DIABETIC NEUROPATHY

A- Alpha 20 um limb proprioception

A- Beta 12 um limb proprioception and vibration
B- Delta 6 um sharp pain
C- - 0.1-0.2 um thermal , temperature and pain

All are myelinated except C fiber.

From + to - (loss).

Last finding the charcot arthropathy (non- traumatic dislocation)

PATHOGENESIS:-

Non-enzymatic glycosylation.

Altered polyol pathway.

Inc. sorbitol production.

Sorbitol induced osmotic dysregulation.

Sorbitol induced demyelination

Uncontrolled aldolase production.

And microvasculopathy of nervi nervorum

 Diabetic neuropathy is further divided:-

Somatic

symmetric or asymmetric myelopathy

polyneuropathy with loss of sensation in hand and foot

mononeuropathy

mononeuritis multiplex.

diabetic amyotrophy:- nerve to skeletal muscle  atrophy

meralgia parasthetica

charcot arthropathy

carpal tunnel syndrome

 neuropathic foot : high arch foot , ulcers on plantar aspect lost reflexes

AUTONOMIC NEUROPATHY:-

- gustatory sweating
- facial nerve palsy
- postural hypotension
- arrhythmia
- impotence
- gastrooparesis
- flushing/ dumping
- fallopian tubes hypomotility

CRANIAL NERVE NEUROPATHY:-

- occulomotor nerve palsy

- abducen nerve palsy
- trochlear nerve palsy
- optic atrophy

INV:-

IEND (INTRA EPIDERMAL NERVE DENSITY)

Below mentioned aggrevates diabetes neuropathy

- amyloidosis
- acromegaly
- cushing syndrome
- hypothyroidism

DIABETIC RETINOPATHY
dulcitol pathway along with sorbitol is responsible for sluggish flow of the RBCs and platelet
aggregation

abnormal VEGF is contributing to excessive growth of vessels with sluggish flow

following changes are the hallmarks of diabetic retinopathy

 MICROVASULAR CHANGES:- VEGF induced blood vessels lacking basement membrane , having
high transcytotic channals.
 MICROANEURYSM :- outpouching of vessles with loss of pericytes.
 DOT BLOT HEMORRHAGES:- hemorrhages in deeper layer of retina
  FLAME SHAPED HEMORRHAGES:- hemorrhages in superficial layers of retina (splinter
hemorrhages).
 HARD EXUDATES:- meta arteriole obstruction with break in blood retinal barrier.
 COTTON WOOL SPOTS:- nerve fiber infarcts
 VENOUS BEADING:- venous looping
 SILVER WIRING VESSELS:- become constrict along with HTN.

NON- PROLIFERATING D.RETINOPATHY:-

- Microaneurysm and microvascular changes

- 4 in 4, 2 in 4, 1 in 4 quadrants.

PROLIFERATIVE RETINOPATHY :-

Neovascularization

Pre-retinal edema

Fibrotic changes

Macular edema

Rubiosis retinitis

Avascular fovea

Viterous hemorrhage

Retinal detachment

C/F:-

Dimness of vision

Scotomas

Cataract of glaucoma

Falling of curtain(black) in front of eye

Tunnel vision

INV:-

Retinal angiography

Flouresence angiography
OCT (ocular coherent testing)

Mx:-

Glycemic control -Ranibizumab

Bevazizumab - Photocoagulation

If retinal detachment then pneumoplexy.

Proliferative : AV nipping

Other findings in eye:- retinal detachment, cataract, glaucoma

INFECTIONS OF DIABETES MELLITUS

organisms :-

Staphylococci aureus

Pseudomonas

Psis. Globartus

Mucor

Infections:-

Carbuncle -emphysematous pyelonephritis

Cellulitis - emphysematous Cholecystitis (cholecystectomy)

Boil -Rhinocerebral mucor mycosis (Cavernous sinuses)

Malignant otitis externa (boxes swimmers poor hygiene EDM).

Pathogenesis:-

-elaboration of adhesive Molecule on endothelin.

-poor actin, myosin Phosphorylation in neutrophils and Macrophages

- defective VEGF.

- Inc. Endothelin locally.

-Dec. Responsiveness for macrophages to IgM and C3b.

 DIABETIC KETOACIDOSIS
Etiology:-

type 1 DM or usually in honey moon period

R/F:-

- MI
- Pyelonephritis
- Stroke
- Missing an insulin dose

C/F:-

- Kussmal breathing
- Epigastric pain
- Acetone breath
- Confusion
- Sweating
- Stupor
- Coma
- Hyperglycemia
- Polydipsia
- Polyuria
- Anorexia
- Nausea
- Vomiting

PATHOPHYSIOLOGY:-

- Absolute deficiency of insulin

- Inc. carnityl transferase
- Inc. glycogen
- Inc. amylase
- Inc. cellular transferase
- 2-3 DPG and PFK abn
- Glycolysis shuts off
- Gluconeogenesis high
- Glycogenolysis inc.
 - HMG-COA synthetase uncontrollable intracellular
- Thiolase inc.

CLINICAL CRITERIA:-

-ketone body in serum ,urine and breath

- high anion gap M. acidosis

- ph of blood = 7.3 or less

- Na2+=125-140

- HCO3= <15mEq

- CO2=25-32mmHg

- blood glucose= 250-600 mg or 13-330 mmol

- plasma osmolarity= 300-320 mOsm

Mx:-

1st phase:-

0.9% saline and insulin .5-.9 IU

2nd phase:-

Salbutamol and HCO3 .

- Pt should be monitored for :- acute erosive gastritis, acute pancreatitis, acute renal shutdown,
mucor mycosis, caverneous sinus thrombosis, and mesenteric angina.
- 2 types of DKA:-
- 1:- known case of type 1 comes to emer. After aggrevation
- 2:- pt completely normal suddenly vomitsdiagnosed DKA  after a period of 3-
6mthssymptomatic type 1 diabetes HONEY MOON DKA.
- Certain DKA takes place after total pancreatomy
- Trauma to the pancreas absolute insulin deficieny.

REFRACTORY = frudrocortisone.

- Missing INSULIN DOSE most common presentation of type 1 DM…

Bad prognosis:-

- Inc. Amylase - inc. LDH.

INV :-

Serum K+ high (never <5)

Immediate electrolytes
Inc. glucose > 500-700 mg
No C- peptide
Urea
ECG
Urine chemistry
CT scan
ABG’s
Check plasma osm
Check alcohol levels
Check instestinal angiography and abd. CT for mesenteric angiography
complications:-
hypothermia
fluid overload
seizures
central pontine myelinosis
If vomiting Mallory Weiss tear , borrhave
Heart atrial fibrillation can co-exist with DKA , diffuse cardiac output and stroke.
StrokeMucor mycosis, histotoxic hypoxia , poor cardiac output.

DIABETIC VASCULOPATHY
Microvasculopathy

Macrovasculopathy

Coronary vasculopathy  cardiac X syndrome

C/F:-

- Cardiac X syndrome
- Ischemia foot:- loss of hairs on foot, Loss of pulsations, Ulcers on heels and toes & Dependent
rubor
- Angina
- MI
- Stroke/TIA
- Central retinal artery obstruction
- Central retinal vein obstruction

PATHOPHYSIOLOGY :-

- Up regulation of endothelin
- Up regulation of Ang 2 gene via advanced glycosylation
- Up regulation of ADH gene
Down regulation of NO synthetase.

Defects in LDL receptordeposits in vessel (atheroma)

Hallmark is up regulation of pro-thrombin complex in DM (inc. in macrovasculopathy)

Uncontrolled T cell activity type 3 HS

Along with fibrin deposition in the vessel fibroid necrosis

Uncontrolled sloughs off PT complexes

R/F :-

- Obesity
- Hyperinsulinemia(defect in JAK/STAT of T cell leading to overexpression )
- Carotid intimal thickening
- Monocular painless blindness central retinal artery obstruction.
- RTA 4

COMPLICATION :-

Renal amyloidosis

Inv:-

- Monitor levels of metalloproteinase

- Levels of NO
- Levels of endothelin
- Levels of PT complex
- Carotid intimal thickness
- Carotid intimal diameter

Mx:

Good glycemic control

Involvement of insulin
Mesenteric angina laparotomy and thrombolysis, if mesenteric angina alone then papavarin if no
Intestinal obstruction.
Pentoxyphyllin : to dec. cytokine release
Cilastazol:- PLT aggregation inhibitor
Also give clopidogrel and ticlodipine
PET scan :- vasovasorum obliterans  cardiac X syndrome
ACEIs and cilastozol to reduce mortality of diabetes
Statin:- underlying foundation of Mx.
Amputation may also be required
 DIABETIC NEPHROPATHY
status normal Impaired glucose DM
tolerance
FPG <100mg 100-125mg > 126 mg
< 5.4 mmol 5.4-6.9 mmol > 7.0
2 hr glucose < 140 mg 140-160 mg > 200 mg
6.0 mmol 6.0-10.9 mmol > 11.0 mmol
Hb A1c < 5.6 5.6 - 6.3 > 6.4

Papillary necrosis

Microalbuminuria (30-300 mg protein loss/day)

Nephrotic syndrome

Kimmelstei l Wilson syndrome

Renovascular HTN

Acute renal failure

PATHOGENESIS OF D. NEPHROPATHY

- Hyper filtration of glomeruli , inc. extracellular matric production

- Extra deposition of collagen
- Mesengial destruction
- T cell induced cytokine production leading to kimmel steil Wilson nodule
- Malignant hyperplasic hyaline areteriiosclerosis
- Microvasculopathy- papillary necrosis
- Immune complex formation leading to membrane glomerulonephritis.

Type 2, 3, 4 HS damaging the interstitium and JG cells leading to RTA type 4.

Renin damaged  hyperaldosteronism , hyporenemia

Inc. D. nephropathy vit D is not activated so pt is in a state of ostemalacia and rickets  give vit D inj.

Erythropoietin cells damage anemic pic (anemia of chronic disease)

Inc. absorption of A.A and glucose from the PCT.

In diabetes proteinuria and glycosuria are present byt proteinuria is more than glycosuria.

Hepatic gluconeogenesis and glycogenolysis is disturbed.

No single dipstick for diagnosis.

At least 3 samples taken  D. proteinuria

- pt will have polyuria , polyphagia and polydipsia.

- INV:-
- BI:- fasting glucose > 140
- Random glucose >180

MA:-

Oral glucose tolerance

ADDITIONAL :-

Hb A1c >7

Retinoscopy - LDL

Total cholesterol - TG

Urine microscopy - 24 hrs urinary protein

ECG - Nerve conduction

24 hrs creatinine clearance - BUN

C-peptide dec. in type 1 - Normal in type 2.

Retinal scan and immunosorbent assay

Cause of death :- renal failure

HYPER OSMOLAR NONKETOTOIC COMA (HONK)

Etiology

Type 2 DM

Precipitating factors

Failure to take sulfonylurea/metformin

Pneumonia

Surgery

Stress
Meningitis

Burns

Dialysis

Tube feeding of proteins and CHO

C/F:-

Confusion - seizures

Polyuria - UTI

fits - stroke

coma -SIADH

no ketosis -pul. edema

profound dehydration -cellulitis

hyperglycemia and inc. serum osmolarity in absence of ketones and acidosis

can be

with lactic acidosis

plasma osm > 40 , glucose 1000, high anion gap

without lactic acidosis

plasma osm >400 , glucose 1000, normal anion gap

INV:-

blood glucose 600 – 1000mg

Na+ =130 – 135mg

Corrected Na has to be applied here

For every 100mg of glucose 1.6mEq of Na will be added if glucose is above 200mg.

calculate plasma osm >400 mOsm

MX:-

- admit the pt
- monitor urine + CHO
 - I/V insulin
- Antibiotic
- Give prophylaxis for anemia , infections and also monitor
- Pt of myxedema coma in tyoe 2 DM with (hashimoto thyroiditis , thyroidectomy) mx the thyroxin.
- Need 3L of saline (0.9 %) with 0.1 IU/kg INSULIN in check glucose reduced or not .
- If not reduced then keep insulin the same and inc. the saline (0.4 – 0.5%)
- For every 50gm of glucose needs 0.5 IU/kg of insulin.

HYPOGLYCEMIA
Status Pre-pro insulin C- Aniti Sulfa
insulin peptide insulin compounds
AB
sulfonylurea N - N- N- +
factitious Dec. Inc. Dec. +
insulinoma Inc. Inc. Inc.
Ectopic Inc. Inc (+/-)
insulin

Insulinoma

Factitious hypoglycemia

Sulfonylurea induced hypoglycemia

Non insulinoma induced pancreatic hypoglycemia

Autoimmune hypoglycemia

Insulin stimulating autoantibody induced hypoglycemia

Insulinoma

Benign insulin producing tumour of pancrease

INSULINOMA

Benign insulin producing tumour of pancreas

Rarely it’s an isolated tumour
Part of MEN -1 along with ZES
If ectopic producing then following sites
- Hepatic cell ca
- Renal cell ca
- Esophageal ca
- Fibrosarcoma
- Carcinoid tumour
- Small cell lung cancer
INV:-
- Inc pro insulin
- Inc. pre-pro insulin
- Serum insulin
- Inc. signal peptidase
- Inc. C-peptide
- Blood glucose level
- PET scan
- Urine glucose
Mx:-
Admit pt
Keep NPO
Do somatostatin challenge test
Exclude ectopic insulin production.

HYPOGLYCEMIA:-

- Blood glucose controlled by counter regulatory hormones(GH, EPI, N.EPI, Glucagon, thyroxin)
- Dec by insulin
- Blood glucose (BG) fall 80 or below neurogenic symptoms start ( sweating , tachycardia, hunger )
- If 60 or below  neuroglycopenic symptoms begin( in addition to neurogenic symptoms seizures ,
fatigue, coma, tiredness, confusion)
- If BG <45  degenerative changes and death may follow
- Pt of HALF (hypoglycemia adrenergic latency failure):- if pt with BG < 60 has fits comes to ER but
there is no tachycardia , sweating, hunger (can be alcohol and obese is half syn)
- Hypoglycemia unawareness :- B-blocker is contraindicated in diabetes or fluctuating glucose.

ETIOLOGY MEN TYPE 1

ASSOCIATION :- prolactinoma

Parathyroid adenoma

C/F:-

Hypoglycemia

Vertigo

Sweating
Loss of consciousness

INV:-

Whenever hypoglycemia check ketone body

- B-OH butyrate
- Transhepatic and hepatic glucose
- Trans hepatic and hepatc insulin production
- PET scan for pancreas and liver
- IIGF
- 72 hr fasting hypoglycemia test
- Adrenal cortical hormones
- Pancreatic hormones
- Pro-insulin level
- Pre –pro insulin level
- Insulin inc.
- C-peptide inc.
- Anti insulin ab

MX:-

For hypoglycemia correction minimum 25mg/hr glucose

1mg/min= 60mg /hr

If not correcting then loading dose inc. the glucose 25mg/hr or 1mg/min

Emergency I/V glucose

I/V glucagon

CRITERIA FOR INSULINOMA:-

Insulin >6 micro units

Proinsulin 40 mg

c-peptide > 5 pico moles

FACTITIOUS HYPOGLYCEMIA
1. Malingering
2. Maunchusen syndrome
3. Munchusen syndrome by proxy
4. Doctors, pharmacists, nurses
C/F:-

Injection marks

Hypoglycemia

Sweating

Vertigo

INV:-

Endogenous insulin decreased

Dec. C-peptide

Auto antibody against exogenous insulin inc.

Glucose dec. (< 60mg)

Pro –insulin dec.

U/S and CT pancreas is normal

Confirmation by anti insulin antibody positive

MA:-

72 hr supervised fasting hypoglycemia

PET scan

Resection

High calorie low caffeine intake

AUTOIMMUNE HYPOGLYCEMIA

1. RA
2. POLYMYOSITIS
3. SLE

INSULIN STIMULATING AUTOANTIBODY INDUCED HYPOGLYCEMIA

1. Graves disease.

NEW CRITERIA FOR D/M :-

Hba1C > 6.5
Fasting blood glucose > 126 mg/dl on two occasions
Random blood glucose > 200 mg/dl at 2hrs after OGT (diagnostic)

MANAGEMENT:-

 Laser photocoagulation for retinopalsty

 Pneumoplexy for retinal detachment
 Metachlorpromide / erythromycin for gastroparesis
 Gabapentin/ pregabalin for neurpathic pan , neuropathic foot or any other neuropathy
 ACEI for microalbuminuia + nepghrotic syndrome
 Statin for hyperlipidemia
 Capsacin for diabetic foot
 Sildenafil for erectile dysfunction

GENERAL MANGEMENT:-

 Type 1 (0.5%) unit/kg of insulin

 Calculate the dose give 2/3rd in morning (2/3 NPH , 1/3 regular)
 1/3 in evening (1/2 NPH, ½ REGULAR)

Dose adjustment:-

 If CHO too high inc. the evening dose of long acting

 If morning CHO too low reduce the evening long acting
 If evening CHO too high increase the morning dose
 If evening CHO too low dec. morning dose

Type 2

- Normal weight : sulfonylurea

- If obese : give metformin
- If any refractory : metformin + sulfonylurea
- If still refractory rosiglitazone
- Nowadays type 2 is managed by metformin + exanetide
- If cardiac failure , renal failure , and hepatic failure than stop the above
- Now give insulin
- In emergency situations , if patient suddenly develops MI stop medications and give I/V insulin
infusion
- For itinerant : ultra-long acting galargine , single dose a day
- But these patients may require 2-3 doses of lispro daily
- Foot care
- Change the life
Pharmacological pointers:-

INCREINS:- these include exanetide and praxitide and sitagliptin. These drugs are GLP agonists. These
promote release of GLP on oral consumption of food and promote insulin release.
- In type 2 DM , GLP is dec. therefore, these drugs act as GLP and promote insulin release.
- Exentide always given with metformin
- Pramlinitide act as GIP decreases stomach peristalsis and inhibits release of glucagon and dec.
blood
- Sitagliptin: these are DDP4 antagonists and therefore dec. catabolism of GLP certain other drugs
reduce glucose absorption and promote weight loss. Therefore and ideal drug for obese can be :
- ACARBOSE  glucosidase inhibitor
- ORLISTAT REDUCES FAT ABSORPTION
- EXUBERA inhalational insulin used for diabetes but not with poisoning results
- Insulin detimir is a latest insulin analogue with tyrosine residues given in pregnancy
- Other insulin analogues are galargine – glycine and arginine containing and ultra long acting
- Lispro : proline containing ultra-short acting
- Aspart : aspartic acid containing ultra-short acting
- Detemir : tyrosine containing –17 hrs duration therefore twice daily therapy is needed
- Renoprotective is affected by ACEI’s in type 1 and ARB’s in type 2
- Sulfonylurea may cause hypoglycemia unawareness and used to sudden collapse
- B-blockers can also trigger hypoglycemia unawareness and therefore contraindicated in diabetes
- Hypertensive in diabetes are helped by ACEI or alpha – blocker
- Regular foot care , laced up shoes and antifungal prophylaxis is most needed
- Long term injectable – only insulin
- Human placental transplant and human islet transplant for the management of diabetes.

CALCULATION OF INSULIN DOSES

1 unit of insulin  10- 50 g of glucose
60 g (sugar after food)  1 unit or 1.2 unit of insulin
For Body wt :
Body wt = Ibs = Ibs ÷ 4
Or
Body wt = kg = 0.55 × kg

INSULIN IN PREGNANCY
This rule is applied for pregnancy

17 week 0.7 IU/kg

24 week 0.8 IU/kg
33 week 1.2 IU/kg
33 – 38 week 2.2 IU/kg

MEAL CORRECTION INSULIN

1unit covers = 60mg
6 unit covers = 360 mg

Ideal is 120 BG
Pt is with 220
So, 220 – 120 = 100 needs 2 units
6+2 = 8.
PRE MEAL CORRECTION
6 + 2 = 8 units
40 units out of which 20 units is basal

Day coverage :-
1 : 8 --- breakfast
1 : 15 --- lunch
1 : 12 --- dinner

INSULIN FOR TYPE 2 DM

 Galargine ONCE daily (OD)

 Aspart and lispro before meal (breakfast, lunch , dinner)
 Glulysine is not given in type 2 DM

2nd approach :-

 3 doses of NPH … each before breakfast, lunch and dinner

 AND
 1 large dose of NPH at bed time.

SLIDING SCALE INSULIN

 Usually adopted for type 1 DM

 Can also be applied in MODY , type 2 DM , double diabetes.

 Once daily long acting insulin

+
regular insulin and NPH (twice a day)

 Or

 Regular + NPH (twice a day )

 With mixed short acting

 Or
  Long acting once a day
 Short acting (1 before meal)
 1 at bed time

INSULIN DOSE ADJUSTMENT IN PREGNANCY

LATEST APPROACH:-
- Calculate insulin dose
- Give 10 units at night
- And rest divided in two dosage in morning and evening

NEW APPROACH:-
- 10 units at night
- 6 units in day – divided into 2 doses.
- At night given is galargine
- At day given is lispro + regular

OLD APPROACH:-
- Calculate the dose 2/3 in morning (NPH and regular) in morning, 1/3 in evening (half NPH and half
regular).