/pressure. If the patient has autonomic diabetic neuropathy, he may not has the chest pain

Decreased tolerance for physical activity Chronic fatigue Shortness of breath Swelling of the legs and ankles Palpitation

refers to a group of conditions that affect the circulation of blood to the brain, causing limited or no blood flow to affected areas of the brain

Atherosclerosis is one of the conditions that can cause cerebrovascular disease.

During this process, high cholesterol levels coupled with inflammation in areas of the arteries in the brain can cause the cholesterol to build up in the vessel in the form of a thick, waxy plaque.

This plaque can limit, or completely obstruct, blood flow to the brain, causing a stroke, transient ischemic attacks, or dementia, which may lead to a variety of other health complications.

Hyperglycemia

↓

Non-enzymatic glycosylation of collagen and others

protein in interstitial tissue and blood vessel wall

↓

Formation of irreversible advanced glycosylation end

products (AGES)

↓

Cause cross link between polypeptides + interstitial

proteins, including low-density lipoprotein (LDL)

↓Promote the deposition of the cholesterol in the

blood vessel intima↓

Accelerates atherogenesis↓

Atherosclerosis↓

Compromised the blood supply to the tissue

↓To brains vessels

↓Coma and stroke

Atherosclerosis

compromised the blood supply

Coronary artery lower extremities vessel brain vessel

MI, angina, IHD coma, strokecoagulative necrosis + infections

gangrene

In the walls of the large blood vessels, AGE-modified collagen accumulates, thickening the vessel wall and narrowing the lumen.

AGE-modified arterial collagen immobilizes circulating LDL, contributing to atheroma formation.

The cumulative effect of these changes is a progressive narrowing of the vessel lumen and decreased perfusion of affected tissues.

The binding of AGEs to specific cellular receptors that have been identified on the surface of smooth-muscle cells, endothelial cells, neurons, monocytes, and macrophages results in increased vascular permeability and thrombus formation, proliferation of smooth muscle in vessel walls, and phenotypic alteration in monocytes and macrophages

This last result causes hyper-responsiveness of monocytes and macrophages upon stimulation, with resultant increases in the production of proinflammatory cytokines and certain growth factors.

These cytokines and growth factors contribute to the chronic inflammatory process in the formation of atherosclerotic lesions.

Another condition related to heart disease and common in people with diabetes.

The blood vessels in the legs are narrowed or blocked by fatty deposits, decreasing blood flow to the legs and feet.

Increases the chances of a heart attack or stroke occurring. Poor circulation in the legs and feet also raises the risk of amputation.

Intermittent claudication - pain, weakness, numbness, or cramping in muscles due to decreased blood flow

Rest pain - occurs when the artery occlusion is so critical that there is not enough blood and oxygen supply to the lower extremities even at rest and represents a more serious form of the condition.

Numbness of the extremities Weakness and atrophy (diminished size and strength) of the

calf muscle A feeling of coldness in the legs or feet Changes in color of the feet; feet turn pale when they are

elevated, and turn dusky red in dependent position Hair loss over the dorsum of the feet and thickening of the

toenails on affected limbs and digits Painful ulcers and/or gangrene in tissue where there is critical

ischemia; typically in the toes ( heals slowly or not all )

In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.( Diapedesis - The movement or passage of blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue)Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of L-arginine.The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell proliferation and migration.

Conversely, the loss of endothelium-derived NO permits increased activity of the proinflammatorytranscription factor nuclear factor kappa B (NF-κΒ), resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines.These actions promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, characterizing the initial morphological changes of atherosclerosis.Thus, decreased levels of NO in diabetes may underlie its atherogenic predisposition.The bioavailability of NO reflects a balance between its production via NOS and its degradation, particularly by oxygen-derived free radicals.Many of the metabolic derangements known to occur in diabetes, including hyperglycemia, excess free fatty acid liberation, and insulin resistance, mediate abnormalities in endothelial cell function by affecting the synthesis or degradation of NO.

To reduce the risk of progression and of cardiovascular disease by Improved control of blood glucose

▪ Reduced intake of blood glucose

▪ Control diet!!!

Aggressive reduction of blood pressure

▪ For DM 1, ACE inhibitor provide greater benefit

▪ For DM 2, angiotensin 2 receptor blocker has better effect

Aggressive cardiovascular risk factor reduction

▪ Eg; reduced in cholesterol intake

Treatment

Antihypertensive (ACEi, ARB)

To prevent hypertension

Statin

To prevent lipid abnormalities

ACE inhibitor / ARB

To prevent cardiovascular risk

Low-dose aspirin (antiplatelet)

To reduce arteriolar thrombosis & macrovascular risk

DIABETIC RETINOPATHY DIABETIC NEUROPATHY DIABETIC NEPHROPATHY

Diabetic retinopathy is a complication of diabetes and a leading cause of blindness.

Is the result of damage to the tiny blood vessels that nourish the retina

They leak blood and other fluids that cause swelling of retinal tissue and clouding of vision

Usually affects both eyes The longer the person has diabetes, the more

likely they will develop diabetic retinopathy

Hyperglycemia will increase retinal blood flow and metabolism and has direct effects on retinal endothelial cells and pericyte loss

which will impair vascular autoregulation The uncontrolled blood flow will dilates capillaries and

increase production of vasoactive substances and endothelial proliferation, resulting in capillary closure

This causes chronic retinal hypoxia and stimulates growth factors (VEGF) production

VEGF – will stimulate changes of endothelial cell growth (new vessel formation) and increase vascular permeability (causing retinal leakage and exudation)

There are 4 types of diabetic retinopathy1. Non-proliferative without maculopathy No immediate threat to vision It includes venous dilatation, peripheral

(microaneurysms, exudates and blot haemorrhages)2. Maculopathy Is a sight threatening Presence of exudation, haemorrhage, ischemia and

oedema3. Pre-proliferative Is a sight threatening Presence of venous loops and beading, microaneurysms,

haemorrhages, intra-retinal microvascular abnormalities, multiple cotton wool spots, macular oedema with reduced visual acuity and exudation

Proliferative Is a sight threatening

Involves pre-retinal haemorrhage, neovascularisation, fibrosis and exudativemaculopathy

• Microaneurysmstiny, discrete, circular, dark red spots near the retinal vessels. most cases, this is the earliest clinical abnormalities.

• Retinal haemorrhagesoccur in deeper layer of retinaround, regular in shape- `blot’ haemorrhage.

• Exudatescharacteristics of dibetic retinopathyoccur in perimacular area.

• Cotton wool spotsfeatures of pre-proliferative diabetic retinopathy.

• Venous changes• Neovascularisation• Pre-retinal haemorrhage• Vitreous haemorrhage• Fibrosis

microaneurysm

(soft exudates)

Increase intracellular glucoseActivation of polyol pathway

Osmotic effect(intracellular overhydration)

Reduce in Na/K ATPase activity

Non enzymatic glycosylation of terminal end amino groups

Intermediate glycosylated compund

Advanced glycosylation end products. ( AGEs)

Changes in cellular function

Imbedded lens

Swelling and opacity

Blurring of vision (retinopathy)

Prevention Rapid reduction in blood glucose

Blood pressure lowering

Annual screening for retinopathy (in those with risk factor) Retinal photocoagulation (laser treatment) Focal laser to treat leaking microaneurysm, retinal

thickening, reduced macular edema

To destroys area of retinal ischemia, thus reduce the intra-ocular levels of VEGF (important for neovascularisation)

Reduced risk of recurrent haemorrhage (by inducing fibrosis of the new vessel)

Opacification of the lens Due to sorbitol infiltration Senile cataract develops 10-15 years earlier in

diabetic patients Clinical features Gradual painless deterioration of vision

Reduced visual acuity Treatment Cataract extraction

Insertion of an intraocular lens

Increased intraocular pressure damaging optic nerve and results in visual field defects

Leaky new vessel formation reduced outflow of aqueous humour through trabecular meshwork increased intraocular pressure glaucoma

Diagnosis is made after IOP is measured Treatment Beta-blocker Prostaglandin analogue Carbonic anhydrase inhibitors

Diabetic Neuropathy

•Neurological disorder associated with diabetes mellitus

•Affects all peripheral nerves including pain fibers, motor neurons

and autonomic nervous system

•Symptoms vary according to the nerves affected

•Common symptoms includes:

•Numbness & tingling of extremities (‘Gloves & stockings

distribution’)

•Dysesthesia (abnormal sensation to a body part)

•Dizziness

•Urinary incontinence

•Muscle weakness

•Difficulty swallowing

Pathogenesis

The pathogenesis is not clearly understood but these 4 factors are

thought to be involved:

1. Microvascular disease

a. Diabetes causes narrowing of blood vessels, abnormal

vasoconstriction, capillary membrane thickening and

endothelial hyperplasia which contributes to tissue (nerve)

hypoxia

b. Nerve hypoxia can lead to neuronal ischemia which impairs

nerve functions

2. Advanced glycated end products (AGE)

a. Elevated intracellular levels of glucose can cause a non-

enzymatic covalent bonding with proteins which alters their

structure and inhibit their function.

b. Seen in cells that unable to reduce glucose intake due to

hyperglycemia (e.g. endothelial cells).

c. A complex pathway involving oxidative stress or reactive

oxygen species.

3. Protein Kinase C (PKC)

a. Increased levels of glucose cause an increase in intracellular

diacylglycerol which activates PKC

b. PKC inhibitors will be activated to compensate the abnormal

activation of PKC

c. PKC inhibitors increase nerve conduction velocity by

increasing neuronal blood flow, causing abnormal sensation.

4. Polyol pathway

a. Aka sorbitol/aldose reductase pathway.

b. Increase glucose level will activate this alternative

biochemical pathway.

c. This pathway decreases glutathione and increase reactive

oxygen species & is dependent on enzyme aldose reductase.

d. Cells of retina, kidney & nervous tissues are not insulin

dependent.

e. Any glucose not used will enter the polyol pathway and be

converted to sorbitol

4. Polyol pathway

f. Under normal condition, this interchange will cause no

problem as aldose reductase has low affinity for glucose at

normal concentration.

g. In hyperglycemic state, sorbitol accumulates.

h. Sorbitol can’t cross cell membrane, when it accumulates, it

produces osmotic stress by drawing water into cell.

i. Fructose which is also made further on in this chemical

pathway has the same effect.

j. The deposition of sorbitol and fructose can damage the

Schwann cell membrane and causes abnormalities or decrease

nerve conductions.

hyperglycemia

Accumulation of sorbitol and fructose in the cell and also depletion of NADPH needed for GSH production

Osmotic stress of Schwan cell and also production ROS

Activation of sorbitol/aldose pathway

Abnormality or delayed nerve conduction

Diabetic neuropathy

DEFINITION :

Any deleterious effect on kidney structure and/or function

caused by diabetes mellitus.

Chacterized by albuminuria, hypertension, and progressive renal insufficiency

Approx. 20-30% of patients with diabetes (type 1 and type 2) develop nephropathy

The earliest clinical manifestation is the presence of small but abnormal levels of albumin in the urine (microalbuminuria) generally precedsovert proteinuria by 5-10 years.

Once proteinuria is detected, renal function gradually

deteriorates over 10-15 years

Diabetic nephropathy may result in end-stage renal

disease (ESRD) requiring dialysis or kidney

transplantation.

Considerably fewer people with type 2 diabetes

progress to ESRD

Microalbuminuria is a risk factor for premature

coronary artery disease in diabetics

Coexisting hypertension accelerates the

development of renal failure.

Diabetic KidneyThe kidney may be damaged by diabetes inthree main ways :1) Glomerular damage diabetic

nephropathy2) Ischaemia resulting from hypertrophy

and hyalinization of afferent and efferent arterioles ischaemic damage to kidneys.

3) Ascending infection UTI due to bladder stasis resulting from autonomic neuropathy and infections.

STAGE CHARACTERISTICS

STAGE 1 Hypertrophy and hyperfunction- Increase in size of kidney- Higher blood flow and rate of filtration

STAGE 2 Thickening of basal membrane

STAGE 3 Onset of Nephropathy - Microalbuminuria- Rise in blood pressure

STAGE 4 Clinical nephropathy-Macroalbuminuria-High blood pressure

Microalbuminuria

testing:

Normal range :

<20mg/l

Microalbuminuria:

20 – 200mg/l

Macroalbuminuria

: >200mg/l

=> Renal hypertrophy and increase in glomerularfiltration rate

High levels of blood sugar

Kidney filter too much blood stress on basal membranes

More vasolidation of afferent arteriole than efferentglomerular arteriole

Increases intraglomerular furtherfiltration pressure damage glomerular

capillary

PATHOPHYSIOLOGY

intraglomerularfiltration pressure

Further damage glomerularcapillary

Local shearing forces (mesangial cell hypertrophy) and

secretion of extracellular mesangial matrix material

Glomerular sclerosis

Thickening of BM

Disruptions of protein cross lingkages that makes an effective filter

Progressive leak of large molecules(proteins) into urine

Small amount of protein appears in urine; microalbuminuria 30-300mg/day

Overt nephropathy with macroalbuminemia>300mg/day + HPT

May develop end stage renal failure Requiring dialysis or renal transplant

Screening for microalbuminuria 30-300mg/day

Microalbuminuria is the earliest evidence of the diabetic nephropathy

The amount is so small to be detected.

Have to be tested by using special dipstick or radioimmunoassay

DM↓

Defective insulin action↓

Hyperglycaemia↓

Impairs immune good medium for glycosylation ofsystem bacterial growth polymorphnuclear cells

↓ ↓

prone to get infection impaired effectiveness& function

bacterial invasion & proliferation↓

INFLAMMATION↓

Capillary dilatation, fluid exudation, neutrophils exudation↓

Liquefactive tissue necrosis↓

ULCER (red, warm, swollen, tender skin lesion)

minor trauma

tissue injury

Gangrene

AMPUTATION

ischaemia neuropathy

symptoms ClaudicationRest pain

Usually painlessSometimes painful neuropathy

inspection Dependent ruborTrophic changes

High archClawing of toesNo trophic changes

palpation Coldpulseless

WarmBounding pulses

ulceration PainfulHeels and toes

painlessPlantar (pressure point)

Dorsum of 2nd toe shows ischaemic lesion. Whitish color on the tip d/t ischaemia

Ulcer on the 1st metatarsal head. Health granulation tissue on its bed. Callus formation on its surrounding ulcer lesion.

Death of tissue Generally d/t loss of vascular supply&

followed by bacterial infection

Laboratory testFBC – presence & severity of infectionblood sugar – hyperglycemia

X-raysign of damage to bones or arthritisgas in soft tissue-indicate gangrene

Ultrasounddoppler ultrasound-blood flow through the arteries & veins in lower extremities

Resolve infection-antibiotics

Wound care- surgical debridement- improvement of circulation- special dressing- maggot therapy Follow up

-compliance to antibiotic-sign of improvement-less pain, swelling, redness, shrinkage

Poorly controlled diabetes entails increased susceptibility of infections Skin infection

GIT infection

Urinary tract infection

Pyelonephritis

Pneumonia

Pulmonary tuberculosis

Pathophysiology

Hyperglycemia impaired neutrophil superoxide generation chemotaxis & phagocytosis of neutrophil are impaired infections

Infection also leads to loss of glycemic control and ketoacidosis

Increase insulin dose for DM patient complicated with infections