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Diabetes Mellitus

Outline

A.Diabetes Mellitus vs Diabetes Insipidus
    1. Diabetes Insipidus- failure of posterior lobe of pituitary to secrete
        ADH, characterized by polyuria (up to 15 liters/day)

    2. Diabetes Mellitus- failure to regulate glucose, characterized by
        hyperglycemia (normal blood sugar = 80 -120 mg%)

B. Summary of Hormones With Major Metabolic Effects on Glucose

C. Epidemiology
    1. one of the most common diseases affecting humans
    2. 6 million known diabetics in US, probably another 4 million
        undiagnosed
    3. found mostly in those over age 40, incidence increases to age 70
    4. woman > men

D. Etiology
1. Genetic- certain HLA tissue types correlate with increased
     incidence, esp. in Type1

2. role of viruses - may act as a trigger to begin autoimmune
   destruction of beta cells in genetically predisposed

3. obesity is major contributing factor to  Type 2

E. Classification

F. Pathophysiology
1. DM is due to either
      a. absolute lack of insulin (Type 1)
      b. relative lack of insulin (possibly Type 2)
      c. ineffective utilization of insulin (most common cause in
           Type 2) = insulin resistance
G. Metabolic Complications of Diabetes
    1. Hypoglycemia (also called insulin reaction, insulin shock)
        a. precipitating factors- too much insulin, insufficient food,
            too much exercise

        b. Signs and symptoms- related to two factors
            1.. Increased Autonomic nervous system stimulation (early)-
            causes pallor, perspiration, piloerection, increased heart rate,
            palpitations, nervousness, irritability, weakness, trembling

            2.. Effects of decreased glucose on CNS (later onset) -
            headache, blurred vision, diplopia, incoherent speech,
            emotional changes, fatigue, mental confusion, convulsions,
            coma

    2. Diabetic Ketoacidosis (DKA)
        a. precipitating factors- excessive food, infection, too little insulin,
            too little exercise

        b. mostly occurs in Type 1

        c. signs and symptoms- increased thirst, vomiting, abdominal pain,
            increased temperature, Kussmaul respirations, hot, dry, flushed
            skin, loss of skin turgor, decreased BP,  lethargy, coma. Onset of symptoms is rapid, 1- 24 hrs

d. N.B. most signs and symptoms due to dehydration caused by
    hyperglycemia and acidosis caused by elevated ketones

    3. Hyperglycemic Hyperosmolar Non Ketotic Syndrome (HHNK,
        HHNC or HOC)
        a. 1/6 as frequent as DKA but mortality is 40 -60%
        b. occurs mostly in Type 2
        c. precipitating factors- excessive food, infection, too little
            exercise

d. signs and symptoms - thirst, vomiting, increased temperature,
decreased BP, hot, dry, flushed skin, loss of skin turgor. motor  deficits, focal seizures, lethargy coma. Onset of symptoms is insidious, 24 hours to 2 weeks.

e. signs and symptoms caused by hyperglycemia, there is no ketosis. Usually blood sugar elevated much higher than in DKA

H Somogyi Effect and Dawn Phenomenon
    1. Somogyi Effect - rebound hyperglycemia, insulin induced
       hypoglycemia triggers off excess secretion of glucagon, cortisol
        leading to hyperglycemia

    2. Dawn phenomenon - hyperglycemia elevated in morning due to
         circadian rhythm release of growth hormone, no hypoglycemia
        during night

I. Long Term Complications
    1. As a direct result of hyperglycemia, there is a thickening of capillary
        basement membrane which results in two major consequences
        a. membrane becomes more permeable to proteins and fluids-
            leading to more viscous plasma- increased platelet aggregation-
            increased formation of microthrombi- tissue ischemia

    b. membrane becomes less permeable to leukocytes leading to
    increased susceptibility to infection, delayed wound healing

    2. Also, as a direct result of hyperglycemia - increased production
of sorbitol- nerve damage

    3.Accelerated atherosclerosis- increased CVA, PVD and MI

    4. Renal changes - range from mild proteinuria to ESRD

    5. Vision changes
        a. diabetes is leading cause of blindness in persons 20 -65
        b. causes cataracts and retinopathies, 2 types of retinopathies
            1. proliferative retinopathy
            2. background retinopathy

    6. Neuropathies
        a. peripheral neuropathies- sensory fibers usually affected before
            motor fibers

        b. effects on ANS- gastric motility changes, bowel changes
            urinary incontinence, impotence

    7. The diabetic foot

J. Diabetes and Pregnancy
    1. complicates 1/300 pregnancies in US

    2. first half of pregnancy-  increased fetal use of glucose predisposes
        to hypoglycemia

    3. second half of pregnancy- increased output of placental hormones
     which are diabetogenic override effects of increased fetal uptake
      of glucose and insulin requirements increase by 67%- hyperglycemia
        major problem

    4. Macrosomia - occurs in infants born to mothers with mild
        diabetes

    5. Microsomia - occurs in infants born to mothers with severe
        diabetes

    6. Fetal mortality and morbidity
        a. mortality - stillbirths (5-!0%), neonatal deaths (5-10%)

        b. morbidity- hypoglycemia, congenital abnormalities (include
            anencephaly, menigocele, transposition of great vessels, ventricular
            septal defects, coarctation of aorta), respiratory distress syndrome,
            hyperbilirubinemia

Discussion  

    Aretaeus the Cappodcian who lived AD 81- 138 is quoted as saying, "diabetes is a wonderful affection.. being a melting down of the flesh into urine". Through his observations he captured well one of the major pathophysiological consequence of hyperglycemia- dehydration. Often, the first symptoms a person with diabetes becomes aware of is a polydipsia and an associated polyuria. As the disease progresses, chronic hyperglycemia leads to alterations in tissue structure causing long term complications such as CVA, MI, PVD, gangrene, increased susceptibility to infection, delayed wound healing, visual changes, motor and sensory abnormalities. The degree and duration of hyperglycemia seems to directly correlate with the degree of tissue damage. The message for teaching patients with diabetes is the need for good glucose control. The more successful they are in maintaining normal glucose levels, the less tissue damage will ensue and the better will be the long term prognosis
    The major pathophysiological change in Type 2 diabetes is insulin resistance. There is an associated phenomenon called Syndrome X (also referred to as Metabolic Syndrome) which is capturing a lot of attention. Syndrome X (which is not Type 2 diabetes but may exist as a prodrome to Type 2 diabetes or as a stand alone condition) is the name given to a syndrome characterized by hypertension, dyslipidemia, vascular disease and insulin resistance (manifesting as a hyperinsulinemia). People with Syndrome X are at increased risk for heart disease. Execs insulin itself seems to accelerate atherosclerosis. Interestingly enough, woman with polycystic ovary disease are often found to be insulin resistant. Apart from a blood test to demonstrate elevated insulin levels in the blood (not readily available), those with Syndrome X can often be recognized clinically by the presence of obesity (android or apple shaped obesity as opposed to gynecoid or pear shaped obesity)  and acanthosis nigricans. Acanthosis is a velvety hyperpigmented rash found on the nape of the neck or axillae. Treatment for Syndrome X (if identified ) is to improve insulin sensitivity by loosing weight, and by treatment with a biguanide type drug (e.g. Metformin) .Biguanide drugs somehow work to improve insulin sensitivity. They are useful, therefore, in the treatment of Type 2 diabetes as well as Syndrome X

Clinically  

    Because Type 1 diabetes is due to destruction of the beta cells   resulting in an inability to produce insulin, Type 1 diabetics have no choice except to be treated with insulin. Type 2 diabetics, on the other hand, have functioning beta cells that can produce insulin. There problem, mostly, is insulin resistance. Insulin resistance can be overcome by increasing the level of insulin already present or by improving the effectiveness of insulin at the tissue level. Type 2 diabetics have a greater range of pharmacological options available to them. 1. They can take insulin (just as Type 1 diabetics) to directly increase insulin levels, or 2.  they can stimulate the pancreas to produce more insulin (the mechanism of sulfonylureas or oral hypoglycemic agents such as Glucotrol, Micronase, Tolinase, or Orinase) or 3. they increase sensitivity of the tissues to insulin (with biguanides such as Metformin or thiazolidinediones such as Rezulin) or 4. they can delay the absorption of carbohydrates from the gut by inhibiting the enzyme (alpha - glucosidase) which operates in the intestine to break down complex carbohydrates with alpha glucosidase inhibitors such as Acarobase.
    Hyperglycemia will increase the amount of glucose which becomes bound to hemoglobin (glycosylated hemoglobin). A measurement of glycosylated hemoglobin, A(1c), can be a useful determinant of the degree of hyperglycemia experienced in the previous 2 - 3 months( since once glycosylated, hemoglobin persists for 120 days until destroyed by the spleen). Normal levels of A(1c) are 4 - 6%. It is recommended that any levels above 8% warrant the initiation of corrective measures. Is the patient compliant?, do insulin levels need to be increased etc.