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Diabetes Mellitus

   INTERNET SOURCES
                                                              2


          DIABETES TABLES

Etiologic Classification of Diabetes
              Mellitus
I. Type 1 diabetes* (b-cell destruction, usually leading to
              absolute insulin deficiency)
 1. Immune mediated
 2. Idiopathic


  II. Type 2 diabetes* (may range from predominantly
  insulin resistance with relative insulin deficiency to a
   predominantly insulin secretory defect with insulin
                        resistance)
                 III. Other specific types
 1. Genetic defects of -cell function (42)
       1. Chromosome 20q, HNF-4
       2. Chromosome 7p, glucokinase (MODY2)
       3. Chromosome 12q, HNF-1
       4. Chromosome 13q, insulin promoter factor
          (MODY4)
       5. Chromosome 17q, HNF-1
       6. Chromosome 2q, Neurogenic differentiation 1/b-
          cell e-box
          transactivator 2 (MODY 6)
       7. Mitochondrial DNA
       8. Others
 2. Genetic defects in insulin action
       1. Type 1 insulin resistance
       2. Leprechaunism
       3. Rabson-Mendenhall syndrome
       4. Lipoatrophic diabetes
       5. Others
 3. Diseases of the exocrine pancreas
       1. Pancreatitis
       2. Trauma/pancreatectomy
       3. Neoplasia
       4. Cystic fibrosis
       5. Hemochromatosis
       6. Fibrocalculous pancreatopathy
                                                  3


      7. Others
4. Endocrinopathies
      1. Acromegaly
      2. Cushing's syndrome
      3. Glucagonoma
      4. Pheochromocytoma
      5. Hyperthyrodism
      6. Somatostatinoma
      7. Aldosteronoma
      8. Others
5. Drug- or chemical-induced
      1. Vacor
      2. Pentamidine
      3. Nicotinic acid
      4. Glucocorticoids
      5. Thyroid hormone
      6. Diazoxide
      7. -adrenergic agonists
      8. Thiazides
      9. Dilantin
      10.         -interferon
      11.       Others
6. Infections
      1. Congential rubella
      2. Cytomegalovirus
      3. Others
7. Uncommon forms of immune-mediated diabetes
      1. "Stiff-man" syndrome
      2. Anti-insulin receptor antibodies
      3. Others
8. Other genetic syndromes sometimes associated
   with diabetes
      1. Down's syndrome
      2. Klinefelter's syndrome
      3. Turner's syndrome
      4. Wolfram's syndrome
      5. Friedreich's ataxia
      6. Huntington's chorea
      7. Laurence-Moon-Bieldel syndrome
      8. Myotonic dystrophy
      9. Porphyria
      10.       Prader-Willi syndrome
      11. Others


      IV. Gestational diabetes-melllitus (GDM)
                                                                4


*Patients with any form of diabetes may require insulin
treatment at some stage of their disease. Such use of insulin
does not, of itself, classify the patient. Adapted from
reference #29 with permission.
   PROF. DR. HASSAN EL MAHDY ELCTRONIC LIBRARY


 Diagnosis of GDM with a 100 g glucose
                 load
            TIME                    PLASMA GLUCOSE
Fasting                        ≥95 mg/dl (5.3 mmol/L)
1-h                            ≥180 mg/dl
                               (10.0mmol/L)
2-h                            ≥155 mg/dl (8.6
                               mmol/L)
3-h                            ≥140 mg/dl (7.8
                               mmol/L)
Two or more values must be met or exceeded for a diagnosis
of diabetes to be made. The test should be done in the
morning after a 8 to 14 hour fast.

   PROF. DR. HASSAN EL MAHDY ELCTRONIC LIBRARY




ADA criteria for the diagnosis of diabetes
  mellitus, impaired glucose tolerance
  (IGT), and impaired fasting glucose
                   (IFG)
                   Diabetes         IGT             IFG
FPG*               ≥126            <126          ≥110 to
                                                  125
2-hour             ≥200         ≥140 and           <200
PG*                              <200
                                                                         5


   *FPG = fasting plasma glucose; 2-hour PG = 2-hour
   plasma glucose concentration during a standard oral
   glucose (75 gram) tolerance test

High-risk candidates for regular and early diabetes screening. Adapted from
   the guidelines of the National Health and Medical Research Council of
               Australia, National Health Advisory Committee
                                                                  6




Algorithm for the detection of undiagnosed type 2 diabetes and
         the prediabetes categories (IGT and/or IFG).




Diagnostic venous plasma glucose values for diabetes mellitus
and other categories of hyperglycemia, using fasting and 2-hour
                  post-glucose load samples
                                                            7




      Major characteristics of Type 1 and Type 2
                  diabetes mellitus
          Feature              Type 1             Type 2
     typical age of      childhood, young    middle-age,
     onset               adult               elderly
     onset               acute               gradual
     habitus             lean                often obese
     weight loss         usual               uncommon
     ketosis-prone       ussually            usually not
     serum insulin       low or absent       often normal
     concentration       uncommon            common
     family history of   DR3, DR4            none
     diabetes
     HLA association




      DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS
           A. Diabetes Mellitus in Non-Pregnant Patients
      1. Classic symptoms of OM with fasting plasma glucose > or =
         7.0 mmol/L; or
      2. Classic symptoms of OM with random plasma glucose > or =
         11.1 mmol/L or
      3. 2 hour glucose post 75 g oral glucose tolerance test > or =
         11.1
*In the absence of classical symptoms (polyuria, polydipsia, weight
loss) the test should be confirmed by repeat testing on a different
day before the diagnosis of OM is made.

   B. Impaired Fasting Glucose or Impaired Glucose Tolerance
     1. Fasting plasma glucose between 6.1 and 7.0 mmol/L; or
     2. Two hour value in oral glucose tolerance test between 7.8
        and 11.1 mmol/L

    C. Gestational Diabetes (100 g oral glucose tolerance test)
     Two or more of the following values for glucose must be met
or exceeded:
               Fasting        1 hour          2 hours        3
                                                                       8


hours
     mmol/L          5.8       10.6      9.2       8.1
*This test is performed following a screening 1 hour glucose post
50 gram load exceeding 7.8 mmol/L. Screen is normally done
between 24 and 28 weeks of gestation

                                  D. Normal
      1. Fasting plasma glucose <6.1 mmol/L;
      2. Two hour glucose tolerance test value <7.8 mmol/L.



                Causes of Diabetic Ketoacidosis

    Common             Other causes          Selected drugs that
    causes by                                  may contribute to
    frequency                                diabetic ketoacidosis


Infection,           Acanthosis             Atypical antipsychotic
 particularly         nigricans              agents
 pneumonia,          Acromegaly             Corticosteroids
 urinary tract       Arterial thrombosis,   FK506
 infection, and       including             Glucagon
 sepsis               mesenteric and        Interferon
Inadequate            iliac                 Sympathomimetic
 insulin treatment   Cerebrovascular         agents including
 or                   accident               albuterol (Ventolin),
 noncompliance       Hemochromatosis         dopamine (Intropin),
New-onset            Hyperthyroidism         dobutamin (Dobutrex),
 diabetes            Pancreatitis            terbutaline (Bricanyl),
Cardiovascular       Pregnancy               and ritodrine (Yutopar)
 disease,
 particularly
 myocardial
 infarction
.

                Diabetic Ketoacidosis
                                                              9


http://www.emedicine.com/PED/topic582.htm

                                                    Severe
                         Mild       Moderate       10% and
                         <3%         3-10%          Shock
                                                     15%

                       Thirsty,       Thirsty      Drowsy,
 Appearance
                        alert        lethargic       cold

 Tissue turgor         Normal         Absent        Absent

 Mucous
                        Moist          Dry         Very dry
 membranes

 Blood                              Normal or       Low for
                       Normal
 pressure                              low            age

                                                  Rapid and
 Pulse                 Normal         Rapid
                                                    weak

                                                    Grossly
 Eyes                  Normal        Sunken
                                                    sunken

 Anterior                                           Grossly
                       Normal        Sunken
 fontanelle                                         sunken


      The major clinical and metabolic features
     Clinical and metabolic features of diabetic
                    ketoacidosis
     Clinical Metabolic           Metabolic
  thirst                          hyperglycemia
  polyuria (but oliguria late)    glycosuria
  dehydration                     metabolic acidosis
  hypotension, tachycardia        ketonemia
  and peripheral circulatory      uremia
  uremia failure                  hyperkalemia
  ketosis                         hypertriglyceridemia
  hyperventilation                hemoconcentration
  vomiting
  abdominal pain
  drowsiness and coma
                                                                10


 Diagnostic Criteria for Diabetic Ketoacidosis and Hyperosmolar
                       Hyperglycemic State

                 Mild     Moderate
                 DKA       DKA        Severe DKA       HHS
Plasma          > 250      > 250        > 250         > 600
 glucose        (13.9                                 (33.3)
 (mg per dL        )
 [mmol per
 L])
Arterial pH     7.25      7.00 to       < 7.00        > 7.30
                  to        7.24
                 7.30
Serum           15 to    10 to < 15      < 10          > 15
 bicarbonate      18
 (mEq per L)
Urine           Positi    Positive     Positive       Small
 ketones          ve
Serum           Positi    Positive     Positive       Small
 ketones          ve
Beta-           High       High          High       Normal or
 hydroxybut                                         elevated2
                                                         0
 yrate
Effective       Variab    Variable     Variable       > 320
 serum            le
 osmolality
 (mOsm per
 kg)*
Anion gap†      > 10       > 12          > 12        Variable
Alteration in   Alert    Alert/dro    Stupor/co     Stupor/co
  sensoria or               wsy           ma            ma
    mental
  obtundatio
       n
DKA = diabetic ketoacidosis; HHS = hyperosmolar hyperglycemic
 state.
*-Effective serum osmolality = 2 3 measured Na (mEq per L) +
 (glucose [mg per dL] ÷ 18).
†-Anion gap = Na+ - (Cl- + HCO3- [mEq per L]).

    Standard Laboratory Assessment for Patients with Diabetic
                         Ketoacidosis
                                                               11



Plasma glucose
Electrolytes with calculated anion gap and effective
 osmolality
Phosphorous
Blood urea nitrogen and creatinine
Beta-hydroxybutyrate or serum ketones if not available
Complete urinalysis with urine ketones by dipstick
Arterial blood gas or venous pH level if not available
Complete blood count with differential
Electrocardiography
As indicated
Bacterial cultures of urine, blood, throat, or other sites
 of suspected infection
Chest radiography if pneumonia or cardiopulmonary
 disease is suspected
Magnesium if patient has signs of hypomagnesemia
 such as cardiac arrhythmias, is alcoholic, or is taking
 diuretics
A1C level may help determine whether this is an acute
 episode in a patient with well-controlled, undiagnosed,
 or poorly controlled diabetes.

Osmolality can be calculated using the formula for effective
osmolality (mOsm per kg):

      2 X Na+ (mEq per L) + plasma glucose (mg per dL)

                                         18

     calculated as

      Na (mmol/L) x 2 + glucose / 18 (mg/dL) + BUN / 2.8
                           (mg/dL)

                                or
      Na (mmol/L) x 2 + glucose (mmol/L) + urea (mmol/L)


        Diagnosis of GDM with a 100-g oral glucose load
                                                                  12




                              mg/dl                mmol/l

    PROF.DR. HASSAN EL                              MAHDY
 Fasting                        95                    5.3

 1-h                            180                   10.0

 2-h                            155                   8.6

 3-h                            140                   7.8


Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the
morning after an overnight fast of between 8 and 14 h and after at
least 3 days of unrestricted diet ( 150 g carbohydrate per day) and
unlimited physical activity. The subject should remain seated and
should not smoke throughout the test.

           Diagnosis of GDM with a 75-g oral glucose load

                                 mg/dl               mmol/l

 Fasting                          95                   5.3
 1-h                              180                 10.0
 2-h                              155                  8.6


Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the
morning after an overnight fast of between 8 and 14 h and after at
least 3 days of unrestricted diet ( 150 g carbohydrate per day) and
unlimited physical activity. The subject should remain seated and
should not smoke throughout the test.




           Criteria for the diagnosis of diabetes mellitus
                                                                       13



    Normoglycemia         IFG and IGT           Diabetes mellitus*
             PROF.DR. HASSAN EL                      MAHDY

    FPG <100 mg/dl     FPG 100 mg/dl             FPG 126 mg/dl
                       and <126 mg/dl
                            (IFG)

    2-h PG <140         2-h PG 140              2-h PG   200 mg/dl
                       mg/dl and <200
    mg/dl
                        mg/dl (IGT)
    —                         —          Symptoms of DM and casual
                                         plasma glucose concentration
                                                  200 mg/dl


DM, diabetes mellitus; FPG, fasting plasma glucose; 2-h PG, 2-h
postload glucose.
*
  In the absence of unequivocal hyperglycemia, a diagnosis of
diabetes must be confirmed on a subsequent day by any one of the
three methods included in the chart. In clinical settings, the FPG
test is greatly preferred because of ease of administration,
convenience, acceptability to patients, and lower cost. Fasting is
defined as no calorie intake for at least 8 h.

 This test requires the use of a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in water.

        Diagnosis of gestational diabetes mellitus with a 100-g oral
                              glucose load

                                mg/dL   mmol/L

                    Fasting       95      5.3

                    1-h           180    10.0

                    2-h           155     8.6

                    3-h           140     7.8
                                                                 14


Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the
morning after an overnight fast of between 8 and 14 h and after at
least 3 days of unrestricted diet (>150 g carbohydrate per day) and
unlimited physical activity. The subject should remain seated and
should not smoke throughout the test.

Diagnosis of gestational diabetes mellitus with a 75-g oral glucose
                               load

                                mg/dL mmol/L

                    Fasting       95       5.3

                       1-h       180       10.0

                       2-h       155       8.6


Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the
morning after an overnight fast of between 8 and 14 h and after at
least 3 days of unrestricted diet (>150 g carbohydrate per day) and
unlimited physical activity. The subject should remain seated and
should not smoke throughout the test.

        3 Hour Glucose Tolerance Test for Gestational Diabetes

                                                    Normal Mean
                             Diagnostic Criteria
                                                      Values*
                                                       Blood
                              Blood Glucose
                                                      Glucose
                                  Level
                                                       Level
     Fasting                     105 mg/dl            80 mg/dl
     I hour                      190 mg/dl           120 mg/dl
     2 hour                      165 mg/dl           105 mg/dl
     3 hour                      145 mg/dl            90mg/dl
                                                                  15




    3-Hour Glucose Tolerance Test for Gestational Diabetes




  Oral Glucose tolerance test(100g) values for the diagnosis of
                  gestational diabetes(mg/dL)

            O'                      Carpenter &       Sacks et al
                   NDDG(1979)
          Sullivan                 Coustan (1982)       (1989)
Fasting     90         105               95               96
1 hour     165         190              180              172
2 hour     145         165              155              152
3 hour     125         145              140              131
  http://www.medstudents.com.br/ginob/ginob4t1.htm
                                                              16


         TESTING CUTOFF VALUES COMMONLY USED

1-hour glucose challenge test (50g) - 140 mg/dl [7.8 mmol/l];
many providers will order further testing in the 130-140
range as well, and a few will order further testing in the
120-130 range too.

3-hour glucose tolerance test (100g) - NDDG Scale (National
Diabetes Data Group), most commonly used scale
(ACOG lists this one first)


            Reading                         Cutoff (mg/dl)

Fasting Draw                                105 mg/dl
One Hour Draw                               190 mg/dl
Two Hour Draw                               165 mg/dl
Three Hour Draw                             145 mg/dl


3-hour glucose tolerance test (100g) - Carpenter Scale

            Reading                         Cutoff (mg/dl)
Fasting Draw                                 95 mg/dl
One Hour Draw                               180 mg/dl
Two Hour Draw                               155 mg/dl
Three Hour Draw                             140 mg/dl

3-hour glucose tolerance test (100g) - Coustan Cutoffs

            Reading                         Cutoff (mg/dl)
Fasting Draw                                 95 mg/dl

One Hour Draw                               180 mg/dl

Two Hour Draw                               160 mg/dl

Three Hour Draw                             135 mg/dl




3Hour Glucose Tolerance Test for Gestational Diabetes
                                                                      17


                                                        Normal Mean
                            Diagnostic Criteria
                                                          Values*
                                                      Blood Glucose
                         Blood Glucose Level
                                                          Level
Fasting                        105 mg/dl                 80 mg/dl
I hour                         190 mg/dl                 120 mg/dl
2 hour                         165 mg/dl                 IOS mg/dl

3 hour                         145 mg/dl                 90mg/dl


             From 752 Unselected Pregnancies
http://www.childbirthsolutions.com/articles/pregnancy/ge
                stationalintro/index.php



    Clinical and analytical characteristics of women with prior GDM
included as potentially predictive variables of AGT at 6.16 years (0.05–
                            13.73) of follow-up



              Potentially predictive variables
Family history of diabetes (%)                373/695 (53.7)
Previous hyperglycemia (%)*                       54/695 (7.8)
Age (years)                                        31 (17–44)
Prepregnancy BMI (kg/m2)                     23.3 (15.9–37.9)
One or more previous                          446/694 (64.3)
pregnancies (%)
History of poor obstetric                         93/694 (13.4)
outcome (%)
Gestational age at diagnosis                       30 (8–39)
(weeks)
OGTT at diagnosis (mmol/l)
 Fasting blood glucose                             4.9 (2.8–9)
 60-min blood glucose                         11.9 (7.7–18.6)
 120-min blood glucose                        10.3 (4.7–18.6)
 180-min blood glucose                        7.7 (1.8–14.6)
OGTT AUC                                      28.3 (23.6–47)
                                                                   18


    Number of abnormal values on             2 (2–4)
    OGTT (n)
    GHb (SD)                          -0.62 (-4.29 to 6.91)
    Autoantibody positivity (%)    75/535 (14%: ICA 14%, GAD
                                        1.5%, IA2 0.2%)
    Insulin therapy (%)                  472/695 (67.9)
    Macrosomia (%)                        25/692 (3.6)
    Spontaneous preterm delivery          17/691 (2.5)
    (%)
    Subsequent pregnancies (%)           105/696 (15.1)
    Subsequent diagnosis of GDM           69/105 (65)
    (%)
    BMI at follow-up (kg/m2)            24.5 (16.2–40.3)
    BMI increment at follow-up        1.52 (-3.73 to 12.29)
    (kg/m2)


Data are n (%) and median (range).
*
 Previous hyperglycemia includes IGT, GDM, or nondiagnostic
hyperglycemia,

 poor obstetric outcomes are macrosomia, hypertension, recurrent
miscarriages, unexplained fetal death, hydramnios, major
congenital malformations, recurrent urinary infections, or
pyelonephritis in previous pregnancies;

GHb was measured at a median gestational age of 33 weeks (11–
42);

macrosomia: birthweight 4,000 g.
19
                                                             20




    Values for diagnosis of diabetes mellitus and other
               categories of hyperglycaemia

                      Glucose concentration, mmol l-1 (mg dl-1)
                      Whole blood Whole blood     Plasma*
                        Venous      Capillary      Venous
Diabetes Mellitus:
  Fasting                >=6.1        >=6.1         >=7.0
                        (>=110)      (>=110)       (>=126)
  or
  2-h post glucose       >=10.0       >=11.1        >=11.1
  load                  (>=180)      (>=200)       (>=200)

  or both
Impaired Glucose
Tolerance (IGT):
  Fasting (if            <6.1         <6.1       <7.0 (<126)
  measured)             (<110)       (<110)

  and
  2-h post glucose       >=6.7        >=7.8         >=7.8
  load                  (>=120)      (>=140)       (>=140)
                          and          and           and
                         <10.0        <11.1         <11.1
                                                                      21


                            (<180)        (<200)         (<200)
Impaired Fasting
Glycaemia (IFG):
  Fasting                   >=5.6         >=5.6          >=6.1
                           (>=100)       (>=100)        (>=110)
                             and           and            and
                             <6.1          <6.1       <7.0 (<126)
                            (<110)        (<110)
  and (if
  measured)
  2-h post glucose           <6.7          <7.8       <7.8 (<140)
  load                      (<120)        (<140)


     * Corresponding values for capillary plasma are: for Diabetes
     Mellitus, fasting >=7.0 (>=126), 2-h >=12.2 (>=220); for
     Impaired Glucose Tolerance, fasting <7.0 (<126) and 2-h
     >=8.9 (>=160) and <12.2 (<220); and for Impaired Fasting
     Glycaemia >=6.1 (>=110) and <7.0 (<126) and if measured,
     2-h <8.9 (<160).

     For epidemiological or population screening purposes, the
     fasting or 2-h value after 75 g oral glucose may be used
     alone. For clinical purposes, the diagnosis of diabetes should
     always be confirmed by repeating the test on another day
     unless there is unequivocal hyperglycaemia with acute
     metabolic decompensation or obvious symptoms.

  Summary of Diagnostic Criteria for Diabetes and
           Impaired Glycemic States
 http://clinical.diabetesjournals.org/cgi/content/full/22/2/69

PROF.DR. HASSAN EL MAHDY ELECTRONIC LIBRARY

      1: Values for diagnosis of diabetes mellitus and other
                  categories of hyperglycaemia2
                            Glucose concentration (mmol/L [mg/dL])
                                      Whole blood

                                Venous              Capillary


 Diabetes mellitus
                                                                  22


Fasting                   6.1 (    110)        6.1 (    110)
or 2 h post-glucose
                          10.0 (   180)        11.1 (    200)
load
or both
Impaired glucose tolerance (IGT)
Fasting (if measured)   < 6.1 (< 110)        < 6.1 (< 110)
and 2 h post-glucose
                          6.7 (    120)        7.8 (    140)
load
                        and < 10.0 (<
                                           and < 11.1 (< 200)
                            180)
Impaired fasting glycaemia (IFG)
                         5.6 ( 100)
Fasting                                      5.6 (     100) and
                             and
                        < 6.1 (< 110)        < 6.1 (< 110)
2 h post-glucose load
                        < 6.7 (< 120)        < 7.8 (< 140)
(if measured)


                        Glucose concentration (mmol/L [mg/dL])

                                     Plasma*

                            Venous              Capillary


Diabetes mellitus
Fasting                  < 7.0 (    126)       7.0 (    126)
or 2 h post-glucose
                          11.1 (   200)        12.2 (    220)
load
or both
Impaired glucose tolerance (IGT)
Fasting (if measured)    <7.0 (<126)         < 7.0 (< 126)
and 2 h post-glucose
                          7.8 (    140)        8.9 (    160)
load
                        and < 11.1 (<
                                           and < 12.2 (< 220)
                            200)
Impaired fasting glycaemia (IFG)
                         6.1 ( 110)
Fasting                                      6.1 (     110) and
                             and
                        < 7.0 (< 126)        < 7.0 (< 126)
2 h post-glucose load   < 7.8 (< 140)        < 8.9 (< 160)
                                                                     23


 (if measured)

 For epidemiological or population screening purposes, the fasting
 or 2 h value after 75 g oral glucose may be used alone. For
 clinical purposes, the diagnosis of diabetes should always be
 confirmed by repeating the test on another day, unless there is
 unequivocal hyperglycaemia with acute metabolic
 decompensation or obvious symptoms. Glucose concentrations
 should not be determined on serum unless red cells are
 immediately removed, otherwise glycolysis will result in an
 unpredictable underestimation of the true concentrations. It
 should be stressed that glucose preservatives do not totally
 prevent glycolysis. If whole blood is used, the sample should be
 kept at 0-4oC or centrifuged immediately, or assayed
 immediately. Table reproduced with permission from Alberti
 KGMM, Zimmet PZ. Definition, diagnosis and classification of
 diabetes mellitus and its complications. Part 1: diagnosis and
 classification of diabetes mellitus. Provisional Report of a WHO
 Consultation. Diabet Med 1998; 15: 539-553. Copyright John
 Wiley & Sons Limited.




   Recommendations for Diabetes Screening of Asymptomatic
                          Persons


Timing of first test and repeat tests

Test at age 45; repeat every three years:Patients 45
years of age or older

Test before age 45; repeat more frequently than every
three years if patient has one or more of the following risk
factors:

     Obesity: >=120% of desirable body weight or BMI
     >=27 kg per m2
     First-degree relative with diabetes mellitus
     Member of high risk-ethnic group (black, Hispanic,
     Native American, Asian)
     History of gestational diabetes mellitus or delivering
     a baby weighing more than 4,032 g (9 lb)
                                                                 24


     Hypertensive (>=140/90 mm Hg)
     HDL cholesterol level ¾35 mg per dL (0.90 mmol per
     L) and/or triglyceride level >=250 mg per dL (2.83
     mmol per L)
     History of IGT or IFG on prior testing
     BMI=body mass index; HDL=high density
     lipoprotein; IGT=impaired glucose tolerance;
     IFG=impaired fasting glucose.



Glycated hemoglobin (also known as glycohemoglobin, glycosylated
hemoglobin or HbA1c) is used to monitor treatment in patients with
diabetes mellitus; however, it is not recommended for routine
diagnosis of this condition because of a lack of standardization of
tests and results.

        Criteria for the diagnosis of diabetes mellitus

     1. Symptoms of diabetes plus casual plasma glucose
 concentration 200 mg/dl (11.1 mmol/l). Casual is defined
  as any time of day without regard to time since last meal.
      The classic symptoms of diabetes include polyuria,
           polydipsia, and unexplained weight loss.

                               or
  2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no
              caloric intake for at least 8 h.

                               or
 3. 2-h postload glucose 200 mg/dl (11.1 mmol/l) during
  an OGTT. The test should be performed as described by
 WHO, using a glucose load containing the equivalent of 75
          g anhydrous glucose dissolved in water.


In the absence of unequivocal hyperglycemia, these criteria should
be confirmed by repeat testing on a different day. The third
measure (OGTT) is not recommended for routine clinical use.

http://care.diabetesjournals.org/cgi/content/full/27/suppl_1/s5
                               /T2
                                                                      25



         Diagnosis of GDM with a 100-g or 75-g glucose load

                                             mg/dl        mmol/l


            100-g Glucose load
  Fasting                                     95            5.3

  1-h                                         180          10.0

  2-h                                         155           8.6

  3-h                                         140           7.8

             75-g Glucose load
  Fasting                                     95            5.3

  1-h                                         180          10.0

  2-h                                         155           8.6


Two or more of the venous plasma concentrations must be met or
exceeded for a positive diagnosis. The test should be done in the
morning after an overnight fast of between 8 and 14 h and after at
least 3 days of unrestricted diet ( 150 g carbohydrate per day) and
unlimited physical activity. The subject should remain seated and
should not smoke throughout the test.

 http://care.diabetesjournals.org/cgi/content/full/27/suppl_1/s5/T3



     ATP III Clinical Identification of the Metabolic Syndrome


                    Risk Factor                      Defining Level

Abdominal obesity, given as waist
circumference*
   Men                                               >102 cm (>40
                                                          in)
   Women                                            >88 cm (>35 in)
Triglycerides                                          150 mg/dL
                                                                      26


HDL cholesterol
  Men                                                <40 mg/dL
  Women                                              <50 mg/dL
Blood pressure                                     130/ 85 mm Hg
Fasting glucose                                      110 mg/dL


*Overweight and obesity are associated with insulin resistance and
the metabolic syndrome. However, the presence of abdominal
obesity is more highly correlated with the metabolic risk factors
than is an elevated BMI. Therefore, the simple measure of waist
circumference is recommended to identify the body weight
component of the metabolic syndrome.
 Some male patients can develop multiple metabolic risk factors
when the waist circumference is only marginally increased, eg, 94
to 102 cm (37 to 39 in). Such patients may have a strong genetic
contribution to insulin resistance. They should benefit from
changes in life habits, similarly to men with categorical increases
in waist circumference.
 The American Diabetes Association has recently established a
cutpoint of 100 mg/dL, above which persons have either
prediabetes (impaired fasting glucose) or diabetes.14 This new
cutpoint should be applicable for identifying the lower boundary to
define an elevated glucose as one criterion for the metabolic
syndrome.



          WHO Clinical Criteria for Metabolic Syndrome*

Insulin resistance, identified by 1 of the following:
  • Type 2 diabetes
  • Impaired fasting glucose
  • Impaired glucose tolerance
   • or for those with normal fasting glucose levels (<110 mg/dL),
glucose uptake below the lowest quartile for background
population under investigation under hyperinsulinemic, euglycemic
conditions
Plus any 2 of the following:
 • Antihypertensive medication and/or high blood pressure ( 140
mm Hg systolic or 90 mm Hg diastolic)
  • Plasma triglycerides 150 mg/dL ( 1.7 mmol/L)
  • HDL cholesterol <35 mg/dL (<0.9 mmol/L) in men or <39
                                                                       27


mg/dL (1.0 mmol/L) in women
  • BMI >30 kg/m2 and/or waist:hip ratio >0.9 in men, >0.85 in
women
   • Urinary albumin excretion rate 20 µg/min or
albumin:creatinine ratio 30 mg/g


*Derived from Alberti et al.7,8



  AACE Clinical Criteria for Diagnosis of the Insulin Resistance
                            Syndrome*

  Risk Factor Components              Cutpoints for Abnormality

Overweight/obesity                         BMI 25 kg/m2
Elevated triglycerides                150 mg/dL (1.69 mmol/L)
Low HDL cholesterol
  Men                                <40 mg/dL (1.04 mmol/L)
  Women                              <50 mg/dL (1.29 mmol/L)
Elevated blood pressure                    130/85 mm Hg
2-Hour postglucose                          >140 mg/dL
challenge
Fasting glucose                     Between 110 and 126 mg/dL
Other risk factors                Family history of type 2 diabetes,
                                        hypertension, or CVD
                                     Polycystic ovary syndrome
                                         Sedentary lifestyle
                                           Advancing age
                                  Ethnic groups having high risk for
                                       type 2 diabetes or CVD


*Diagnosis depends on clinical judgment based on risk factors.




  CHD Risk According to Blood Pressure and Lipid Categories
                                                                28




                         Men                     Women
                               Age-                   Age-
                       No. of Adjusted        No. of Adjusted
               Person- Events 10-Year Person- Events 10-Year
                Years (%)      Rate    Years (%)      Rate
                         383                      227
Total          30 154   (100)           38 057   (100)
Blood
pressure
Normal
(including              110                       66
optimal)       13 524   (29)     7.8    20 747   (29)    2.9
                         77                       36
High normal     6307    (20)     12.4   6056     (16)    7.1
Hypertension            115                       72
stage I         6695    (30)     16.0   7254     (32)    13.9
Hypertension             81                       53
stage II–IV     3628    (21)     20.9   4000     (23)    14.1
TC, mg/dL
                        103                       39
<200           11 591   (27)     8.2    13 289   (17)    3.1
                        148                       80
200–239        11 792   (39)     12.0   12 683   (35)    6.6
                        132                      108
 240            6771    (34)     18.6   12 085   (48)    10.3
HDL-C, mg/dL
                         97                       23
<35             5601    (25)     15.8   1506     (10)    14.7
                        260                      146
35–59          21 151   (68)     12.0   20 788   (64)    7.5
                                                  58
 60             3409    26 (7)   8.2    15 761   (26)    3.9
LDL-C, mg/dL
                        104                       50
<130           11 142   (27)     7.3    15 835   (22)    2.3
130–159        10 384    124     11.3   10 455    64     6.5
                                                                     29


                          (32)                       (28)
                          155                        113
 160             8628     (41)     17.3    11 767    (50)     10.6


The age-adjusted 10-year CHD rates were calculated from the Cox
proportional hazards model, based on 12 years of follow-up.

       http://circ.ahajournals.org/cgi/content/full/97/18/1837/T3
30
                                                       31



COMMON RISK FACTORS FOR CORONARY HEART DISEASE.
   http://jada.ada.org/cgi/content/full/133/3/291/T2
                                                                          32


                   Causes of Diabetic Ketoacidosis
  Common causes            Other causes          Selected drugs that
    by frequency                                   may contribute to
                                                 diabetic ketoacidosis



 Infection,           Acanthosis                Atypical
  particularly         nigricans6                antipsychotic
  pneumonia,          Acromegaly7                agents12
  urinary tract       Arterial                  Corticosteroids13
  infection, and       thrombosis,              FK50614
  sepsis4              including                Glucagon15
 Inadequate            mesenteric and           Interferon16
  insulin              iliac5                   Sympathomimetic
  treatment or        Cerebrovascular            agents
  noncompliance4       accident5                including albuterol
 New-onset            Hemochromatosis8           (Ventolin),
  diabetes4           Hyperthyroidism9           dopamine
 Cardiovascular       Pancreatitis10             (Intropin),
  disease,            Pregnancy11                dobutamin
  particularly                                   (Dobutrex),
  myocardial                                     terbutaline
  infarction5                                    (Bricanyl),17 and
                                                 ritodrine
                                                 (Yutopar)18

Abdominal pain may be a symptom of ketoacidosis or part of the inciting
cause of DKA, such as appendicitis or cholecystitis. If surgery is
necessary, the timing needs to be individualized for each patient with
input from a surgical consultant.
                                                                   33




Proposed biochemical changes that occur during DKA leading to
increased gluconeogenesis and lipolysis and decreased glycolysis.
Note that lipolysis occurs mainly in adipose tissue. Other events
occur primarily in the liver (except some gluconeogenesis in the
kidney). Lighter arrows indicate inhibited pathways in DKA. F-6-P,
fructose-6-phosphate; G-(X)-P, glucose-(X)-phosphate; HK,
hexokinase; HMP, hexose monophosphate; PC, pyruvate
carboxylase; PFK, phosphofructokinase; PEP, phosphoenolpyruvate;
PK, pyruvate kinase; TCA, tricarboxylic acid; TG, triglycerides. From
Kitabchi et al.

http://jada.ada.org/content/vol133/issue3/images/large/291tbl3.jpeg
                                                                  34


The triad of DKA (hyperglycemia, acidemia, and ketonemia) and
  other conditions with which the individual components are
                          associated.




             Pathogensis of DKA and HHS.
  Conditions causing erroneous bedside blood glucose
                        results
http://care.diabetesjournals.org/cgi/content/full/27/2/55
                           3/T9


    Sources of Analytical Error      Sources of User Error

Low hematocrit*                    Inadequate meter
                                   calibration
High hematocrit                    Using a test strip that does
                                   not match the meter code
                                   or that has passed the
                                   expiration date
                                                                                  35


         Shock and dehydration                     Inadequate quality-control
                                                   testing
         Hypoxia                                   Poor meter maintenance
         Hyperbilirubinemia, severe                Poor technique in
         lipemia*                                  performing fingerprick
         Specimen additives: sodium                Poor technique of applying
         flouride                                  drop of blood to the test
                                                   strip
         Drugs—acetaminophen                       Failure to record results in
         overdose, ascorbic acid,                  patient’s chart or to take
         dopamine, fluorescein, mannitol,          action if blood glucose is
         salicylate                                out of target range

     *
         Falsely elevates result;

     falsely lowers result;

     can either falsely lower or elevate result, depending on the device
     used.

         Diagnostic Criteria for Diabetic Ketoacidosis and Hyperosmolar
                               Hyperglycemic State

                     Mild DKA       Moderate DKA       Severe DKA            HHS
Plasma glucose        > 250            > 250             > 250         > 600 (33.3)
 (mg per dL           (13.9)
 [mmol per L])
Arterial pH           7.25 to       7.00 to 7.24         < 7.00             > 7.30
                        7.30
Serum                  15 to        10 to < 15            < 10              > 15
 bicarbonate             18
 (mEq per L)
Urine ketones        Positive         Positive          Positive            Small
Serum ketones        Positive         Positive          Positive            Small
Beta-                  High            High               High          Normal or
 hydroxybutyrat                                                         elevated20
 e
Effective serum      Variable        Variable           Variable            > 320
 osmolality
 (mOsm per kg)*
Anion gap†             > 10            > 12               > 12           Variable
                                                                        36


Alteration in      Alert     Alert/drowsy    Stupor/coma      Stupor/coma
 sensoria or
 mental
 obtundation

DKA = diabetic ketoacidosis; HHS = hyperosmolar
 hyperglycemic state.
*-Effective serum osmolality = 2 3 measured Na (mEq per L) +
 (glucose [mg per dL] ÷ 18).
†-Anion gap = Na+ - (Cl- + HCO3- [mEq per L]).


                  LABORATORY EVALUATION

        Standard Laboratory Assessment for Patients with Diabetic
                             Ketoacidosis

      Plasma glucose
      Electrolytes with calculated anion gap and effective osmolality
      Phosphorous
      Blood urea nitrogen and creatinine
      Beta-hydroxybutyrate or serum ketones if not available
      Complete urinalysis with urine ketones by dipstick
      Arterial blood gas or venous pH level if not available
      Complete blood count with differential
      Electrocardiography
      As indicated
      Bacterial cultures of urine, blood, throat, or other sites of
       suspected infection
      Chest radiography if pneumonia or cardiopulmonary disease is
       suspected
      Magnesium if patient has signs of hypomagnesemia such as
       cardiac arrhythmias, is alcoholic, or is taking diuretics
      A1C level may help determine whether this is an acute episode
       in a patient with well-controlled, undiagnosed, or poorly
       controlled diabetes.

                Diabetes Care 2004;27(suppl 1):S94-102.
                                                                   37


Characteristics of an effective bedside glucose monitoring (BGM)
                     quality-control program
http://care.diabetesjournals.org/cgi/content/full/27/2/55
                          3/T10

                        Characteristic


• A specifically designated responsible individual, preferably a
laboratory professional, is involved in the administration and
quality assurance of the BGM program.
• A written procedure for the BGM program.
• An organized training program that involves laboratory
personnel and nursing staff.
• Defined frequencies and requirements for maintenance and
cleaning of BGM instruments.
• Regular performance of quality control testing on each
instrument (daily or by shift), depending on the frequency of
patient testing.
• A policy to regularly compare the BGM results from each
operator and instrument with results from a corresponding
sample tested in the clinical laboratory. Suggest that all BGM
results are, at least, within ±15% variation from the clinical
laboratory results.
• Participation in an external proficiency testing program.
• Acknowledgment of the limitations of BGM and requirement of a
clinical laboratory glucose determination when a BGM result is
outside a defined range.
• Acknowledgment of the effect of hematocrit value variation on
BGM results and establishment of hematocrit value limitations for
the instrument in use.
• Determination of the bias of the instrument in use and
communication of this information to the physicians and the
institutional quality assurance program.
                                                                   38


Summary of major recommendations for hospital management of
                      hyperglycemia

                                                        Level of
               Recommendation                           evidence


• Good metabolic control is associated with                B
improved hospital outcomes. Target plasma
glucose levels are:
 •<110 mg/dl preprandial and <180 mg/dl peak
postprandial.
• Intensive insulin therapy with intravenous insulin,      A
with the goal of maintaining blood glucose 80–110
mg/dl, reduces morbidity and mortality among
critically ill patients in the surgical ICU.
• Intravenous insulin infusion is safe and effective       B
for achieving metabolic control during major
surgery, hemodynamic instability, and NPO status.
• Intravenous insulin infusion is safe and effective       B
for patients who have poorly controlled diabetes
and widely fluctuating blood glucose levels or who
are insulin deficient or severely insulin resistant.
• Intravenous insulin infusion, followed by                A
multidose subcutaneous insulin therapy, improves
survival in diabetic patients after myocardial
infarction.
• For insulin-deficient patients, despite reductions       B
or the absence of caloric intake, basal insulin must
be provided to prevent diabetic ketoacidosis.
• Use of scheduled insulin improves blood glucose          B
control compared with orders based on sliding scale
insulin coverage alone.
• For patients who are alert and demonstrate               E
accurate insulin self-administration and glucose
monitoring, insulin self-management should be
allowed as an adjunct to standard nurse-delivered
diabetes management.
• Patients with no prior history of diabetes who are       E
found to have hyperglycemia (random blood
glucose >125 mg/dl or 6.9 mmol/l) during
                                                            39


hospitalization should have follow-up testing for
diabetes within 1 month of hospital discharge.
• Establishing a multidisciplinary team that sets      B
and implements institutional guidelines, protocols,
and standardized order sets for the hospital results
in reduced hypoglycemic and hyperglycemic
events.
• Diabetes education, medical nutrition therapy,       C
and timely diabetes-specific discharge planning are
essential components of hospital-based diabetes
care.


    Target Plasma Glucose for Inpatient Settings




http://spectrum.diabetesjournals.org/cgi/content/full/18/1/20/
                             TBL1
40
                                                                         41




                Types of Autoantibodies:

1. Islet cell cytoplasmic antibodies: The primary antibodies found
in 90% of type 1 diabetics are against islet cell cytoplasmic proteins
(termed ICCA, islet cell cytoplasmic antibodies). In non-diabetics
ICCA frequency is only 0.5% - 4%. The presence of ICCA is a
highly accurate predictor of future development of IDDM. ICCA are
not specific for the -cells and recognize antigens in other cell types
in the islet. However, the autoimmune attack appears to selectively
destroy -cells. Therefore, the antibodies may play a primary role in
the destruction of islet cells. It is an equally likely possibility that the
production of anti-islet antibodies occurs as a result of the
                                                                                42


         destruction of -cells. Whether a direct cause or an effect of islet
         cell destruction, the titer of the ICCA tends to decline over time.

         2. Islet cell surface antibodies: Autoantibodies directed against
         cell-surface antigens (ICSA) have also been described in as many
         as 80% of type 1 diabetics. Similar to ICCA, the titer of ICSA
         declines over time. Some patients with type 2 diabetes have been
         identified that are ICSA positive.

         3. Specific antigenic targets of islet cells: Antibodies to glutamic
         acid decarboxylase (GAD) have been identified in over 80% of
         patients newly diagnosed with IDDM. Like ICCA, anti-GAD
         antibodies decline over time in type 1 diabetics. The presence of
         anti-GAD antibodies is a strong predictor of the future development
         of IDDM in high-risk populations. Anti-insulin antibodies (IAA) have
         been identified in IDDM patients and in relatives at risk to develop
         IDDM. These IAA are detectable even before the onset of insulin
         therapy in type 1 diabetics. IAA are detectable in around 40% of
         young children with IDDM.




              ORAL HYPOGLYCEMIC AGENTS (OHAs)
       C:\Documents and Settings\Dr.Hassan EL Mahdy\My
           Documents\Oral Hypoglycemic Agents.mht

Oral medication is initiated when 2-3 months of diet and exercise
alone are unable to achieve or maintain their optimal plasma
glucose levels. However, a trial of diet and exercise alone should be
reserved for these patients with asymptomatic hyperglycemia. If
patients are symptomatic, oral antidiabetic agents or insulin should
be initiated in concert with diet and exercise. Current therapy for
the treatment of hyperglycemia of type II diabetes includes the
following oral antidiabetic agents:

MAIN GROUPS OF OHAs

SULFONYLUREAS

Sulfonylureas work primarily by stimulating pancreatic insulin
secretion, which in turn reduces hepatic glucose output and
increases peripheral glucose disposal.
The sulfonylureas are often classified as belonging to the first or
second generation.
                                                                    43




The First generation sulfonylureas:

   Acetohexamide
   Chlorpropamide
   Tolazamide
   Tolbutamide.
The Second generation sulfonylureas :
   Glibenclamide
   Glyburide
   Glipizide
   Glicazide
   Glimepiride


  The first generation sulfonylureas are rarely used now.

BIGUANIDES

Two drugs in this category are phenformin and metformin.

Biguanides work mainly by
     Suppressing excessive hepatic glucose production
     Increasing glucose utilization in peripheral tissues to a lesser
       degree.
     Possibly reduce food intake and thus reduce intestinal glucose
       absorption
                                                                    44


As the biguanides do not stimulate endogenous insulin secretion,
hypoglycemia does not occur when they are used alone and
therefore they are sometimes called anti-hyperglycemic agents
rather hypoglycemic agents.

The use of phenformin has decreased considerably and it is usually
metformin that is now used when a biguanide is prescribed.

ALPHA-GLUCOSIDASE INHIBITORS

Acarbose is an alpha-glucosidase inhibitor that slows down the
breakdown of disaccharides and polysaccharides and other complex
carbohydrates into monosaccharides. The enzymatic generation and
subsequent absorption of glucose is delayed and the postfood blood
glucose values, which are characteristically high in patients with
type II diabetes, are reduced.

MEGLITINIDES

A very recent addition to the OHA group. It is a ultra short acting
drug which acts directly on the the beta cells of the pancreas and
increases the secretion of insulin. It also corrects the problems with
the pulsatile release of insulin which is seen in Type II diabetes.

THIAZOLINEDIONES

Thiazolidinediones are a new class of oral antidiabetic agents
(commercially known as glitazones) that enhance insulin sensitivity
in peripheral tissues. Troglitazone was the first glitazone introduced
to the market, and though widely used, it has now been withdrawn
from the market as its use has been linked with hepatocellular
injury and death secondary to liver failure.

Rosiglitazone and Pioglitazone are now available for clinical use and
are extremely potent in reducing peripheral insulin resistance.

OHAs : Special Aspects

Prior to 1994, the Ohas available for the treatment of Type II
diabetes was limited to some sulfonylureas and biguanides. In the
last few years, four new classes and at least 8 new oral agents have
become available for the treatment. Clearly, the clinical choices
today are more confusing and complicated than they were only a
few years ago.

Sulfonylureas
                                                                     45


The SU class of oral hypoglycemic agents (insulin secretagogues)
has been in existence since tolbutamide was introduced in 1956.

The sulfonylurea drugs have effects which are still not completely
understood. Initially, they work primarily by stimulating pancreatic
insulin secretion, which in turn reduces hepatic glucose output and
increases peripheral glucose disposal. They are potassium channel
blockers whose effect on the pancreatic beta-islet cells is to allow an
influx of calcium into the cell, which causes an increase in the
release of insulin.

However, after several months, blood levels of insulin return to pre-
medication levels, yet blood glucose levels remain reduced. Clearly,
the sulfonylurea drugs must have other effects. Several have been
identified, among them: sulfonylurea medications slow the rate at
which the liver releases glucose into the bloodstream, and they
increase the number of insulin receptors on cell membranes, thus
increasing insulin efficiency.

The efficacy of the first- and second-generation sulfonylureas is
similar, although second-generation agents are better formulated
and, although costlier than the older sulfonylureas, have some
advantages. Second-generation sulfonylureas:

Are more potent on a per milligram basis
Tend to produce fewer side effects
In addition, the pharmacokinetics of these second-generation
agents allows for more effective once-a-day dosing, which enhances
compliance.

Although some consider SUs to be dated compared with the newer
oral hypoglycemic drugs, there remains a large number of patients
that will continue to benefit from them.

Biguanides
                                                                    46




The biguanides were introduced in 1957. Both phenformin and
metformin have been widely used here, although in recent times,
the use of phenformin has decreased significantly and most people
now use metformin when a biguanide is to be used.

Metformin works mainly by suppressing excessive hepatic glucose
production, although it may increase glucose utilization in peripheral
tissues to a lesser degree, by decreasing insulin resistance in
muscle cells. Metformin may also improve glucose levels by
reducing intestinal glucose absorption.

Metformin is not metabolized and is excreted unchanged by the
kidneys.

Metformin has many characteristics that are ideal for treating type 2
diabetes, including weight loss, insulin sensitization, positive lipid
effect, mild hypotensive effect, and low or no incidence of
hypoglycemia.

Because metformin does not stimulate endogenous insulin
secretion, hypoglycemia does not occur when this dose is used
alone, although hypoglycemia may occur if metformin is taken with
insulin, a sulfonylurea, or an excessive amount of alcohol.

Treatment with metformin has beneficial effects on plasma lipids (it
lowers triglyceride and low-density lipoprotein [LDL] cholesterol
levels while increasing high-density lipoprotein [HDL] cholesterol)
that are greater than expected from improved glucose control
alone.

In addition, metformin therapy has been associated with weight loss
or no weight gain. This may be particularly helpful in obese patients
with type II diabetes.
Metformin is effective as monotherapy or in combination with
sulfonylureas, alpha-glucosidase inhibitors, and insulin. The
combination of metformin and troglitazone has also been shown to
be safe and effective, although this combination is not an USA FDA-
approved indication and extensive published data on this
combination is lacking.
                                                                      47


Alpha-Glucosidase Inhibitors




Acarbose (Precose) is an alpha-glucosidase inhibitor that slows
down the breakdown of disaccharides and polysaccharides and other
complex carbohydrates into monosaccharides. The enzymatic
generation and subsequent absorption of glucose is delayed and the
postprandial blood glucose values, which are characteristically high
in patients with type II diabetes, are reduced with acarbose. AGIs
do not prevent the absorption of carbohydrates and complex
sugars, but they do delay their absorption.

Delaying the absorption of carbohydrates is a unique mechanism
among oral diabetic medications for lowering HgbA1c levels. The
effectiveness of this mechanism is one of the physiologic
characteristics of type 2 diabetes. Patients with type 2 diabetes
demonstrate a delayed or sluggish insulin response from the
pancreas to a glucose (a meal) load. By delaying the absorption of
glucose, the insulin response is more matched to the serum
glucose,

resulting in less postprandial hyperglycemia and a lowering of the
HbA1c. The AGIs also demonstrate a lowering of total insulin output
of the pancreas, increased insulin sensitivity, a variable but mild
decrease in triglycerides, with no effect on patient weight.

One disadvantage with the use of acarbose is that it is to be taken
along with the first bite of a meal. Moreover, it has to be taken
three times daily with meals. These factors often lead to non
compliance and a decrease in the efficacy of the drug.
                                                                     48


Although Acarbose is the only available AGI in use in India, there
are three AGIs in current use all over the world. Besides acarbose,
these are miglitol and voglibose. Miglitol and acarbose appear to be
equally effective, but miglitol clearly is the preferred choice.
Acarbose has occasionally been associated with liver toxicity and
requires liver monitoring, whereas miglitol does not. Neither
appears to have any significant drug interactions. Miglitol has been
clinically tested and found effective as a single agent and in
combination with SUs, metformin, and insulin. There have been no
trials comparing AGIs with TZDs or repaglinide; however, there are
no obvious reasons that the AGIs could not be used with the TZDs,
but there are some theoretical concerns in using them with
repaglinide.

Meglitinides

Repaglinide from the meglitinide drug class, acts like an extremely
short-acting SU (an insulin secretagogue) and is potentially useful
as a SU replacement. The effect of repaglinide on the pancreas is
very similar to that of the SUs. Repaglinide, like the SUs, blocks the
potassium channels on the pancreatic islet beta-cells, which causes
an influx of calcium into the cell and increasing the secretion of
insulin. There appears to be 2 similar potassium channels on islet
beta-cells, one of which is predominantly affected by repaglinide
and the other is predominantly affected by SUs.
The repaglinide-affected potassium channel appears to be glucose
dependent, which may partially explain why repaglinide is
associated with a much lower incidence of hypoglycemia.

What makes repaglinide clinically different from the SUs is its ultra-
short half-life (1 hour). Repaglinide is taken just before or with
meals, and the stimulation of the pancreas is limited only to a brief
time around meals. Because of the short duration, the patient does
not have continuous high levels of insulin and the resulting adverse
effects.

Its biggest advantage over the other oral hypoglycemic medications
is that it allows for flexible timing and missed meals.

Repaglinide has been approved for use with metformin, and the
combination appears to be a very effective. There are no clinical
trials of repaglinide with the alpha-glucosidase inhibitors, and of the
TZD class, only 1 clinical trial with troglitazone has been reported.
There are theoretical interactions between repaglinide and the TZDs
through their common metabolism in the P450 pathway, so more
clinical trials are clearly needed.
                                                                    49


Thiazolidinediones




The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly
known as glitazones) was developed in 1997 and offers a new
mechanism for treatment of type 2 diabetes. The first, troglitazone
was taken off the market in 1999 because of its association with
hepatic toxicity. Rosiglitazone and pioglitazone have been available
since 1999, and have recently been introduced in the Indian
market.

The primary effect of TZDs is peripheral, with increasing insulin
sensitivity and increased glucose uptake. The TZDs have some
effect on hepatic glucose uptake and sensitivity to a lesser degree.
They do not stimulate the pancreas to produce more insulin.

TZDs are hepatically metabolized and thus can be used safely in
patients with renal dysfunction. They can be dosed once daily,
although rosiglitazone works better with twice-daily dosing. Reports
have suggested that rosiglitazone works better in women, but the
reason for this is not known.

Both pioglitazone and rosiglitazone are approved for monotherapy
and in combination with metformin, SUs, and insulin.
Besides their effect in lowering the blood glucose levels, both drugs
also have notable effects on lipids. The current data show that
pioglitazone has a minimal effect on low-density lipoprotein (LDL)
cholesterol levels and a favorable effect on high-density lipoprotein
(HDL) cholesterol and triglyceride levels. Rosiglitazone has a
favorable effect on HDL cholesterol levels but a negative effect on
                                                                    50


LDL cholesterol levels.

With use of glitazones, patience is required. Blood sugar levels may
show a significant reduction statistically in as little as two to four
weeks, but the maximum effects are not seen until two or three
months have passed.

				
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