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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.

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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 is the belief that one’s work is terribly important.”

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 is the belief that one’s work is terribly important.”


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

Hyperglycemia Causes Symptomsof Diabetes Mellitus


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

Diagnosis and Ongoing Assessment of Diabetes Mellitus


Types of diabetes mellitus
Types of Diabetes Mellitus concentrations . . .

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
Characteristics of Types 1 and 2 concentrations . . . Diabetes Mellitus

T1DM

T2DM

(~0.25%)

(~5.0%)

Typical Age of Onset (years)

< 30

> 40

Typical Body Habitus

Lean

Obese

More Common in Minorities

No

Yes

Clinical Onset

Weeks

Years

Yes

No

Ketosis - Prone

HLA (DR3/DR4; DQB non-Asp57)

Associations

Yes

No

Yes

No

Islet Cell, Insulin, GAD Antibodies


Type 1 diabetes mellitus

Autoimmune pancreatic concentrations . . . -cell destruction  absolute insulin deficiency  diabetes.

Type 1 Diabetes Mellitus

 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.

Type 2 Diabetes Mellitus

 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 deficiency, then progressive insulin deficiency.: Diabetic Ketoacidosis, Nonketotic Hyperosmolar Syndrome, (Hypoglycemia)

Chronic Complications:

Specific  Retinopathy, Nephropathy, Neuropathy (“microvascular” complications)

Nonspecific  Premature Atherosclerosis (“macrovascular” complications)

Complications of Diabetes Mellitus


Treatment of diabetes mellitus

Treatment , including glycemic control, makes a difference for people with diabetes (DCCT, UKPDS).

Treatment of Diabetes Mellitus

  • Diet/Exercise

  • Oral Hypoglycemic Agents

  • Parenteral GLP-1 Receptor Agonists

  • Insulin

  • Risk Factor Reduction

Sulfonylureas, Glinides Biguanides (metformin) Thiazolidinediones

-Glucosidase Inhibitors DPP-IV Inhibitors

SGLT-2 Inhibitors

(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 contradiction, check your premises. You will find that one of them is wrong.”

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. contradiction, check your premises. You will find that one of them is wrong.”

The Story of the Cori Laboratory

By John H. Exton

Oxford University Press, New York, 2013


Carl and Gerty Cori contradiction, check your premises. You will find that one of them is wrong.”

Born, Prague, 1896 Married, Vienna, 1920

Medical Graduates, Prague, 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 contradiction, check your premises. You will find that one of them is wrong.” Laureates, Cori Lab

1947 Carl and Gerty Cori

Enzymatic mechanisms, and actions of insulin, glucagon and epinephrine on, glycogen and glucose metabolism

1959 Arthur Kornberg DNA polymerase

1959 Severo Ochoa Polynucleotide phosphorylase

1970 Luis Leloir Nucleotide-sugar combinations

1971 Earl Sutherland Cyclic AMP

1974 Christian de Duve Lysosomes

1992 Edwin Krebs Phosphorylation


William H. Daughaday (1918-2013) contradiction, check your premises. You will find that one of them is wrong.”

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 = insulin-like growth factor I and II. Also, Corticosteroid binding globulin. National Academy of Sciences, 1986.


David M. Kipnis (1927- ) contradiction, check your premises. You will find that one of them is wrong.”

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/phosphory- lation 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, contradiction, check your premises. You will find that one of them is wrong.”

American Diabetes Association

1955 Carl F. Cori

1969 Earl W. Sutherland

1970 Paul Lacy

1977 David M. Kipnis

1979 Charles R. Park

1987 Joseph Larner

1994 Philip E. Cryer

1995 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)


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