Transcript IntroToDMWUinSTLDiabRsrch - 2013-08-05 COLOR

Introduction to
Diabetes Mellitus
Philip E. Cryer, M.D.
Irene E. and Michael M. Karl Professor of
Endocrinology and Metabolism in Medicine,
Washington University in St. Louis
“One of the symptoms of an approaching
nervous breakdown is the belief that
one’s work is terribly important.”
Bertrand Russell (1872-1970)
Diabetes is Serious
Increasingly Common
~26 million in U.S.
~285 million world-wide in 2010
(~438 million by 2030)
Potentially Devastating
2 to 4-fold Increased Risk of MI or
CVA, Most Common Cause of
Blindness, ESRD, Nontraumatic
Amputations
Extraordinarily Expensive ~$245,000,000,000/year in U.S.
Treatable, but Incurable,
Chronic Disease
Treatment Makes a Difference for People with Diabetes
c
Hyperglycemia Causes Symptoms
of Diabetes Mellitus
Increased glucose production plus decreased
glucose clearance into insulin-sensitive tissues
(e.g., muscle)  hyperglycemia.
 Polyuria (osmotic diuresis) and polydipsia
 Weight loss despite polyphagia
 Others  Blurred vision, Symptoms of
vulvovaginitis or other infections
Diagnosis and Ongoing Assessment
of Diabetes Mellitus
Diagnosis of Diabetes: Reproducibly elevated plasma
glucose concentrations . . .
 Fasting plasma glucose  126 mg/dL (7.0 mmol/L)
 Random plasma glucose  200 mg/dL (11.1 mmol/L)
Assessment of Glycemic Control:
 Hemoglobin A1c
 Self Monitoring of Blood Glucose
 Continuous Glucose Sensing
Types of Diabetes Mellitus
An estimated 26 million Americans, and 285 million
people world-wide, have diabetes.
 Type 1 Diabetes Mellitus ( 5%)
 Type 2 Diabetes Mellitus ( 95%)
 Other types of diabetes include that due to
pregnancy, pancreatectomy or pancreatitis,
Cushing’s syndrome, Acromegaly,
Pheochromocytoma or Glucagonoma
among others.
Characteristics of Types 1 and 2
Diabetes Mellitus
T1DM
T2DM
(~0.25%) (~5.0%)
Typical Age of Onset (years)
< 30
> 40
Typical Body Habitus
Lean
Obese
No
Yes
Weeks
Years
Ketosis - Prone
HLA (DR3/DR4; DQB non-Asp57)
Associations
Yes
No
Yes
No
Islet Cell, Insulin, GAD Antibodies
Yes
No
More Common in Minorities
Clinical Onset
Type 1 Diabetes Mellitus
Autoimmune pancreatic -cell destruction 
absolute insulin deficiency  diabetes.
 Genetic susceptibility: ~25-50% concordance
in monozygotic twins. ? Genes
 Precipitating factor(s): Unknown (? viral
infection, ? toxins, ? dietary factors)
Type 2 Diabetes Mellitus
Initially insulin resistance with relative insulin
deficiency, then progressive insulin deficiency.
 Genetic susceptibility: ~25-50%
concordance in monozygotic twins.
? Genes
 Precipitating factor(s): Obesity and
Sedentary Life Style
Regardless of which is the primary abnormality,
relative or absolute insulin deficiency causes
clinical diabetes.
Complications of Diabetes Mellitus
Acute Complications: Diabetic Ketoacidosis,
Nonketotic Hyperosmolar Syndrome,
(Hypoglycemia)
Chronic Complications:
Specific  Retinopathy, Nephropathy,
Neuropathy (“microvascular” complications)
Nonspecific  Premature Atherosclerosis
(“macrovascular” complications)
Treatment of Diabetes Mellitus
Treatment , including glycemic control, makes a difference
for people with diabetes (DCCT, UKPDS).
• Diet/Exercise
• Oral Hypoglycemic Agents
Sulfonylureas, Glinides
Biguanides (metformin)
Thiazolidinediones
-Glucosidase Inhibitors
DPP-IV Inhibitors
SGLT-2 Inhibitors
• Parenteral GLP-1
Receptor Agonists
• Insulin
• Risk Factor Reduction
(prevention of
chronic
complications
Were it not for iatrogenic hypoglycemia, diabetes would be
rather easy to treat.
“Contradictions do not exist. Whenever
you are facing a contradiction, check your
premises. You will find that one of them is
wrong.”
Ayn Rand (1905-1982)
Atlas Shrugged (1957)
Washington University in St. Louis
and Diabetes Research
Philip E. Cryer, M.D.
Irene E. and Michael M. Karl Professor of
Endocrinology and Metabolism in Medicine,
Washington University in St. Louis
The Crucible of Science.
The Story of the Cori Laboratory
By John H. Exton
Oxford University Press, New York, 2013
Carl and Gerty Cori
Born, Prague, 1896
Medical Graduates, Prague, 1920
Married, Vienna, 1920
To U.S., Buffalo, 1922
Washington University in St. Louis, 1931-1957/1966
Carl: Chair of Pharmacology, 1931
Chair of Biological Chemistry, 1946
Gerty: Professor
Nobel Prize in Physiology or Medicine, 1947
Nobel Laureates, Cori Lab
1947 Carl and Gerty Cori
1959
1959
1970
1971
1974
1992
Arthur Kornberg
Severo Ochoa
Luis Leloir
Earl Sutherland
Christian de Duve
Edwin Krebs
Enzymatic mechanisms, and
actions of insulin, glucagon
and epinephrine on, glycogen
and glucose metabolism
DNA polymerase
Polynucleotide phosphorylase
Nucleotide-sugar combinations
Cyclic AMP
Lysosomes
Phosphorylation
William H. Daughaday (1918-2013)
Suburban Chicago, Harvard College and Medical School,
and Washington University in St. Louis
1947 Barnes Hospital, Asst. Resident (131I therapy program)
1948 Washington University, Fellow (Cori lab)
1950 Director of the Metabolism Division (through 1984)
Discovery of “sulfation factor” = somatomedin = insulinlike growth factor I and II. Also, Corticosteroid binding
globulin. National Academy of Sciences, 1986.
David M. Kipnis (1927-
)
Baltimore, University of Maryland, John Hopkins, Duke and
Washington University in St. Louis
1955 Washington University, Fellow (Cori lab)
1960 Metabolism Division
1973 Chair, Department of Medicine (through 1993)
Studied insulin stimulation of glucose transport/phosphorylation and of amino acid uptake in muscle, glucagon actions
in vivo, cyclic nucleotides, alanine and glutamine metabolic
cycles and islet biology. Demonstrated the incretin effect,
insulin deficiency as a cause of diabetes, and generic
mechanisms of glucose counterregulation in humans.
National Academy of Sciences, 1981.
Banting Medal for Scientific Achievement,
American Diabetes Association
1955
1969
1970
1977
1979
1987
1994
1995
Carl F. Cori
Earl W. Sutherland
Paul Lacy
David M. Kipnis
Charles R. Park
Joseph Larner
Philip E. Cryer
Franz M. Matschinsky
Koch Medal, The Endocrine Society
William H. Daughaday
More Recent Senior Washington University
Diabetes Investigators
M. Alan Permutt – islet biology including ER stress,
Wolfram Gene
Philip E. Cryer – glucose counterregulation and
hypoglycemia in diabetes
Emil R. Unanue – immunology of type 1 diabetes
Clay F. Semenkovich – fatty acid synthase
Kenneth Polonsky – calculation of insulin secretory rate
Fumihiko Urano – islet biology including ER stress,
Wolfram syndrome
Jean E. Schaffer and Many Others (The Diabetes
Research Center lists 119 investigators)