Insulin

Physiology

• Insulin increases energy stores
  • Liver
    • Promotes anabolic synthesis of glycogen, TG, cholesterol, VLDL, and protein in liver.
    • Inhibits breakdown of hepatic glycogen and gluconeogenesis - controling overnight hepatic glucose production.
  • Muscles:
    • Enhances ribosomal protein synthesis, increases amino acid transport.
    • Increases glucose transport into muscle, Enhances activity of glycogen synthase, inhibits glycogen phosphorylase.  -> muscle glycogen synthesis.
  • Adipose:
    • Promotes TG storage in adipocytes.
    • Increases glucose transport into fat cells.
    • Enahances lipoprotein lipase activity, inhibits lipolysis.
• Terminology:
  • Insulin-To-Carb Ratio
    • Used by Type I DM patients to determine insulin requirements for each meal
    • ICR = 500 / TotalDailyInsulin
    • Example:  70kg male, requires 70*0.7=49 u/day.  ITC = 500 / 49 = 10 (1 unit of Insulin will cover 10g of carbs)
  • Insulin Sensitivity Factor
    • 100 / TotalDailyInsulin = ISF
    • Can be used to calculate insulin corrections
    • (CurrentGlucose - Target Glucose) / ISF = Units of Insulin Required
    • Example:
      • (i.e. 70kg male requires 70*0.7 = 49 u/day.  ISF =100/49 =2.0)
      • If current BG is 12, targets 7.  Then:  (12 - 7)/2.0 =2.5 units to correct to 7 mmol/L glucose

Benefits of Insulin

Type I - Diabetes control and complications trial (DCCT): 

• Multi-center, randomized controlled trial
• MDI or continuous SC insulin infusion (Intensive Therapy) vs. 1-2 daily injections (conventional)
  • Intensive therapy: LOWER Microvascular complications
    • Lower HbA1c, RRR 76% for retinopathy, 39% RRR for microalbuminuria, 64% RRR of neuropathy, and 40% RRR of developing high LDL (also decreases progression).
  • Benefit of macrovascular complications there, but not statistically significant.
• ​Meta analysis: Other studies: decreases macrovascular complications

Type II - United Kingdom Prospective Diabetes Trial (UKPDS)

• Multicenter randomized controlled study
  • Whether intensive BG control affects microvascular and macrovascular end-points.
  • 12% reduction of DMII endpoints, 25% reduction in microvascular end-points
  • No difference WITHIN intensive therapy group (i.e. sulfonylureas vs. insulin).
  • Macrovascular complications: Non-statistically significant drop in 16%

Diabetes Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) Trial

• Insulin therapy after MI decreases all-cause mortality by 58%

Risks of Insulin

• MAIN RISKS:
  • Weight Gain
  • Hypoglycemia
• Insulin risks in Type I Diabetes: (DCCT trial)
  • Hypoglycemia (inversely related to HbA1c)
  • Weight Gain
  • Rarely: Allergy and Infection
• Insulin Risks in Type II Diabetes (UKPDS)
  • Same as DMI -
    • hypoglycemia (less than in DMI)
    • weight gain (significant - 4kg wt increase UKPDS P<0.001)
    • allergy
    • infection.
  • Long-standing debate about causing atherosclerosis (but it's association rather than causation - insulin resistance causing hyperinsulinemia).

Types of Insulin

• For 50 years - only available as bovine or porcine preparations.
• 1980's: human insulins and analogues, and animal insulins became obsolete.

• Insulin forms hexamers in solution, once injected, they dissociate.  Rapid acting insulins, dissociate faster, causing more rapid

  absorption.

   

Class	Name	Numbers	Comments
Very Rapid Acting	Lispro (Humalog) [1996]	Onset: 10-15min Peak: 1-1.5h Duration: 4-5h	- First VRA Insulin - Lower postprandial glucose and less hypoglycemia compared to regular Insulin - No difference in HbA1c (vs. reg. insulin).
	Aspart (Novorapid, Novolog) [2000]		- NEWER THAN Lispro - No difference in hypoglycemia comp to regular insulin - Lower HbA1c in Type I DM, and no diff in Type II DM.
	Glulistine (Apidra) [2004)
Short Acting	Regular Human (Humulin R, Novolin R) [1982]	Onset: 15-60min Peak: 2-4hrs Duration: 5-8h	- Slow rate of absorption from SC space, cannot mimic physiologic post-prandial insulin. - If using for post-prandial, give 30-45min before a meal.
Intermediate Acting	Insulin NPH (Humulin N, Novolin N) - Neutral Protamine Hagedorn [1982]	Onset: 2.5-3h Peak: 5-7h Duration: 13-16h	- NOT for post-prandial control - Effective for lowering fasting and pre-dinner glucose
	Lente	Onset: 2.5h Peak: 7-12hrs Duration: 18hrs
Long-Acting	Ultralente	Onset: 4hrs Peak: 8-10hrs Duration: 20hrs	- HUMAN long-acting insulin - RARELY USED
	Glargine (Lantus)	Onset: 1.5-2hr Peak: None Duration: Up to 24 hrs	Advantages: - No insulin peaks (unlike human long-acting) - Less nocturnal hypoglycemia - Slower absorption - Prolongued duration (higher isoelectric point) - Lower pH (CANNOT MIX WITH OTHER INSULINS)
	Detemir (Levemir)

• Combinations;
  • Humulin 70/30 - Insulin Regular and NPH Insulin
  • Humalog Mix 75/25 or 50/50 - Insulin lispro protamine and insulin lispro
  • Novolog Mix 70/30 - Insulin aspart protamine and insulin aspart

Insulin Dosing

1. First figure out how much insulin needed (TDI = total daily insulin):
   • If person is on insulin: Use home insulin requirement, add up all the insulins during the day.
     OR
   • Newly diagnosed type 1 diabetes,start with 0.3 units/kg/day.  Over time,most patients with type 1 diabetes require 0.7 unit/kg/day.  Some patients with type 1 diabetes and obesity develop insulin resistance and may require > 0.7 units/kg/day.  
   •  
2. Determine Regimen
   • Multiple Daily Insulin (MDI) Dosing (aka Basal-Bolus Regimen)
     • Advantage: Excellent glycemic control.
     •  
     • After calculating total daily dose of insulin
     • Give 1/2 as basal insulin (i.e., glargine at bedtime)
     • Give remaining 1/2 divided by 3 before each meal
     •  
     • teach patient how to adjust insulin based on blood glucose readings before each meal
     •  
     •  
   • 
     
     • Ideally teach patient how to perform carbohydrate counting for the meal time insulin
     • To calculate 500 divided by TDD = 1 unit for ____ grams of carbohydrate
     •  
     • Also teach them how to calculate a correction bolus
     • To calculate insulin sensitivyt factor:  100 divided by TDD
   •  
     • Patient takes current blood glucose - minus target glucose (typically 7 mmol/L) divide by your insulin sensitivity factor
     •  
     • 
       
       • Also calculat
         • 1 (prandial breakfast) : 1 (prandial lunch) : 1 (prandial supper) : 2 (basal bedtime)
         • 8 : 8 : 8 : 16
         • Can add supplemental insulin:   (measure insulin TID before meals for hyperglycemia)

           • Before Meal (glucose)	LOW DOSE (< 50u daily)	HIGH DOSE (> 50u daily)
             8.1-10	0 units	2 units
             10.1-12	1 units	4 units
             12.1-14	2 units	6 units
             14.1-16	3 units	8 units
             >16	4 units	10 units

       • Example regimen #2:
         • 50% Basal (i.e. 20U)
         • 50% Bolus (i.e. 20U)
       • Example regimen #3:
         • 60% daytime bolus ( 1/3 for each of the 3 meals) (lantus = better due to pharmacokinetics)
         • 40% bedtime basal long acting (glargine, detemir)
            
       • Basal Insulin Only
         • Advanage: Once/day injection, easy to administer, cheap.
         • Disadvantage: No mealtime adjustments.  Only useful for early insulin-dependent TIIDM
         • All TDI given as evening Lantus or Detemir insulin 
            
       • Fixed Split/Premixed
         • Advantages: less injections.
         • Disadvantages: not recommended for Type I DM due to poor control.
            
       • Continuous Subcutaneous Insulin Infusion (CSII)
         • Advantages: Recommended for TIDM, Excellent glycemic control.
         • Disadvantages: Requires a device, risk of hyperglycemia due to catheter blockage.
            
       • Sliding Scale
         • A scale that allows pre-defined insulin doses given based on the measured glucose levels.
         • OBSOLETE, DO NOT USE
         • Advantages: NONE (Less pages overnight)
         • Disadvantages:
           • Triples rate of hyperglycemia (Queale et al 1997)
           • Increases incidence of sepsis, admission to ICU(McMaster Study in pts with pneumonia)
           • Increases incidence of infection (RABBIT 2 trial)
           • No difference in hypoglycemia rates compared to basal-bolus insulin regimen (RABBIT 2 trial)
              
       • Regimen "Three-Times-a-Day Dosing"
         • No longer used due to newer "Lantus" release which can be given once at bedtime.
           Total Daily Insulin (TDI)

         • 	Before Breakfast	Before Dinner	Bedtime
           Total Daily Insulin (TDI)	Breakfast Dose = 2/3 of TDI	Evening Dose: 1/3 of TDI
           NPH Insulin	2/3 of Breakfast Dose	NONE	2/3 of Evening Dose
           Mealtime Insulin	1/3 of Breakfast Dose	1/3 of Evening Dose	None

         • Adjust basal NPH before breakfast --> based on afternoon glucose (before dinner)
         • Adjust basal NPH at nightime --> based on morning fasting dose
            
       • Regimen "Once Daily" or "Twice Daily"
         • No longer recommended.
         • Level 1A evidence in Type I DM -> MDI and CSII achieves lower HbA1c levels and significan reduces microvascular complications compared to once-daily and twice-daily regimens. (DCCT trial)

NOTES:

• Long-acting given before dinner increases risk of hypoglycemia at night
• Twice-daily dosing not recommended for Type 1 diabetics.
• Insulin-Only regimens are EQUIVALENT to Insulin + Oral agent regimens. (3 references in "Insulin for treating Type 1 and Type 2 Diabetes; Cheng et al"
  • HOWEVER: Adding metformin to insulin in poorly controled TIIDM lowers glucose+lipids better than insulin alone (same reference above)
• Best Regimen: Bedtime NPH + metformin (better glycemic control, less hypoglycemia, and prevention of wt gain"
  • ​Some evidence of weight loss  of evening NPH + oral agents group compared to other regimens.        
• Insulin Infusion Pump (IIP)
  • ​Same HbA1C as MDI, but less glycemic variation, less wt gain, less hypoglycemia episodes, better quality of life.
  • Biggest risk is blocked catheter.

Chart that may or may not be helpful: