Insulin

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    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 analysisOther 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).

    RapidInsulin.png

    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.

    ShortActingInsulin.png
    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

    IntermediateInsulin.png
    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

    LongActingInsulin.png
    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:

    InsulinDosingChart.png

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