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Diabetes Mellitus

Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action.

Type 1 DM Beta cell destruction, usually leading to absolute insulin deficiency
A. Immune Mediated (90%)
B. Idiopathic (10%)
Type 2 DM May range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance
Others
 
A. Genetic defects of beta cell function
B. Genetic defects in insulin action
C. Diseases of the exocrine pancreas
D. Endocrinopathies
E. Infections
F. Drug- or chemical-induced
H. Other genetic syndromes sometimes associated with diabetes
Type 4 DM Gestational Diabetes Mellitus


Insulins

  1. 51 amino acid peptide; discovered by Benting and Best in 1920.
  2. Synthesized as a preprohormone: neither prohormone nor C peptide synthesied during process has any hypoglycemic activity
  3. C-peptide assay is being used as a secretogogue activity of pancreas
  4. Two main animal sources:
     
    i.  Bovine        
     
    ii. Porcine
  5. Bovine differs in 3 amino acids
  6. Porcine differs only in 1 amino acid (More related physiologically) 

MAO

  1. Binds to autophosphorylation receptors; also called tyrosine kinase receptors
  2. Increased expression of GLUT-1 & GLUT-4 occurs 

Actions

  1. Inhibits gluconeogenesis and stimulates glycolysis
  2. Inhibits glycogenolysis and stimulates lipogenesis
  3. Increases TAG synthesis; hence increases fat deposition
  4. Increased protein synthesis occurs 

P/K

  1. Short acting molecule                                      
  2. Half life=5-10 minutes
  3. Physiologically, it is complexed as hexamer              
  4. Rapidly acting insulins are monomers
  5. Insulins are formulated in zinc          
    1. Endogenous zinc is important for storage  
    2. Exogenous zinc is important for increasing shelf-life
  6. Metabolised by insulinase enzyme
    1. Hepatic inactivation in case of endogenous       
    2. Renal inactivation in case of exogenous insulin 

Types of insulins and duration of actions
 

Ultra short acting (1-2 hours) a. Insulin lispro  b. Insulin lysine c. Insulin aspart
Short acting (2-4 hours)  a. Regular insulin (only insulin given IV)  
Intermediate (4-8 hours) a. Neutral Protamine Hagedron b. Semi lente
Long acting (8-16 hours) a. Lente b. Protamine Zinc Insulin
Detemir (insulin+ fatty acid complex)    
Longest (16-32 hours) a. Insulin glarzine  

 
 

  Appearance
 
Added proteins Zinc
 
Buffer Onset (hrs) Peak
(hrs)
Duration
(hrs)
Lispro Clear - + Phosphate 0.25 1.5 5
Aspart Clear - + Phosphate 0.25 1 5
Glulisine Clear - None - - 1.5 5
Regular Clear - + - 0.5 4 8
NPH (Isophane) Cloudy Protamine + Phosphate 1-2 6-12 18-24
Lente Cloudy - + Acetate 1-2 6-12 18-24
Ultralente Cloudy - + Acetate 4-6 16-18 20-36
Protamine zinc Cloudy Protamine + Phosphate 4-6 14-20 24-36
Glargine Clear - + - 2-5 - 18-24
Detemir Clear - + Phosphate 1-2 4-14 6-24


*Most insulin preparations are supplied at pH 7.2–7.4 (basic).
* Except Glargine and Detemir are supplied at a pH of 4.0 (acidic), hence are Not Combined with other preparations.

Insulin indications

  1. Type-1 diabetes                                       
  2. Maturity onset diabetes of young (MODY)
  3. Infections, trauma and surgery in diabetes               
  4. Sulfonylureas resistance
  5. Late cases of type-2 diabetes                           
  6. Diabetes in pregnancy
  7. Hyperkalemia       

Side effects

  1. Hypoglycemia is MC side effect                
  2. Weight gain occurs
  3. Hypokalemia                                   
  4. Lipodystrophy occurs with human insulin
  5. Anaphylaxis: very rare (IGE mediated)            
  6. Resistance: (IgG mediated)  





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