Phcpm1

• Alpha cell


  Secretes glucagon and proglucagon
• Beta cell


  Secretes insulin, C-peptide, proinsulin, amylin
• Delta cell


  Secretes somatostatin
• Epsilon cell


  Secretes ghrelin
• Insulin


  Released from the Beta cells, molecular weight 5808, 51 amino acids arranged into 2 chains

  
• Effects of insulin on the organs

  1. Liver: Reversal of catabolic features, Inhibits glycogenolysis, Inhibits conversion of fatty acids and amino acids to keto acids, Inhibits conversion of amino acids to glucose, Anabolic action, Promotes glucose storage as glycogen

  2. Muscle: Increased protein synthesis, Increases amino acid transport, Increases ribosomal protein synthesis, Increased glycogen synthesis, Increases glucose transport

  3. Adipose tissue: Increased triglyceride storage, Lipoprotein lipase is induced and activated, Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids, Intracellular lipase is inhibited

  
• Glucagon


  Synthesized by the Alpha cells, Single cell chain of 29 amino acids, Molecular weight 3485, Converts glycogen → glucose

  
• Effects of glucagon

  1. Metabolism: Catabolism of stored glycogen, Increased gluconeogenesis, Increased ketogenesis

  2. Cardiac muscles: Inotropic and chronotropic effect on the heart by activating cAMP

  3. Smooth muscles: Large doses - Relaxation of the intestine
• Adverse drug reactions with glucagon include transient nausea and vomiting, and it should not be used in pheochromocytoma
• Diabetes mellitus


  Elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action

  
• Type 1 diabetes


  Selective beta cell destruction and severe or absolute insulin deficiency, Insulin replacement therapy is necessary to sustain life, If insulin is not administered, diabetic ketoacidosis and death may happen
• Subtypes of type 1 diabetes

  • Type 1a: Immune-mediated
  • Type 1b: Idiopathic
• Type 1a diabetes


  Immune mediated, Most common form, Most patients are younger than 30 at the time of diagnosis, Increased incidence in northern Europe and Sardinia, May have antibodies to: Glutamic acid decarboxylase 65 (GAD 65), Insulin autoantibody, Tyrosine phosphatase IA2 (ICA 512), Zinc transporter (ZnT8)
• Type 2 diabetes


  Tissue resistance to the action of insulin combined with relative deficiency in insulin secretion, Affects fat metabolism resulting in increased free fatty acid flux and triglyceride levels, decreased HDL, Insulin therapy may be necessary if patients develop progressive beta cell failure

  
• Type 3 diabetes


  Refers to multiple other causes of elevated blood glucose, such as pancreatectomy, pancreatitis, non pancreatic diseases, and drug therapy
• Gestational diabetes mellitus


  Any abnormality in glucose levels noted for the first time during pregnancy, Around 7% of pregnant women in US, 14% in the Philippines, During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester

  
• Fasting blood sugar


  A plasma glucose level of 126 mg/dL (7 mmol/L) or higher on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes mellitus

  
• (Oral glucose tolerance test)

  Adults 75 g of glucose in 300 mL of water; children 1.75 g of glucose per kilogram of ideal body weight, The glucose load is consumed within 5 minutes, Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose,

  
  

  Normal: 0 hour : < 100 mg/dL, 2 hour: < 140 mg/dL,

  With DM: 0 hour: >/=126mg/dL, 2 hour: >200mg/dL,

  Impaired glucose tolerance if 2 hr is between 140mg/dL-199mg/dL

  
• HbA1C: Glycosylated Hemoglobin


  When plasma glucose levels are in the normal range, about 4–6% of hemoglobin A has one or both of the N terminal valines of their beta chains irreversibly glycated by glucose, Abnormally elevated in patients with chronic hyperglycemia, HbA1c value reflects plasma glucose levels over the preceding 8–12 weeks

  
• Urine/ Blood ketones

  Betahydroxybutyrate levels >0.6 mmol/L require evaluation, A level >3.0 mmol/L, which is equivalent to very large urinary ketones will require hospitalization
• Regular insulin


  Intravenous infusions are particularly useful in the treatment of diabetic ketoacidosis and during the perioperative management of insulin-requiring diabetics

  
• Rapidly acting insulin analogs

  • Lispro (Humalog): proline at position B28 is reversed with the lysine at B29
  • Aspart (Novolog): single substitution of proline by aspartic acid at position B28
  • Glulisine (Apidra): the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic acid
• NPH insulin


  Intermediate acting insulin, After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption, Onset of approximately 2–5 hours and duration of 4–12 hours, Usually mixed with short acting insulins and given 2 to 4 times daily for insulin replacement

  
• Insulin Glargine


  Peakless, long acting insulin, Slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours, This maximum activity is maintained for 11–24 hours or longer, Once daily regimen (unless very insulin-sensitive or very insulin resistant; 2 doses, split), Should not be mixed with other insulins

  
• Insulin Detemir


  The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the B29 lysine, Has four to five times lower affinity than human soluble insulin, Duration: 17 hours, Administered once or twice daily

  
• Insulin Degludec


  Threonine at position B30 has been removed and the lysine at position B29 is conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer, T1/2: 25 hours, Onset: 30-90 minutes, Duration: >42 hours, Available in U100 and U200, May be given once or twice daily to achieve stable basal coverage

  
• Insulin Glargine and Detemir are not mixed with regular or analogs

  
• Insulin pens


  Cartridges of insulin lispro, insulin aspart, and insulin glargine are available for reusable pens, All insulin are now made by recombinant technology; they should be refrigerated and brought to room temperature just before injection

  
• Continuous Subcutaneous Insulin Infusion Devices


  The devices have a user- programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results

  
• Insulin Glargine and Detemir


  Not mixed with regular or analogs

  
• Syringe and needles

  • 1-mL (100 units)
  • 0.5-mL (50 units)
  • 0.3-mL (30 units) - "low dose" syringe; most patients do not take more than 30 units in a single injection
• Insulin pens


  • Cartridges of insulin lispro, insulin aspart, and insulin glargine are available for reusable pens
  • All insulin are now made by recombinant technology; they should be refrigerated and brought to room temperature just before injection

  
• Continuous Subcutaneous Insulin Infusion Devices


  • The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results

  
• Inhaled Insulin (Afrezza)


  • Dry powder formulation of recombinant regular insulin
  • to 2.5-μm crystals of the excipient, fumaryl diketopiperazine - Provide a large surface area for adsorption of proteins like insulin
  • Peak: 12-15 mins after inhalation, Decline to baseline after 3 hours
  • Faster in onset and shorter in duration than subcutaneous insulin

  
• Insulin Allergy


  An immediate type hypersensitivity, is a rare condition in which local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies
• Immune insulin resistance


  Low level of IgG anti insulin antibodies may neutralize the action of insulin - Rare, May be associated with other autoimmune diseases such as SLE
• Lipodystrophy at Injection Sites


  Hypertrophy of subcutaneous fatty tissue remains a problem if injected repeatedly at the same site - May be corrected by avoiding the specific injection site
• Agents that bind to the sulfonylurea receptor and stimulate insulin secretion

  • Sulfonylureas
  • Meglitinide Analogs
• Sulfonylureas


  • Bind to sulfonylurea receptors that inhibits the potassium channel
  • This inhibits the efflux of potassium ions through the channel and results in depolarization
  • Depolarization will open calcium channel resulting in calcium influx and release of preformed insulin
• First generation sulfonylureas


  • Chlorpropamide
  • Tolazamide
  • Acetohexamide