History of My Clinical Investigations

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History of My Clinical Investigations
1946 AD 1977 AD 2002 AD
1977 AD 2002 AD 2004 AD
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History of Diabetes and Insulin
2000 BC 1900 AD 1980 AD
2004 AD 2004 AD 2004 AD
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Insulin Old Story - New Twists

• 80 years since the discovery of insulin
• Discovery to worldwide use in lt 2 years
• Landmarks in science and medicine
• Refinements in delivery the changing scene
• How does it work
• Landmarks of science and medicine

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Insulin Old Story - New Twists

• Discovery to worldwide use in lt 2 years
• Development of methods for large scale protein
  isolation from porcine and bovine pancreas
• Technology exchange between corporations on
  efforts to purify, stabilize and concentrate
  insulin.
• Standardization of a unit - 2.5 mM glucose

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Insulin Old Story - New Twists

• Landmarks
• Sequence 51 AA insulin protein - F. Sanger
  1962
• Immunoassay 1963 Berson and Yalow
• Crystal structure Hodgkin 1972
• Pro-hormone and pre-prohormone
• Recombinant protein 1983 Human insulin
• Insulin analogs primary structure changes

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Insulin Therapy

• Late 1930s Slow release insulin based on
  self association of insulin or insulin binding to
  proteins (protamine).
• 1940-1990 - Combination therapy with intermediate
  and short- acting insulin.
• 1975 low dose insulin for treatment of DKA
• 1991- DCCT Trial MDI and insulin pumps

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Insulin Therapy

• 1923-1973 DKA treated with doses of insulin of
  25-100 U every hour.
• 1973-74 3-4 papers in Lancet and BMJ showing
  DKA patients successfully treated with 5 U/hr.
  Argued that these patients were insulin
  sensitive
• HNKK patients reported to be exquisitely insulin
  sensitive
• How could sick people be insulin sensitive.

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Insulin Therapy

• Compare insulin action in patients with DKA or
  HHNK with insulin action in healthy subjects.
• Experiment measure the rate of decline of blood
  sugar in response to a fixed dose of insulin in
  patients with DKA, HNKK and controls and compare

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BLOOD GLUCOSE RESPONSE TO INSULIN INFUSION
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BLOOD GLUCOSE RESPONSE TO INSULIN INFUSION
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Insulin Newer Twists

• Inhaled insulin
• Oral Insulin
• Closed loop feed back
• Insulin in the ICU
• How does insulin work?

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Results

• 1548 pts. ? 783 conventional (C)
  765 intensive (I)
• Similar age, gender, BMI, severity of illness,
  diabetes (13), malignancy
• I - 99 given insulin, avg. daily dose 71
  u, avg. 0600 BG 103
• C - 39 given insulin, avg. daily dose 33
  u, avg. 0600 BG 173

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How does Insulin work?

• Lowers glucose by driving glucose into muscle
  cells - MIRKO mouse
• Lowers glucose by decreasing hepatic glucose
  production - LIRKO mouse
• Brain IRKO mouse
• Beta cell IRKO mouse
• Adipose IRKO mouse

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Insulin

• The holy grail - cells that make insulin in
  response to glucose and are not
  recognized/destoyed by the immne system