Biochemistry of diabetes mellitus

1. DIABETES MELLITUS

2. • Definition of diabetes
• Types of diabetes
• Metabolic derangements in diabetes
• Clinical presentations
• Acute & chronic complications of
diabetes
• Laboratory investigations
• Management

3. • Diabetes mellitus is metabolic cum vascular
syndrome of multiple etiology characterized by
chronic hyperglycemia with disturbance of
carbohydrate, fat & protein metabolism
• May be due to defect in insulin secretion ,
insulin action or both.
• Leading to changes in small blood
vessels(microangiopathy) & large
blood vessels(macroangiopathy)

4. • DM is disease known from very ancient times
• Charaka (400 BC) : elaborate clinical description of
Madhumeha
• 1670: Thomas willis noticed sweet taste of Diabeticurine
• 1848: Fehling discovered qualitative test for urinesugar
• 1908: Benedict discovered reagent for semi-quantitativetest for urine
sugar
• 1919: Folin identified quantitative method fordetermination of blood
glucose

5. • Worldwide, more than 425 million adults sufferfrom Diabetes.
• T2DM comprises 85-95% of all cases of DM
• Occurs even in non obese people. Occasionally seenin children
also
• More prone to develop cardiovasculardisease
• Top 5 countries : China, India, USA, Brazil, Mexico
• In India T2DM occurs a decade earlier than in thewest

6. As per American DiabetesAssociation(ADA)
1. HbA1C > 6.5%
2. FPG > 126 mg/dL
3. 2 hrs PP > 200 mg/dL
4. If both fasting & 2 hr values are above normalon same
occasion
5. Random plasma glucose > 200 mg/dL on 2 occasions

7. 4 main types
1.Type 1 Diabetes Mellitus: β- cell destruction, usually leading to absolute
insulin deficiency)
a. Immune mediated
b. Idiopathic
2. Type 2 Diabetes Mellitus : may range from predominant IR with
relative insulin deficiency to a predominant secretory defect with IR)
3. Other specific types:
a. MODY
b. Endocrinopathies: Cushing’s, Thyrotoxicosis,Acromegaly
c. Drug or chemical induced: steroids, β- blockers,etc
d. Pancreatic diseases: FCPD, chronic pancreatitis, cystic fibrosis.
4. Gestational diabetes mellitus (GDM)

8. • Absolute insulin deficiency due to destruction of β-cells
• Patient depends on insulin injection for survival &health
Epidemiology
5 – 10% of all individuals with diabetes haveT1DM
Onset at childhood / adolescence (usually <30 yrs of age)
Symptoms
Abrupt onset of severe symptoms
May present with DKA
Antibodies
Anti-insulinAb
Anti islet cellAb

9. TYPE 2 DIABETES MELLITUS
• About 60% of patients are obese
• They have high plasma insulinlevels.

11. Ask for symptoms of Diabetes
Polyuria
Polydipsia (Thirsty)
Polyphagia (Hunger)
Weight loss
Delayed wound healing
Tiredness
Itching especially in the genitalarea
Tingling & numbness
Visual disturbances
>60% of the patients do not have anysymptoms

12. • Previous treatment & outcomes
• Present treatment
• Drug allergy/ intolerance
• H/O Hospitalisation
• H/O hypoglycemia, DKA, HHS (Hyperosmolar
hyperglycemic state), Acute coronary event,
Cerebrovascular event

13. • Height, weight, BMI, waist circumference, hipcircumference, W/H
ratio
• BP, including postural variation if needed (lying , sitting & standing)
• Examination of abdomen
• Thyroid examination
• Skin examination for acanthosis nigricans, skin tags &insulin injection
site inspection (if on insulin)
• Dilated retinal (fundus) examination
• Dental examination

14. Comprehensive foot examination
• Inspection
• Palpation of dorsalis pedis & posterior tibial pulses
• Ankle brachial index
• Ankle & knee jerks
• Proprioception, vibration & monofilament testing

15. Metabolic derangements in
Diabetes

16. 1. Diabetic ketoacidosis (DKA)
• Most common in T1DM
• FFAbreakdown  more acetyl-CoAavailable but it cannot be
efficiently oxidized by TCA cycle, because of limited availability of
oxaloacetate.
• The excess acetyl-CoA, is diverted to ketonebodies
production , leading to ketonemia & ketonuria
• Normally the ketone bodies level in blood is <1mg/dL,only traces
excreted in urine
• But when the rate of synthesis exceeds the abilityof
extrahepatic tissues to utilize them accumulation
• Ketosis: Ketonemia, Ketonuria, Acetone smell inbreath

17. Diagnosis:
• Rothera’s test: saturate 5 ml of urine with solidammonium
sulfate  few drops of freshly prepared sodium nitroprusside
 2ml of liquid ammonia along the sides of the test tube 
purple ring  presence of ketone bodies in urine.
Supportive evidence:
• Estimation of serum electrolytes
• ABG
• Glucose estimation

18. • Metabolic acidosis: Acetoacetate & β hydroxybutyrate are
acids. When they accumulate  Metabolic acidosis. There
will be increased anion gap
• Reduced buffers: the plasma bicarbonate is used forbuffering
these acids
• Kussmaul’s respiration: Acidotic breathing due to
compensatory hyperventilation
• Smell of acetone in breath
• Osmotic diuresis: induced by ketonuria dehydration
• Sodium loss: ketone bodies are excreted in urine astheir
sodium salt

19. • High potassium: due to lowered uptake of potassium
by cells with the absence of insulin
• Dehydration: The sodium loss further aggravates
the dehydration
• Coma

20. • IV insulin infusion
• IV bicarbonate to correct acidosis
• IV saline to correct sodium & waterimbalance
• IV potassium infusion: With insulin infusion, more potassium
moves from ECF to ICF  Hypokalemia. Potassium infusion
should be started along withinsulin infusion.

21. HHS: Hyperosmolar hyperglycemic state
• Marked hyperglycemia (extremely high)
• Profound dehydration
• High plasma osmolarity
• Normal pH
• Severe CNS obtundation: stupor, coma, convulsions
• Focal neurological sign : hemisensory deficits,hemiparesis, aphasia &
seizures
• Ketonemia, ketonuria & metabolic acidosis absent
• Typically presents in elderly T2DM patients withother significant
comorbidities

22. • Plasma glucose: usually much higher than DKA
• Plasma osmolarity : > 320mosm/L
• Serum pH : Normal or only slightly reduced
• Serum Bicarbonate: > 15 mEq/L
• Urine & serum ketones: Negative
• Serum sodium & potassium : Decreased

23. • Patient needs immediate hospitalization
• Primary treatment goal: To correct hyperosmolar state &
dehydration
• Adequate fluid replacement insulin therapy: same asDKA
• Potassium replacement: same as DKA
• Bicarbonate replacement : not necessary

24. 3. Lactic acidosis
• Relatively rare complication of diabetes
• In earlier days, it was seen in patients treatedwith Biguanides
(Tolbutamide)
• The newer preparation Metformin do not have thiseffect
• Due to overproduction and/or underutilization of lacticacid
• Another important cause of lactic acidosis:Excessive alcohol
consumption

25. • Hypoglycemia is defines as a clinical state with low plasma glucose
levels usually associated with signs & symptoms of autonomic
hyperactivity & neuroglycopenia.
• ADA : Plasma glucose < 54 mg/dL
Plasma glucose < 70 mg/dL (alert value)
• Common side effect of treatment with insulin & sulfonylurea drug
• The neural tissue requires continuous supply ofglucose
• If this supply is interrupted even for few minutes CNS
dysfunction, impaired cognition & coma.
• Thus avoidance of hypoglycemia is a very crucial factor in the
management of Diabetes.

26. Sympathetic
Faintness
Weakness
Pallor
Nervousness
Irritability
Palpitations
Tachycardia
Diaphoresis
Hunger
Neuroglycopenic symptoms
Blurred vision
Diplopia
Headache
Inability to concentrate
Confusion
Motor incoordination
Sensory dysfunction
Seizures
Coma

27.  Excessive dosage
Error by doctor, patient or
pharmacist
Poor matching to patient’s
needs or lifestyle
Deliberate overdose
 Increased bioavailability
Accelerated absorption
Renal failure (reduced
insulin clearance)
Other factors
Exercise
Alcohol: inhibits
hepatic glucose
production
Drugs: Sulfonylureas,
non- selective β blockers,
etc

28. Hypoglycemia- Treatment
If patient is conscious
• Oral carbohydrate: Sugar, Candy, Orange juice, Glucose
• Check blood glucose 15-20 minutes. Confirm recovery
• After recovery : identify cause, re-educate, take measures to avoid
hypoglycemia
If patient unconscious
• IV Glucose : 100 mL of 25% solution
• Glucagon 1 mg S.C or IM injection
• Check blood glucose 15-20 minutes. Confirm recovery
• If not recovered  IV 5% or 10% glucose
• After recovery : identify cause, re-educate, take measures to avoid
hypoglycemia

29. Prevention strategies for hypoglycemia
• Regularity of diet, insulin & exercise
• Between- meal & bedtime snacks
• Regular blood glucose testing
• Keeping sugar, candy or glucose tablets handy at alltimes
• Education regarding subtle changes of hypoglycemia
• Identification card
• Use of analog insulin

30. • Maturity onset diabetes of young
• Mutation in single gene – monogenicdiabetes
• Presents during childhood & adolescence
• Defective insulin secretion of betacell
• Diagnosis : Genetic testing (Gold standard but veryexpensive)
3.MODY

31. 4. Gestational Diabetes Mellitus (GDM)
Gestational Diabetes mellitus (GDM) is defined as any degree of impaired
glucose tolerance of with onset or first recognition during pregnancy.
Many are denovo pregnancy induced
some are type 2(35-40%)
10 % have antibodies
Risk factors: Race, PCOS,FH of Diabetes, Obesity, Age older than
25years,persisitant glucosuria.

32. Vascular diseases: Macro & Micro angiopathies
 Macroangiopathies
• Atherosclerosis  plaque formation  intravascularthrombosis
• In coronary artery: Myocardial infarction
• In cerebral vessels: Paralysis
• Eyes: Retinopathy
 Microangiopathy
• Endothelial & mural cells are damaged.
• Microangiopathy  Diabetic retinopathy &Nephropathy

33. Complications in eyes
• Hyperglycemia  increased rate of sorbitol formation 
Cataract of lens
• Retinal microvascular abnormalities  Retinopathy & Blindness
Neuropathy
• Peripheral neuropathy with paresthesia is verycommon
• Causes: increases sorbitol accumulation in schwann cells& production
ofAGE’s (Advanced Glycation End products)
• Leads to foot ulcer & gangrene

34. Laboratory investigations
• FBS, PPBS
• HbA1C
• Fasting lipid profile
• Urea
• Creatinine
• Urine microalbumin
• LFT
• TFT
• Chest X ray, ECG, ECHO
• Dilated retinal examination
• Foot examination

35. Glycated Hemoglobin (HbA1c)
• Best index for long-term control of bloodglucose
• Glycosylation: enzymatic addition of any sugar to aprotein
• Glycation : Non-enzymatic process
• In hyperglycemia, proteins in the body undergo glycation
• Once attached, Glucose will not be removed from theHb
• It remains inside the RBC, throughout its life span(120days)

36. • Reveals mean glucose level over the previous 10-12weeks
• Unaffected by recent food intake or change inblood
glucose level
• Expressed as fraction of total Hb
• Normal
• Impaired
• DM
• Good control
• Adequate control
• Inadequate control
• Poor control
: <5.5%
: 5.6 – 6.4%
: > 6.5%
: 6.0%
: 7%
: 8%
: > 9%

37. 4 testing methods currently available
 HPLC assay : Gold standard
Ab- based latex enhanced immunoassay
Enzyme based enzymatic assay
Ion exchange chromatography
• No fasting required
• Low intra individual variability
• Values not altered by acute factors
• Reflects long term glucosecontrol
• Better index for predicting complications

38. Diet & Exercise
• First line
• Diet should be tailored to each patient
• Balanced diet with high protein, low calories, devoid of
saturated fat & refined sugars with adequate PUFA,fiber
• Vegetables: major source of minerals, vitamins & fiber
• Exercise of minimum 150 minutes per week or more
• Brisk walking with strengthening exercises

39. Oral Hypoglycemic agents
• Biguanide: Metformin
• Insulin secretagogues: Sulfonylureas- Glipizide, Glimepiride, etc
• Insulin secretagogues: Meglitinides- Repaglinide, Nateglinide
• Thiazolidinediones: Pioglitazone
• Alpha glucosidase inhibitor: Acarbose,Voglibose
• DPP4 inhibitors: Sitagliptin, Vidagliptin,Linagliptin
• SGLT2 inhibitors: Dapagliflozin, Canagliflozin
• Incretin mimetics: Liraglutide, Dulaglutide

40. Management of Diabetes
Insulin replacement therapy
 Rapidly acting Insulin
Absorbed quickly from SC
tissue
Insulin Aspart, Lispro,
Glulisine
Onset of action: 5-15
minutes
Peak: 2-4 hrs
DOA: 4-6 hrs
 Short acting Insulin
Regular human insulin
Peak: 2-4 hrs
DOA: 6-8 hrs
 Long acting Insulin
Insulin Glargine, Detemir
DOA: 12 – 24 hrs

41. Thank you…