Complication of Diabetes

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DIABETES MELLITUS Dr.V.S.Ampadi MD (Hom)
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DIABETES MELLITUS

• Ancient disease transformed by
• Introduction of insulin in 1922
• OHA in 1950
• Diabetes To flow
• Mellitus Sweet

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• Definition
• Disorder in which blood sugar is persistantly
  above normal
• Lack of insulin
• Insulin resistance
• Factors opposing action of insulin

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Diagnosis Fasting plasma glucose gt 126 mg/dl
(ADA) Post prandial plasma glucose gt 200 mg/dl
(WHO) IGT Post prandial plasma glucose 140 199
mg/dl (WHO) IFG Fasting plasma glucose 110 125
mg/dl (ADA)
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• Classification
• Type 1 Due to Beta cell destruction insulin
  deficiency
• Immune mediated
• Idiopathic
• Type II
• Immune deficiency
• Insulin resistance

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Genetic defects of Beta cell function MODY-
Chromosome 12 HNF 1 (MODY 3) - Chromosome 7
glucokinase defect (MODY 2) - Chromosome 20 HNF
4 (MODY 1) - Insulin promoter factor 1 (MODY
4) Others - mitochondrial DNA 3423 Mutation -
Wolframs Syndrome (DI, DM, Optiatrophy,
Deafness, DIDMOAD)
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Genetic defects in insulin action - Type A
insulin resistance - Lipoatrophic
diabetes Diseases of exocrine pancreas -
Pancreatitis - Pancreatectomy - Carcinoma
Pancreas - Cystic fibrosis - FCPD -
Haemochromatosis - Alpha 1 antitrypsin deficiency
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• Endocronopathies
• Acromegaly
• Cushings disease
• Glucogonoma
• Pheochromocytoma
• Conns Syndrome
• Drug induced
• Steroids
• Thiazides
• Beta adrenergic agonists
• Diazoxide
• Alpha interferon

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• Infections
• Congenital rubella
• Cytomegalovirus
• Genetic Syndromes
• Downs
• Turners
• Klinefelters
• Laurence Moon Biedel
• Myotonic dytrophy
• Porphyria

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Type II Diabetes in children and young adult 8
45 of recently diagnosed among children 12
14 years of age Girls, obesity, physical
inactivity Lean physique LDA MODY Specific
genetic defect inherited HNF 1 alpha MODY 3
(69) Glucokinase gene defect MODY 2 (14)
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Epidemiology
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• Risk factors for Type II Diabetes
• Age
• Ethnic group Pima Indians, Asian
• population, South Indian, Polynesian,
• Maltese
• Family history
• Western diet
• Obesity
• Physical inactivity
• Urbanisation

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• Birth weight and Type II Diabetes
• Observational study by Barker and Hales
• (Hertfordshire)
• Smaller birth weight greater likely hood of DM,
• CAD
• Smaller birth weight largest at 1 year old
• Poor fetal nutrition may have adverse effect on
• islet cells

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• Genetic Factors
• Type II strong genetic background
• Identical twins 90 chance
• MODY
• Parents Father/Mother 40 chance

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Vasculopathy ethnic variations Complications
vary substantially between racial
groups Nephropathy Asians Black
Americans Mexican Americans Pima
Indians Foot ulcer White population
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• Management of Type II Diabetes Mellitus
• Life style disease, hence life style
  modifications.
• Type II DM is a progressive disease of insulin
  
• resistance with increasing loss of insulin
• secreting capacity
• While adequate insulin secretory reserve
  remains
• treat for insulin resistance
• Insulin secretagogues/insulin replacement
  
• therapy along with sensitizers
• Regular review for development of
  complications

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• Remember 3 principles in management
• Type II Diabetes is a Life Style Disease
• Type II Diabetes is a Progressive Disease
• Type II Diabetes is a major risk factor for
  premature Cardiovascular Disease

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• OHAs
• Insulin Sensitizers
• Insulin Secretagogues
• Inhibition of glucose absorption

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Sensitizers
Sensitizers
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Secretagogues
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Complication of Diabetes
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Disease of Blood Sugar is disease of Blood vessel

• Micro vascular complications
• Diabetic Retinopathy
• Diabetic Neuropathy
• Peripheral Neuropathy
• Automatic Neuropathy

• Macro vascular Complications
• Cerebro vascular Disease
• Coronary Artary Disease
• Peripheral Vascular Disease

• Macro vascular Complications
• Cerebro vascular Disease
• Coronary Artery Disease
• Peripheral Vascular Disease

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• Skin
• Necrobiosis Lipoidica
• Nerves
• Carpal Tunel Syndrome
• Cranial Nerve Palsises
• Mononeuropathies

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Association of Complications

• Micro vascular complication develop with
  increasing duration of diabetes
• Retinopathy proceeds nephropathy
• Almost all nephropathy patients have retinopathy
  and not vice-versa
• Neuropathy can develop independently but is
  usually with established nephropathy
• Nephropathy patients are prone for macro
  vascular esp.CAD

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Pathogenesis of Complications

• Both not mutually exclusive
• Metabolic Change Structural Change in Micro
  
• vascular Circulation
• Basement membrane thickening of small blood
  vessel.
• Familial trends in development of complications
  noted
• So far no particular gene identified

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Glycation Proteins

• Glucose binds to many proteins lysine residue
• Glycation proportional to glucose
  concentration(a )
• Glycation products formed on collagen
• Irreversivable Chemical
  rearrangement AGE
• AGE (p) Advanced Glycated end products
• AGEp form at constant but slow rate and
  accumulate with time.
• Formation of AGE is accelerated in DM

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• AGE
• Function and structure of tissues altered
• Activity of enzyme changed
• Physical property changed
• Collagen altered/ cell rigidity increases

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Glucose Metabolism
Normal
Abnormal

• Glucose
• Glucose 6Po4
• Fructose 6 Po4
• Glyceraldehydes 3 Po4
• Pyruvate
• L lactate

Glucose Glucose 6Po4 Fructose 6 Po4
Glyceraldehydes 3 Po4 Triosephosphate
Protein kinase (pathway)
or Oxoaldehyde Micro
Macro AGE
Polyol pathway Hexose amine pathway
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• AGE
• Micro vascular Macro vascular
• Retinopathy Cardio vascular
• Neuropathy Cerebro Vascular
• Nephropathy Peripheral vascular

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Polyol Pathway (aldose Reductase Pathway)

• Glucose
• Gl.ucose 6Po4 polyolpathy
  SORBITOL
• Lens Cataract
• SORBITOL
• Nerve Brain Neuropathy

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Hexosamine Pathway

• Complex change in gene expression
• Complication of diabetes

• Advanced Glycated EndProduct Pathways (AGEp)
• Toxic and main cause of end organ damage
• Increases oxidative stress cell death
• Stimulates cytokine release tissue
  damage
• Disturbs glomerular structure and normal
  kidney function

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Protein kinase C pathway

• Protein kinase C
• Potent inflammatory medicator
• Micro and macro vascular complications

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? Hyperglycemia
Poyol Pathway Hexosamine Pathway Protein Kinase
CPathway AGE Pathway
Retinopathy Nephropathy Neuropathy Cardiovascular
GLUCOTOXINS
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AGEp and Atherosclerosis

• Hyperglycemia
• Glycalated LDL-C( AGEp)
• Glycated phospholipids and apolipoproteins
• Impairment of Endothelial function
• Macroangiopathy (atherosclerosis)

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Vascular Endothelial Cells

• No
• VEC Vascoactive mediators Endothelins
• Prostanoids
• Production of above vascoactive mediators espNO
• is defective in DM
• Capillary pressure early on diabetes
• Blood flow Basement membrane
  thickening
• arteroriolar Sclerosis
• defective Vascular auto regulation
  

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UKPDS(Type ii DH)

• Largest study 5102 Type ii Patients
• Result published 1998
• For 1 rise of H BAIC
• Microvascular Compilcations increased by 37
• Any diabetes related end point (micro and
  macro)increased by 21
• Death related to diabetes increased by 21
• For every 10 mmHg increase in Systolic blood
  pressure
• Any compilcation related to diabetes increased by
  12
• Death related to diabetes increased by 15
• AMI increased by 11
• Microvascular complications increased by 14

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Prevention of complication

• Annual Screening procedure
• Early detection
• Pharmacological intervention
• Target for Control
• Very good Acceptable less than ideal
• BMI(kg/m2) lt25 lt27 gt27
• Hb AIC lt6.5 6.5-7.5 gt7.5

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Annual Screening Programme

• BMI
• BP
• Eye Examination - Visualacity, fundoscopy
• Foot Examination- deformities, abrasions,
  sensation(monofilament,
• biothesio)
• vascularity (Doppler,palpate pulses)

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• Blood Tests - Hb AIC
• RFT
• Lipid profile
• Urine - Micro albuminuria
• Assess - Smoking Status
• Symptoms of Neuropathy
• History of angina,elaudication Hypo
• Co-existing medical conditions

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Neuropathy

• Slowly progressive distal symmetrical sensory
  polyneuropathy associated with autonomic
  dysfunction.
• Sensory impairment predominant and is symptom
  less.
• Symptoms include NUMBNESS, PARAESTHESIA and
  sometimes PAIN.

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• Severe neuropathic pain can occur but resolves in
  6-24 months time.
• Symptomatic autonomic neuropathy is relatively
  rare.Symptoms are DIARRHOEA, GASTROPARESIS,
  POSTURALHYPOTENSION, ERECTILE DYSFUNCTION.
• Mononeuropathy include proximal motor neuropathy,
  various radiculopathies and cranial nerve
  palsies.

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Classification of Neuropathies

• Progressive Neuropathy
• Symmetrical Sensory Neuropathy Gradual
  onset
• Autonomic neuropathy associate with
  duration of diabetes and
  other complications
• 
  No recovery.

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• Reversible Neuropathy
• Mononeuropathies.
• Femoral Radiculopathy Rapid onset
• Truncal Radiculopathy No association with
• Cranial Nerve Palsies duration or
  other complication
• Recovery usual

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• Pressure Palsies
• Carpal tunnel Syndrome
• Ulnar nerve compression
• Lateral popleateal nerve
• compression

No specific for Diabetes
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Mechanism of Neuropathy

• Nerve function deteriorates due to
• Vascular
• Metabolic
• Pressure Changes
• Vascular endothelial defect No
• Nerve blood flow
• Metabolic AGE, NGF(nerve growth factor)
• Pressure Carpal tunnel syndrome
• Ulnar nerve compression
• Lateral popletal nerve
  compression

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Scheme of vascular and metabolic changes
Endothelial Defect
Nerve Blood Flow
DM
Nerve Conduction Velocity
Aldose Reductose Mechanism
Metabolic Changes
Polyol Dehydrogenase
Aldose Reductose
Fructose
Glucose
Sorbital
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Autonomic Neuropathy

• Clinical Features
• Cardiovascular Postural hypo
• Tachy
• Sweating Gustatory Sweating
• Genitourinary Erectile Dysfunction
• Neurogenic bladder
• Gastrointestinal Diarrhea oesophageal mobility
• Gastro paresis GB emptying
• Respiratory Arrests sleepanea
• sudden death cough reflex
• Eye Pupillary responses
• Pupillary size
• Neuroendocrine Catachol amines

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Erectile Dysfunction

• Psychogenic
• Neurogenic
• Vascular ( arterial flow, venous leak)
• Endocrine
• Only NEUROGENIC Erectile Dysfunction is specific
  to Diabetes
• Gonadotrophins and Testosterone levels-Normal
• Develops in relation to other diabetic
  complications
• Not always present even in presence of severe
  Neuropathy
• Sometimes can be earliest symptom of neuropathy

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ED (Contd)

• Neuropathic ED is permanent and irreversible
• Onset is gradual and slowly progressive
• Erectile ability affected first, ejaculation
  retained
• Retrograde ejaculation occurs sometimes
• Nocturnal erections are absent
• Libido is normal

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ED (contd.)

• Diagnosis
• History - Distinguish from Psychogenic
• (abrupt onset, nocturnal,
• erection present, reversible)
• Drugs - hypotensive agents (Beta blocker)
• Physical - hypogonadisim
• Neurological Examination for Somatic and
  autonomic neuropathy
• Estimation of gonadotrophins, testosterone
  (Endocrine cause)
• Penile blood pressure by Doppler probes
  (vascular)

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Treatment

• Psychosexual counseling
• Phosphodiesterase Type 5 Inhibitors
• Sildenafil 50mg 100mg ½ Hour to 1 Hour
  before Contraindications Patients on
  nitrates BP lt 90/50 Recent
  MI/CVA Side effects Dyspepsia, Nausea,
  Vomiting,Flushing, dizziness
• Tadalafil 10mg 30 minutes before
• Vardenafil 10mg 25-60 minutes before

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ED Treatment (contd.)

• Sublingual apomorphine HCL
• Effective within 10-20 minutes
• Dose 2-3 mg
• Prostaglandins
• Tran urethral or Intercavernosal injection of
• Alprostadil (Prostaglandin E1)
• Vacuum Devices
• External cylinder fitted
• Air is pumped out creating semi vacuum
• penile enlargement(ring fitted at base)
• Penile Prosthesis

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Treatment of Neuropathy

• Benfotiamine
• Present in Garlic and other vegetables(allium
  genus)
• Inhibits Triose phosphate, hexosamine and Protein
  kinase C pathway
• Prevent formation of Reactive Oxygen species.
  Activates Pentose phosphate pathway

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Treatment Of Neuropathy

• Glucose

Glucose 6-Po4/Fructose 6-Po4
Glyceraldehyde 3-Po4
Pentose Po4 Pathway
Recycling NAD PH
Triose Po4
Hexosamine
ProteinkinaseC Pathway
Ribose (harmless)
Age
Micro vascular
Macro vascular
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Benfotiamine (contd.)

• Effectively boosts transketolase activity,
  prevents and normalise AGE levels and prevents
  complications of Diabetes
• Improves nerve Conduction velocity and vibration
  perception
• Delays or avoids hyperfiltration there by
  reducing loss of albumin in urine

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Benfotiamine (contd.)

• Normalize AGE level in retina preventing
  retinopathy
• Normalises Protein C kinase and NF Kappa B
  (potent inflammatory mediator)
• Enhances glutothione recycling by increasing
  NADPH (Free Radial Scavengers)

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Neuropathy Treatment (Contd.)

• AGE blocker
• Amino guanidine Trials not encouraging
• Methyl Cobolamin
• Vitamin B12 analogue
• Nervous tissue needs Methyl form of Cobolamin for
  metabolic activities
• Methyl cobolamine protects-neurons by unknown
  mechanism
• Promotes Nerve regeneration
• Protects against glutamate induced neurotoxicity

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Alpha Lipoic Acid

• Sulphur containing fatty acid
• Found inside every cell
• Helps in generating energy
• ALA is synthesised in body
• DM, Cirrhosis Liver, Heart failure synthesis of
  ALA is reduced
• Natural antioxidant
• Raises glutathione levels

Level of Reactive O2
Oxidation Stress
Cell Damage
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GLASome effects in slowing progress of
neuropathy not widely accepted

• Folic Acid
• Synergistic action with Methyl Cobalmin
• Reduces levels of homocyteine (
  arteriosclerosis)
• 20 lower risk of stroke
• 13 lower risk of MI

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• B6
• B12,folic acid and B6 help in reducing
  homocyteine level
• Vit E
• Powerful antioxidant
• Nerve Conduction improved
• Selenium
• Antioxidant effect

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Diabetic Nephropathy

• Kidneys
• Mainly three functions
• Removes waste products from body
• Maintains the level of water,electrolyte and
  mineral levels in the body.
• Production of hormones.

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• Reasons for nephropathy
• Genetic
• Duration of Diabetes
• Advancing age
• High blood pressure
• Smoking.

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Nephropathy contd.

• Genetic Reasons
• Familial tendency for heart disease
• Hypertension in parents
• Familial incidence of nephropathy
• Small birth weight
• Men
• Incidence
• Parents free of nephropathy 14
• Mother or father having nephropathy 23
• Both parents having nephropathy 46

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Stages of Nephropathy

• Stage of hypertension
• Incipient stage of nephropathy(Hyperperfusion)
• Microalbuminuria
• Stage of established Nephropathy
• Stage of end stage Renal Disease

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• Importance of 3rd Stage
• All patients should have microalbuminuria tested
  once in 6 months
• Normal below 30 mg/dl.
• Daily 30-300 mg. stage of Microalbuminuria
• Prophylactic treatment with ACE inhibitor

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• Importance of 4th Stage
• Kidney functions start deterioratiry
• Importance of 5th stage
• Following intervention is needed to maintain
  normal life
• Treatment to increase Hb
• Dialysis
• Renal Transplant

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Treatment

• Control level of glucose
• OHA
• Insulin
• Target for control
• FBS lt 110 mg/dl
• PPBS lt 140 mg/dl
• HbAiC lt 6.5
• Control BP
• Salt
• Daily 6 Gm salt
• Medicine to reduce BP

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• Microalbuminuria present
• Protein intake 0.8 gm/kg/day
• Saturated fats lt10 energy from
  saturated fats
• Daily Cholesterol intake lt300 mg
• Omega 3 fatty acid (Fish)
• LDL Cholesterol lt 100 mg/dl
• HDL Cholesterol gt 50 mg/dl
• TG lt 150 mg/dl

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Metabolic Syndrome

• Cluster of 3 major groups of amendable risk
  factors for CVD
• Dyslipidaemia
• Insulin Resistance/Glucose intolenence
• hypertension
• Syndrome is associated with
• obesity (abdominal type)
• highly metabolically active adipose
  tissue
• High risk for DM 20-40

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• Syndrome X (Reaven 1988 Banding lecture)
• Resistance to insulin stimulated glucose
• uptake
• Glucose intolerance
• Hyperinsulinaemia
• High VLDL TG
• Low HDL
• Hypertension

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ATP III definition

• Risk factor Defining level
• Abdominal obesity Waist Circumference
• women gt88 cm
• men gt102 cm
• Triglycerides gt150 mg/dl
• HDL
• women lt50
• men lt40
• BP gt130/85
• Fasting glucose gt110 mg/dl

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WHO Definition

• Risk factor Defining level
• Insulin Resistance Group
• FPG gt110 mg/dl
• Insulin resistance
  
• Metabolic group
• a) Obesity
• BMI gt30 kg/m2
• W/H ratio
• women
  gt0.85
• men
  gt0.9
• b) Triglycerides
  gt150 mg/dl
• c) HDL
• women
  lt50 mg/dl
• men
  lt35 mg/dl
• d) BP
  lt160/90
• e) Microalbuminuria
  gt20 mg

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Summary of abnormalities

• ABDOMINAL OBESITY FFA
• INSULIN RESISTANCE UA
• HYPER GLYCAEMIA Prothrombotic
  state
• DYSLIPIDAEMIA
  Proinflammatory state
• ELEVATED B.P Endothelial
  dysfunction

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Treatment

• Lifestyle Modification
• Treatment for Insulin Resistance/1GT
• Met formin
• Treat Hypertension
• Dyslipidaemia

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Recent Advances in Treatment of Diabetes

• Vaccination
• Type I Diabetes Autoimmune Disorder
• Basis of vaccination Immunological Concept
• Small trial of 31 patients
• Newly detected type I Diabetes
• Residual C-peptide activity above 0.1 nmol/2
• Peptide called p277 1 mg in vegetabeleoil40 mg
  mannitol(Diapep277)
• 4 injections Day 1, 1 month, 6 month , 12
  months
• C.Peptide level increased (endogenous insulin
  )
• Need for exogenous insulin
• Acts by preventing .. cell destruction

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Pancreatic / Islet cell Transplantation

• Kelley Co-workers 1966-at Minneapolis-First
  human pancreas transplant.
• As on 2001 Total 15,000 11,000 USA
• 
  4000 outside USA
• 3 categories
• PTA Pancreas Transplant Alone
• SPK Simultaneous Pancreas and Kidney
• PAK Pancreas After Kidney
• Exogenous insulin not needed after successful
  transplant.
• Better outcome on complication also.
• Technical failure 1987-89 15
• Technical failure 1998-200 7
• Mortality after 1 year 3-5
• Mortality after 3 year 5-7

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Islet Cell Transplantation

• Advantage that minimally invasive procedure.
• Islets are per fused percutaneously to liver
  (via) Portal vein.
• Patient survival after 1 year is 96.
• Graft survival is 45.
• Insulin independence is 11 only.
• Longest insulin independence obtained is 6 years.
• Stem cell research can probably offer success in
  islet cell transplantation.

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Insulin Analogues

• 1921 Discovery of Insulin by Banting,Best,
  Collip
• and McLeod.
• 1922 Leonard Thompson was first patient to
  receive
• insulin.
• 1936 Hagedorn added protamine to Insulin.
• 1946 NPH (Neutral Protamine Hagedorn) insulin
• 1980s Recombinant DNA tech Human insulin.
• 1990s Insulin Analogues introduced

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• Proinsulin 86 amino acid polypeptide (AB chains
  of insulin C-peptide)
• Insulin 51 amino acid-
• A chain 21 amino acid
• B chain 30 amino acid
• Amino acid sequence of B or A chain is reversed
  to produce analogues.
• Advantages-
• Rapid absorption
• absorption is near complete
• Hypos less

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Analogues(contd.)

• Insulin Lispro
• 1996 - Ist Analogue available
• Normal insulin B28 proline B29 Lysine
• Lispro insulin B28 Lysine B29 Proline
• Insulin Aspart B28 Asp (B28 proline)
• Long acting analogue
• Near physiological replacement
• Mealtime bolus shortacting and Basal insulin

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• Insulin glargine
• A21 Gly B31Arg B32Arg
• Available from 2000
• Insulin detemir
• 14 carbon aliphatic fatty acid B29
• Amino acid at B30 removed
• Premixed analogues
• Humalog premix IL NPL
• Noromix (insulin aspart premix)

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GLP-1 Glucagon Like Peptide 1

• Plasma glucose after IV glucose than oral
  glucose
• Plasma insulin after oral glucose than IV
  glucose
• Entero-insulin - axis
• Several hormonal factors (incretins) potentiate
• Beta cell action after oral ingestion of
  carbohydrate
• Incretin is insulinotropic intestinal hormone
  released in response to nutrient challenge.

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GLP-1 Glucagon Like Peptide 1 Contd-

• GLP-1 Insulin Glucose
• GLP-1 Glucagon Glucose
• Peptidase resist analogues of GLP-1 (Incretin)
  are undergoing trials.
• Exenatide - peptide with 53 homology GLP-1
  also under trial

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Endothelial Dysfunction
Glucose
Lipid Oxidation
Alteroscelerosis Alterothrombosis and Sudden death