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Overview of clinical presentation: Type I diabetes:

• Onset:IDDM -- before the age of 40
  • Peak incidence: age 14
• Most symptoms secondary to hyperglycemia:
  • polyuria (excessive urination)
  • polydipsia (excessive thirst)
  • polyphagia (excessive or voracious eating)
• First event may be metabolic:
  •  acute metabolic decompensation: diabetic coma
• First event may be degenerative, e.g. neuropathy
• Diabetic metabolic abnormalities due to:
  • relative or complete insulin deficiency
  • relative or significant glucagon access
  • metabolic decompensation may follow an increase in glucagon/insulin ratio

• Type II diabetes:
  • a group of milder forms of diabetes
  • occurring mainly in adults
  • endogenous insulin: sufficient to prevent ketoacidosis --
    • abnormal insulin secretion
    • resistance to insulin action at the tissue.
  • Obesity: common risk factor
  • NIDDM patients: deficiency in pancreatic B cell response to glucose
    • impaired response worsened by hyperglycemia
• Clinical Presentations:
  • NIDDM: appears in middle age or later; mainly in overweight patients
  • gradual onset of symptoms
    • Presenting symptoms:
      1.  extreme hyperglycemia
      2.   hyperosmolality
      3.   volume depletion
      4.   CNS symptoms (ranging from clouded sensorium to coma)
         1. seizure activity (Jacksonian)
         2. transient hemiplegia
      5.   Infections -- pneumonia and gram-negative sepsis (common, associated with very negative prognosis)
  • patients with NIDDM: do not develop ketoacidosis
  •   patients with NIDDM: may develop hyperosmolar, nonketotic coma
    • Syndrome properties:
      • results from sustained hyperglycemia diuresis if patient cannot drink enough water to keep up with urinary fluid loss
      • complete manifestation occurs when volume depletion decreases urine output
    • Hyperosmolar coma can occur in insulin-dependent diabetics if the insulin given is sufficient to prevent ketosis but not enough to control hyperglycemia.
  • Hyperosmolar coma can also be caused by:
    • peritoneal/hemodialysis
    • tube feeding of high-protein formulas
    • high-carbohydrate in fusion loads
    • osmotic agents (mannitol and urea)
  •   Prognosis:
    • Mortality rate and hyperosmolar coma: > 50%

• Insulin structure

• Insulin Receptor

Stimuli to insulin secretion and proposed mechanisms

• Insulin Secretion

  • normally low basal rate from pancreatic B cells

  • higher stimulated rate in response to:

    1. glucose

    2. other sugars (e.g. mannose)

    3. certain amino acids (e.g. leucine, arginine)

    4. vagal nerve activity

  • Proposed secretion mechanism:

    1. hyperglycemia

    2. increased intracellular ATP concentration

    3. higher intracellular ATP closes ATP-dependent potassium channels

    4. decreased outward potassium current causes pancreatic B cell depolarization and opens voltage-gated calcium channels

    5. increased intracellular calcium promotes insulin secretion

    6. intracellular second messengers modulate release:

       • cyclic AMP

       • inositol triphosphate

       • diacylglycerol

Action of Insulin: Target Sites

• Glucose Transporters

  • GLUT 4: most important lowering blood glucose

    • found in muscle and adipose cell membranesto

    • inserted from storage vesicles

  • GLUT-2: abnormalities in GLUT-2 transport into pancreatic B cells: may contribute to reduced insulin secretion (NIDDM)

• Liver:

  • Endogenous insulin reaches the liver first (portal circulation)

  • Hepatic Insulin Actions:

    • increases glucose storage as glycogen

    • resets liver to "fed" state -- influencing:

      1. glycogenolysis

      2. ketogenesis

      3. gluconeogenesis

    • Mechanisms for insulin-hepatic actions results, in part, from:

      • insulin-induced phosphorylations activating:

        1. pyruvate kinase

        2. hophofructokinase

        3. glucokinase

      • in the "fed" state repression of gluconeogenic enzymes occurs:

        1. pyruvate carboxylase

        2. phosphoenolpyruvate carboxykinase

        3. fructose bisphosphatase

        4. glucose 6-phosphatase

    • Insulin also decreases hepatic:

      • urea production

      • protein catabolism

      • cyclic AMP

    • Insulin promotes:

      • triglyceride synthesis

      • increases hepatic phosphate and potassium uptake

• Muscle:

  • Insulin enhances:

    1. protein synthesis (increasing amino acid transport; stimulation of ribosyl action)

    2. glycogen synthesis

       • by increasing glucose transport to the muscle

       • inducing glycogen synthase

       • inhibiting phosphorylase

• Adipose Tissue:

  • Insulin: reduces free fatty acids in the circulation, promoting adipocytes triglyceride storage -- three main mechanisms-- which involves cAMP production suppression and suppression of fat cell lipases:

    1. lipoprotein lipases induction

       • promotes triglyceride hydrolysis from circulating lipoproteins

    2. enhances glucose transport, promotes glycerophosphate generation: permitting fatty acids esterification

    3. reduces adipocytes intracellular lipolysis of stored triglyceride (inhibits intracellular lipase)

Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 684-703

Insulin preparations: Overview

• Four principal types:

  • ultra-short-acting-- (very rapid onset; short duration)

    • clear solutions; neutral pH; zinc added to enhance stability

    • insulin lispro (ultra-short-acting)

  • short-acting --(rapid onset of action)

    • clear solutions; neutral pH; zinc added to enhance stability

    • regular insulin (short-acting)

  • intermediate-acting

    • lente insulin (intermediate-acting)

  • long acting -- (slow onset of action)

    • ultra-lente insulin (long-acting)

• Insulin modifications:

  • intermediate-acting and long acting insulins:

    • turbid suspensions;neutral pH

    • protamine and phosphate buffer added (NPH insulin)

    • zinc in acetate buffer added (ultralente; lente insulins)

    • note: protamine sink insulin-- discontinued; semilente insulin preparations -- discontinued

    • Note: excess zinc in ultralente and lente insulin can precipitate some soluble regular insulin--affecting absorption

  • Subcutaneously insulin therapy: split-dose injection

    1. mixtures of short-acting and intermediate-acting insulins (NPH or lente)

    2. multiple doses of ultra-short-acting or short-acting insulin before meals in association with prolonged duration insulin (NPH, lente or ultralente suspensions) for overnight maintenance.

• Ultra-short-acting insulin:

  • Insulin lispro: new, monomeric insulin analog; recombinant technology

    • interchange of two amino acids near the B chain terminal decreases tendency to form hexameric species-- lysine-proline switch

    • insulin lispro binding to insulin receptor: unaffected by structural change

    • insulin lispro half-life: unaffected by structural change

    • insulin lispro immunogenicity: unaffected by structural change

    • Following subcutaneous administration, insulin lispro dissociates to monomers, rapidly absorbed -- peak serum values within one-hour (much more rapidly than hexameric human insulin)

    • duration of action: no more than 3-4 hours for insulin lispro.

• Short-acting insulin:

  • Regular insulin -- short-acting, soluble crystalline, zinc insulin

    • onset of action: 30 minutes

    • duration of action: 5-7 hours

    • duration and intensity of action: increases with dosage

  • Clinical Use:

    1. IV treatment for diabetic ketoacidosis

    2. management for rapidly changing insulin requirements (e.g. post surgery, acute infection)

• Intermediate-acting and long acting insulins:

  • Lente insulin (30% semilente {rapid onset}and 70% ultralente forms {delayed onset, prolonged duration of action})

•  NPH (neutral protamine Hagedorn or isophane) insulin:

  • intermediate-acting; onset of action delayed by combining correct amounts of protamine insulin such that neither is uncomplexed.-Onset and duration of action: NPH insulin -- similar to lente insulin:

  • NPH insulin usually mixed with regular insulin: for twice daily administration

• Insulin Mixtures:

  • insulin lispro (popular, convenient pre-perennial insulin) may be mixed with a more sustained preparation for post-absorption control; acute insulin lispro mixing is acceptable

• Glycemic control in diabetes mellitus

  • Tight glycemic control is advantageous except for:

    •   patients with advanced renal disease-- detrimental risks associated with hypoglycemia

    •   the elderly-- detrimental risks associated with hypoglycemia

    •   children under the age of 7 years (hypoglycemia poses a significant risk in the developing brain)

  •  Complications of insulin treatment:

    • Hypoglycemia:

      • most common complication

      • causes:

        • delay in eating

        • unusual physical exertion

        • inappropriately high insulin dosage for the immediate need

      • Autonomic hyperactivity -- manifestation of hypoglycemia

        • sympathetic -- tachycardia, palpitations, sweating, tremor

        • parasympathetic-- nausea, hunger

        • Autonomic indications of hypoglycemia are less frequent perceived by elderly patients. These patients may exhibit impaired CNS function 22 hypoglycemic reactions including: mental confusion, bizarre behavior, coma

      • Treatment of hypoglycemia:

        • Glucose administration

        • For mild reactions: orange juice, glucose, sugar containing beverage, food (assumes patient is conscious)

        • For more severe hypoglycemia (unconsciousness patient):

          • intravenous infusion -- 20-50 mL. All of 50% glucose solution over a 2-3 minute interval.

          • Alternatively, in the absence of intravenous infusion, 1 mg of glucagon (subcutaneous or intramuscular administration) should restore consciousness within about 15 minutes (then allowing food consumption)

 Complications of insulin treatment:

• Hypoglycemia:

  • most common complication

  • causes:

    • delay in eating

    • unusual physical exertion

    • inappropriately high insulin dosage for the immediate need

  • Autonomic hyperactivity -- manifestation of hypoglycemia

    • sympathetic -- tachycardia, palpitations, sweating, tremor

    • parasympathetic-- nausea, hunger

    • Autonomic indications of hypoglycemia are less frequent perceived by elderly patients. These patients may exhibit impaired CNS function 22 hypoglycemic reactions including: mental confusion, bizarre behavior, coma

  • Treatment of hypoglycemia:

    • Glucose administration

    • For mild reactions: orange juice, glucose, sugar containing beverage, food (assumes patient is conscious)

    • For more severe hypoglycemia (unconsciousness patient):

      • intravenous infusion -- 20-50 mL. All of 50% glucose solution over a 2-3 minute interval.

      • Alternatively, in the absence of intravenous infusion, 1 mg of glucagon (subcutaneous or intramuscular administration) should restore consciousness within about 15 minutes (then allowing food consumption)

• Beef and pork insulins:

  • Most commercial insulin contained: beef insulin -- primary component

  • Beef hormone: slightly more antigenic compared to pork insulin

  • common ratio: 70% beef/30% pork insulin

  • Recombinant DNA techniques have allowed mass production of human insulin

• Human insulins:

  • Readily available: in regular, NPH, lente, or ultralente form.been

  • Premixed formulation of 70% NPH and 30% regular human insulin is available

  • Human insulin: Advantages

    1. as effective as animal insulins

    2. much less immunogenic than beef-pork insulin; slightly less immunogenic import insulin

  • Human insulin: more rapidly absorbed; slightly shorter duration of action