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Complication of Diabetes

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Title: Complication of Diabetes


1
DIABETES MELLITUS Dr.V.S.Ampadi MD (Hom)
2
DIABETES MELLITUS
  • Ancient disease transformed by
  • Introduction of insulin in 1922
  • OHA in 1950
  • Diabetes To flow
  • Mellitus Sweet

3
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4
  • Definition
  • Disorder in which blood sugar is persistantly
    above normal
  • Lack of insulin
  • Insulin resistance
  • Factors opposing action of insulin

5
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)
6
  • Classification
  • Type 1 Due to Beta cell destruction insulin
    deficiency
  • Immune mediated
  • Idiopathic
  • Type II
  • Immune deficiency
  • Insulin resistance

7
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)
8
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
9
  • Endocronopathies
  • Acromegaly
  • Cushings disease
  • Glucogonoma
  • Pheochromocytoma
  • Conns Syndrome
  • Drug induced
  • Steroids
  • Thiazides
  • Beta adrenergic agonists
  • Diazoxide
  • Alpha interferon

10
  • Infections
  • Congenital rubella
  • Cytomegalovirus
  • Genetic Syndromes
  • Downs
  • Turners
  • Klinefelters
  • Laurence Moon Biedel
  • Myotonic dytrophy
  • Porphyria

11
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)
12
Epidemiology
13
  • 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

14
  • 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

15
  • Genetic Factors
  • Type II strong genetic background
  • Identical twins 90 chance
  • MODY
  • Parents Father/Mother 40 chance

16
Vasculopathy ethnic variations Complications
vary substantially between racial
groups Nephropathy Asians Black
Americans Mexican Americans Pima
Indians Foot ulcer White population
17
  • 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

18
  • 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

19
  • OHAs
  • Insulin Sensitizers
  • Insulin Secretagogues
  • Inhibition of glucose absorption

20
Sensitizers
Sensitizers
21
Secretagogues
22
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23
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24
Complication of Diabetes
25
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

26
  • Skin
  • Necrobiosis Lipoidica
  • Nerves
  • Carpal Tunel Syndrome
  • Cranial Nerve Palsises
  • Mononeuropathies

27
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

28
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

29
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

30
  • AGE
  • Function and structure of tissues altered
  • Activity of enzyme changed
  • Physical property changed
  • Collagen altered/ cell rigidity increases

31
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
32
  • AGE
  • Micro vascular Macro vascular
  • Retinopathy Cardio vascular
  • Neuropathy Cerebro Vascular
  • Nephropathy Peripheral vascular

33
Polyol Pathway (aldose Reductase Pathway)
  • Glucose
  • Gl.ucose 6Po4 polyolpathy
    SORBITOL
  • Lens Cataract
  • SORBITOL
  • Nerve Brain Neuropathy

34
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

35
Protein kinase C pathway
  • Protein kinase C
  • Potent inflammatory medicator
  • Micro and macro vascular complications

36
? Hyperglycemia
Poyol Pathway Hexosamine Pathway Protein Kinase
CPathway AGE Pathway
Retinopathy Nephropathy Neuropathy Cardiovascular
GLUCOTOXINS
37
AGEp and Atherosclerosis
  • Hyperglycemia
  • Glycalated LDL-C( AGEp)
  • Glycated phospholipids and apolipoproteins
  • Impairment of Endothelial function
  • Macroangiopathy (atherosclerosis)

38
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

39
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

40
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

41
Annual Screening Programme
  • BMI
  • BP
  • Eye Examination - Visualacity, fundoscopy
  • Foot Examination- deformities, abrasions,
    sensation(monofilament,
  • biothesio)
  • vascularity (Doppler,palpate pulses)

42
  • 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

43
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.

44
  • 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.

45
Classification of Neuropathies
  • Progressive Neuropathy
  • Symmetrical Sensory Neuropathy Gradual
    onset
  • Autonomic neuropathy associate with
    duration of diabetes and
    other complications

  • No recovery.

46
  • Reversible Neuropathy
  • Mononeuropathies.
  • Femoral Radiculopathy Rapid onset
  • Truncal Radiculopathy No association with
  • Cranial Nerve Palsies duration or
    other complication
  • Recovery usual

47
  • Pressure Palsies
  • Carpal tunnel Syndrome
  • Ulnar nerve compression
  • Lateral popleateal nerve
  • compression

No specific for Diabetes
48
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

49
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
50
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

51
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

52
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

53
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)

54
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

55
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

56
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

57
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
58
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

59
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)

60
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

61
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
62
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

63
  • B6
  • B12,folic acid and B6 help in reducing
    homocyteine level
  • Vit E
  • Powerful antioxidant
  • Nerve Conduction improved
  • Selenium
  • Antioxidant effect

64
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.

65
  • Reasons for nephropathy
  • Genetic
  • Duration of Diabetes
  • Advancing age
  • High blood pressure
  • Smoking.

66
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

67
Stages of Nephropathy
  • Stage of hypertension
  • Incipient stage of nephropathy(Hyperperfusion)
  • Microalbuminuria
  • Stage of established Nephropathy
  • Stage of end stage Renal Disease

68
  • 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

69
  • 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

70
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

71
  • 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

72
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

73
  • Syndrome X (Reaven 1988 Banding lecture)
  • Resistance to insulin stimulated glucose
  • uptake
  • Glucose intolerance
  • Hyperinsulinaemia
  • High VLDL TG
  • Low HDL
  • Hypertension

74
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

75
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

76
Summary of abnormalities
  • ABDOMINAL OBESITY FFA
  • INSULIN RESISTANCE UA
  • HYPER GLYCAEMIA Prothrombotic
    state
  • DYSLIPIDAEMIA
    Proinflammatory state
  • ELEVATED B.P Endothelial
    dysfunction

77
Treatment
  • Lifestyle Modification
  • Treatment for Insulin Resistance/1GT
  • Met formin
  • Treat Hypertension
  • Dyslipidaemia

78
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

79
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

80
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.

81
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

82
  • 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

83
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

84
  • 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)

85
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.

86
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

87
Endothelial Dysfunction
Glucose
Lipid Oxidation
Alteroscelerosis Alterothrombosis and Sudden death
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