Glucose Metabolism

1. Physiology
   1. Blood Glucose
      1. Released from hepatic stores between meals
      2. Derived from ingested carbohydrates
         1. Postprandial Glucose >20 fold over hepatic release
   2. Insulin
      1. General
         1. Insulin produced by pancreatic beta cells
         2. Insulin release stimulated by Blood Glucose
         3. Insulin response to Glucose is linear
            1. Insulin response is based on Glucose sensitivity
            2. Glucose sensitivity depends on Ambient Glucose
               1. Normal: Rapid Insulin release with a meal
               2. Fasting: Steeper rate of Insulin release
               3. Prolonged Hyperglycemia: Flattened response
      2. Phase 1 Insulin Release
         1. Duration: 10 minutes
         2. Suppresses hepatic Glucose release
      3. Phase 2 Insulin Release
         1. Duration: 2 hours
         2. Controls mealtime carbohydrates
      4. Basal Insulin Release
         1. Low continuous Insulin level
         2. Covers metabolic needs between meals
2. Pathophysiology: Type II Diabetes Mellitus
   1. Loss of Glucose sensitivity (see above)
      1. Loss of phase 1 Insulin response
      2. Insufficient phase 2 Insulin response
   2. Insulin production by beta cell
      1. First: Insulin increases to overcome Glucose toxicity
      2. Results in beta-cell exhaustion (Glucose Toxicity)
         1. Initially reversible beta cell exhaustion
         2. Permanent later as amyloid replaces beta cells
      3. Insulin levels decrease as beta cells fail
         1. Beta-cell function reduced to <50% by DM diagnosis
   3. Impaired incretin action
      1. Incretins manage postprandial Glucose levels
         1. Incretin released from GI tract following meals
      2. Endogenous Incretin effects
         1. Increases Glucose dependent Insulin secretion
         2. Delays gastric emptying
         3. Decreases food intake (improves satiety)
      3. Progressive incretin reduced activity
         1. Glucagon-Like Peptide 1 (GLP-1) activity decreases
   4. Medications
      1. Increase Insulin sensitivity
         1. Metformin
         2. Thiazolidinediones
      2. Stimulate Insulin release from beta cells
         1. Meglitinides (act on phase 1 release)
         2. Sulfonylureas (act on phase 2 release)
      3. Replace Insulin
         1. See Insulin
      4. Increase incretin levels (GLP-1)
         1. Exenatide (Byetta)
         2. Sitagliptin (Januvia)