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Chronic complications

Chronic Complications of diabetes are:

  1. Vascular:
    a. Micro vascular    
    b. Macro vascular
  2. Non vascular. 

Table 344-7 Chronic Complications of Diabetes Mellitus (Ref. Hari.18th ed., Pg-2980)

  1. Microvascular
    1. Eye:
      1. Retinopathy
      2. Macular edema
    2. Neuropathy
    3. Nephropathy
  2. Macrovascular
    1. CAD
    2. PAD
    3. CVA
  3. Non vascular
    1. Gastrointestinal (gastroparesis, diarrhea)
    2. Genitourinary (uropathy/sexual dysfunction)
    3. Dermatologic
    4. Infectious
    5. Cataracts
    6. Glaucoma
    7. Periodontal disease

Vascular Diseases

  1. Cardiovascular disease is increased in individuals with type 1 or type 2 DM.
  2. There is a marked increase in PAD, CHF, CAD, MI, and sudden death (risk increase from three- to fivefold) in DM.
  3. MI is 3-5 times commoner in and is more likely to be 'silent' (without classic symptoms). Diabetes is a major risk factor for CAD.
  4. CAD is the commonest cause of death in diabetic.
Extra Edge:

Major risk factor 8 for CAD (Ref. Hari.18th ed. , Pg - 2985)

  1. Smoking           
  2. Hypertension                
  3. Hyperlipidemia             
  4. Diabetes


Recent Advances:

In diabetic patients BP. Target is <130/<80mmHg(PNQ) (as per JNC VII criteria) or <125/<75 with renal disease(PNQ): (↑ creatinine, microalbuminuria, or proteinuria).


ACEI are the drug of choice in diabetic with hypertension

  1. Strict blood pressure control significantly reduced both macro- and microvascular complications.
  2. In fact, the beneficial effects of BP control are greater than the beneficial effects of glycemic control.
  3. Lowering BP to moderate goals reduced the risk of DM-related death, stroke, microvascular end points, retinopathy, and heart failure (risk reductions between 32 and 56%). 
Recent Advances:
  1. Telmisartan is the only ARB which acts on PPAR gama receptor. So it is the ARB of choice that should be   used in diabetes (This point is not given in 18th edition of Harrison also!!!).
  2. Seroglitazaar : Acts on PPAR alpha & gamma receptor so it reduces both blood sugar & lipid.  (It is a new drug. It is not given in 18th ed. of Harrison also!!!)


Recent Advances (Ref. Hari.18th ed., Pg- 2985)
  1. Improved glycemic control started soon after the diagnosis of diabetes reduces cardiovascular complications in DM, but the glycemic goal for individuals with long-standing diabetes remains unclear.
  2. In both the DCCT (type 1 diabetes) and the UKPDS (type 2 diabetes), cardiovascular events were not reduced immediately by intensive treatment during the trial but were reduced at follow-up 10–17 years later (this effect has been termed legacy effect or metabolic memory). 



Fig, 272-1, Progression of chronic renal injury in diabetes (Ref: Hari.18th ed. , Pg -1749)

  1. Increases GFR is the 1st manifestation of diabetic nephropathy. (PNQ)
  2. Then is the stage of Microalbuminuria. It is the most reliable marker of diabetic nephropathy.
  3. Macro albuminuria
  4. CRF (diabetes is the commonest cause of CRF). 


  1. Microalbuminuria is one of the earliest marker of diabetic nephropathy.        
  2. Microalbuminuria is associated with Increased long term cardiovascular morbidity.
  3. Strict glycemic control may prevent or revert microalbuminuria. 
  4. Protein restriction is helpful in diabetic nephropathy - (Ref. Hari.18th ed., Pg- 2985)

Pathology:  (AIPG 12)            

  1. Capillary BM thickening       
  2. Diffuse glomerulosclerosis (Most common). In this there is increase in mesangial matrix. It is PAS positive
  3. Nodular glomerulosclerosis. (It is the most characteristic feature).
  4. It is accompanied by accumulation of hyalin material.
  5. If it is within capillary loop (Fibrin cap) or it is attached to Bowman capsule (Capsular drop)   
  6. DM are prone to radio contrast induced nephropathy
  7. Armani Ebstein Reaction : Collection of glycogen clumps within the renal tubules found in diabetic nephropathy
  8. Dietary advice - Protein intake = 0.8 gm/kg/day in micro Albuminuria, < 0.8 gm/ kg /day = in macro albuminuria
Extra Edge:

In diabetes, patient may develop hyperkalemia without renal failure because of RTA type IV. (MCQ)


Potential important causes of false positive microalbuminuria

  1. UTI  
  2. Exercise       
  3. Menstruation                
  4. Pregnancy   
  5. Febrile illness           
  6. Congestive heart failure


Extra Edge:
  1. An annual microalbuminuria measurement is advised in individuals with type 1 or type 2 DM
  2. Screening for microalbuminuria should commence 5 years after the onset of type 1 DM and at the time of diagnosis of type 2 DM.
  3. Regardless of protein excretion results, the GFR should be estimated using the serum creatinine in all patients on an annual basis.


Important Points:
  1. Pancreatic transplantation (or Beta-islet cell transplantation) may improve proteinuria in early stages.
  2. ACEI are given as nephro protective drug
  3. ACEI are contraindicated in CRF because they cause hyperkalemia.


Recent Advances:

New nephro protective drug in diabetes : Ruboxistaurin. (PNQ) It is a protein kinase C beta inhibitor.
Ruboxistaurin is a newly developed drug. Its name is not there in Harrison 18th Edition also!!!.

Eye involvement in diabetes

Extra Edge:

Do annual funduscopy for all patients ( AIIMS Nov 09)

  1. Retinopathy:
    Types of Retinopathy
    1. Non proliferative
    2. Proliferative
  1. Background retinopathy:  
    1. Microaneurysms (dots)
    2. Hemorrhages (blots)
  2. Pre-proliferative retinopathy:
    1. Cotton wool spots (infarcts)
    2. Hemorrhages.
  3. Proliferative retinopathy: New vessels form which can lead to retinal detachment, vitreous hemorrhage.
  1. Maculopathy: This is often not visible at an early stage. It leads to profound Decresed in visual acuity.
    1. Laser photo coagulation for vision preservation
    2. Proliferative RP: panretinal laser photo coagulation
    3. Macular oedema: Focal laser photocoagulation (Aspirin has no benefit effect on natural history of diabetic RP). (MCQ)
  2. Cataracts: May be juvenile 'snowflake' form, or 'senile'-which occur earlier in diabetic subjects due to Osmotic changes in the lens induced by acute hyperglycemic state.
  3. Rubeosis iridis: New vessels on iris: occurs late and may lead to glaucoma. 

Recent Advances: Ruboxistaurin is used for prevention of both diabetic nephropathy & ophthalmopathy. Its name is not there in Harrison 18th Edition also!!!.


Recent advances (Ref. Hari.18th ed. , Pg- 235)
  1. Proliferative RP can be treated with intraocular injection of a vascular endothelial growth factor antagonist. 
  2. Either bevacizumab or ranibizumab is administered by direct injection into the vitreous cavity.
  3. These antibodies cause the regression of neovascular membranes by blocking the action of vascular endothelial growth factor, thereby improving visual acuity.
  4. Ranibizumab injection has been approved for the treatment of diabetic macular edema
  5. Pegaptanib sodium injection  is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It is a new drug, not given in Harrison 18th edition also !!!
  6. Tafluprost ophthalmic solution has been approved for the treatment of elevated intraocular pressure,
  7. Aflibercept has been approved for the treatment of neovascular (wet) age-related macular degeneration


Important Points: (Ref: Hari.18th ed. , Pg -2982)
  1. DM is the leading cause of blindness
  2. Individuals with DM are 25 times more likely to become legally blind than individuals without DM.
  3. The pathophysiologic mechanisms invoked in nonproliferative retinopathy:
    1. Loss of retinal pericytes          
    2. Increased retinal vascular permeability
    3. Alterations in retinal blood flow                
    4. Abnormal retinal microvasculature
    5. All of which lead to retinal ischemia.
  4. Fluorescein angiography is useful to detect macular edema, which is associated with a 25% chance of moderate visual loss over the next 3 years.
  5. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy.
  6. Hypertension is also a risk factor.

Diabetic foot care

  1. DM is the leading cause of nontraumatic lower extremity amputation.
  2. Occurs due to ischaemia (absent dorsalis pedis pulses) and peripheral neuropathy (injury or infection over pressure points, eg the metatarsal heads).
  3. Foot ulceration Usually painless, punched-out ulcer in an area of thick callus + superadded infection. Can lead to cellulitis, abscess and osteomyelitis.  Great toe & MTP areas are most common site.
  4. Microangiopathic changes in blood vessels in the form of peripheral arterial disease contribute to the generation of foot ulcers and non microangiopathic changes. 

Pathogenic Factors in generation of foot ulcers in DM

  1. Neuropathy (Peripheral Sensory neuropathy): Trophic changes. Loss of Sensation (MCQ: vibration is the first to be lost) in gloves & 'stocking' distribution, absent ankle jerks, neuropathic deformity: pes cavus, claw toes, loss of Transvene arch, rocker-bottom sole. 
  2. Abnormal foot biomechanics (Due to disordered proprioception and sensorimotor neuropathy)
  3. Peripheral arterial disease (Macroangiopathy) and poor wound healing
  4. Autonomic neuropathy anhidrosis and altered superficial blood flow in foot)
  5. Poor wound healing. 
Important Points:

Callus formation is the earliest manifestation of diabetic foot.


Frequency of the tuning fork used to assess vibration sense is 128.


Risk factors for foot ulcers or amputation (Ref. Hari.18th ed. , Pg - 2987)

  1. Male sex                                           
  2. Diabetes >10 years' duration  
  3. Peripheral neuropathy               
  4. Abnormal structure of foot (bony abnormalities, callus, thickened nails)         
  5. Peripheral arterial disease                         
  6. Smoking
  7. History of previous ulcer or amputation   
  8. Poor glycemic control.


Types of neuropathy in diabetes     
  1. Sensory neuropathy (it is the most common type of diabetic neuropathy) (LQ 2012)
    Symmetric sensory polyneuropathy, distal numbness (glove and stocking' distribution).
  2. Diabetic painful neuropathy
    Drugs useful for painful diabetic neuropathy - 
    1. Aspirin/paracetamol
    2. Tricyclic (amitriptyline)                
    3. Carbamazepine   
    4. Lamotrigine            
    5. Capsaicin cream (a counter-irritant)     
    6. Phenytoin.  
Recent Advances (Ref. Hari.18th ed. , Pg- 2984): 

New drug Duloxetine (PNQ) is being used for painful diabetic neuropathy. It acts by inhibiting neural reuptake of both serotonin and nor epinephrine.


Important Points:
  1. The development of neuropathy correlates with the duration of diabetes and glycemic control.
  2. Additional risk factors are BMI (the greater the BMI, the greater the risk of neuropathy) and smoking.
  3. The ADA recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and screening for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM.
  4. All individuals with diabetes should then be screened annually for both forms of neuropathy.
  1. Mononeuritis multiplex
    III & VI cranial nerves. In DM IIIrd nerve is involve most commonly but pupillary reaction remains normal. (MCQ) (AIIMS Nov 12)
  2. Amyotrophy
    Painful wasting of quadriceps and other pelvifemoral muscles.
  3. Autonomic neuropathy (ANP)
    1. Postural Hypotension                
    2. Tachycardia                 
    3. Gastroparesis
    4. Urine retention        
    5. Erectile dysfunction (ED)      
    6. Retrograde ejaculation           
    7. Diarrhea. /Constipation.
    8. Gastroparesis : It may respond to erythromycin, (MCQ: It acts on the motilin receptor)
    9. Hypoglycemic unawareness. 
Extra Edge:

In diabetic ANP, Diarrhea occur in 95%. Cases, constipation in 5% cases)


Important Points:
  1. Drug used for ED:-
    1. Sildenafil,
    2. Apomorphine,
    3. Yohimbine,PgE1 (AIIMS Nov 2010)
      {Extra Edge: Sildenafil is a 5 phosphodiesterase inhibitor Q (PD 5 inhibitor)}
  2. Drug used in treatment of Postural hypotension:
    1. Fludrocortisone
    2. Midodrine
    3. Clonidine
    4. Octreotide
    5. Yohimbine


Recent Advances: Newer PD 5 inhibitors for ED are:
  1. Vardenafil      
  2. Tadalafil


Extra Edge:
  1. Midodrine is a prodrug, belongs to sympathomimetic class. It has useful vasoconstrictor properties owing to alpha agonistic actions. It is used for orthostatic hypotension.
  2. Yohimbine is an alpha-2 receptor blocker.


Other complications

  1. Malignant otitis externa – It is cause by pseudomonas infection, it lead to pain, discharge from external ear.  It is potentially fatal Treatment aminoglycoside, 2 IIIrd generation cephalosporin.
  2. Rhino cerebral mucormycosis – It is caused by fungus. It is potentially fatal.
    Treatment is amphotericin. (AIIMS Nov 2012)
  3. Emphysematous pyelonephritis caused by E. coli. It is potentially fatal. 
  4. Emphysematous cholecystitis : It is more common is males
Important Points:

Malignant otitis externa, Rhino cerebral mucormycosis & Emphysematous pyelonephritis are fatal complications. (AIPG 12)

  1. Skin involvement in DM
    1. Pigmented pretibial papules            
    2. Necrobiosis lipoidica                
    3. Acanthosis nigricans    
    4. Granuloma annulare                      
    5. Lipoatrophy and lipohypertrophy           
    6. Scleredema
    7. Dupuytren’s contracture. 
Important Points:

Protease inhibitor can cause lipodystrophy.

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