Medical Pharmacology Chapter 29:  Diabetes

• Diabetes mellitus is the most important disease involving endocrine pancreas.

  • Major manifestations:

    1. inappropriate hyperglycemia

    2. metabolic disorders

  • Two types:

    • Type I diabetes:  insulin-dependent diabetes mellitus (IDDM)

    • Type II diabetes: non-insulin dependent diabetes mellitus (NIDDM)

  • Properties of Type I diabetes

    • The severe form may be associated with ketosis if untreated.

    • Usually juvenile in onset, but occasionally adult onset.

    • Catabolic disorder:

      • Insulin nearly absent

      • Plasma glucagon elevated

      • Pancreatic B cell is not responsive to insulinogenic stimuli.

      • Exogenous insulin required to:

        1. Prevent ketosis

        2. Reduce hyperglucagonemia

        3. Reverse catabolic state

    • Possible causes

      • Infectious etiology possibly associated with a genetic predisposition.

      • Toxic environmental factor possibly also associated with a genetic predisposition.

      • Mumps virus

      • Coxsackievirus B4

      • Destructive cytotoxins and antibodies from sensitized immunocytes

      • Autoimmune component suggested given that pancreatic B cell damage is reduced when immunosuppressive drugs e.g. cyclosporine/azathioprine, are administered early in Type I diabetes.

        • Pancreatic tissue transplanted from a nondiabetic monozygotic twins into the diabetic twin is rapidly destroyed in absence of immunosuppression.

      • Autoimmune Mechanism

        • Immune system mediation of pancreatic beta cell obstruction (Type I diabetes)

          • Associated with other autoimmune endocrinopathies:

            1. Adrenal insufficiency

            2. Hashimoto's thyroiditis

          • Most patients have antibodies against insulin and other beta cell antigen.

      • Pancreatic beta cell destruction -- development of insulin-dependent diabetes mellitus

        • Slow loss of insulin reserve

        • Prediabetic stages:

          1. Islet cell tumor on a development (normal glucose; normal glucose tolerance; normal insulin response to glucose load)

          2. Decreased glucose tolerance (fasting blood glucose: normal; last prediabetic phase)

          3. Fasting hyperglycemia (no ketosis, even with poorly control diabetes)-- looks like NIDDM

          4. Insulin-dependent stage -- ketoacidosis occurs, especially following stress (in this point life-long insulin therapy is required or pancreatic transplant)

      •  Immune-directed pancreatic beta cell destruction

        • Humoral and cell-mediated processes (cell-mediated mechanisms more important)

        • Islet cell antibodies: -- antibodies against:

          1. Insulin

          2. Proinsulin

          3. Glutamic acid decarboxylase (two forms)

          4. Ganglioside ganglioside antigens

        • Immune cell involvement:

          1. Activated cytotoxic T lymphocytes (CD8+)

          2. Macrophages

          3. Releases cytokines (interleukin 1, tumor necrosis factor alpha, a.k.a., TNF-α.

        • By the time overt diabetes clinically presents, most insulin-producing cells have been destroyed.