Transcript Diabetes - 9/14

How We Got To Know What We Know About Diabetes
Moe Goodman
September 21, 2016
Diabetes is an Ancient Disease
~1550 BC papyrus by physician Hesy-Ra found in 1862
contains a description of a disease resembling diabetes.
Treatment: a 4 day course of a liquid extract of bones,
wheat, grain, grit, green lead, and earth
Ebers Papyrus
~600 BC Indian description of diabetes, Madhumeha
meaning urine of honey.
~500 AD Susruta described honeyed urines produced by
big eaters.
The Chinese name for diabetes táng niǎo bìng means
sugar urine disease.
The term "diabetes" or "to pass through" was first
used in 250 BCE by the Greek physician Apollonius of
Memphis.
Aretaeus of Cappadocia’s Description of Diabetes
Aretaeus of Cappadocia
Around 100 AD
“Diabetes is … not very frequent ... being a melting
down of the flesh and limbs into urine … for the patients
never stop making water, but the flow is incessant, as if
from the opening of aqueducts. It consists in the flesh
and bones running together into the urine … the illness
develops very slowly. The nature of the disease is
chronic, and it takes a long period to form; but the
patient does not live long once the disease is fully
established; for the melting is rapid, the death speedy.
Moreover life is disgusting and painful; thirst,
unquenchable … and one cannot stop them either from
drinking or making water".
1674
Willis Coins the Term “Mellitus” to Describe the
Sweet Taste of the Urine of Diabetics
In his “Pharmaceutice Rationalis”, Willis devoted a
chapter to the “pissing evil”.
Thomas Willis
1621-1675
1776
He also reported a case of “a certain noble earl” who
suddenly “became much inclined to excessive pissing…
in the space of twenty-four hours, he voided almost a
gallon and a half of limpid, clear, and wonderful sweet
water, that tasted as if it has been mixed with honey”.
Dobson Finds Sweetness is Due to Sugar
He also found increased sugar in blood
Matthew Dobson
1732-1784
1855
Claude Bernard Discovers Glycogen and the Production
of Glucose by The Liver
In animals fed only protein more glucose leaves by the hepatic vein
than enters through the portal vein.
Claude Bernard
1813-1878
Extracts of freshly excised livers contain little glucose, but after
standing contain large amounts of glucose.
Boiling the extract prevents the appearance of glucose.
A “fermentation process” released glucose from a precursor which
he called glycogen.
Livers of animals fed only meat for two weeks, but not other
tissues, contain large amounts of stored glucose.
He concluded that liver forms and secretes glucose into the blood.
1869
Paul Langerhans
1848-1888
Langerhans Discovers Small Islets of Tissue Embedded
in the Pancreas
Dietary Therapy in Treatment of Diabetes Mellitus
1858
Recommended diabetics consume large amounts of
sugar to replace that lost in the urine.
Pierre Adolphe Piorry
1794-1879
1871
during the 4-month siege of Paris in the Franco-Prussian
war, diabetics who suffered from starvation had diminished
glucose in their urine.
He experimented with periodic fasting as diabetic therapy. He
observed that exercise increases tolerance to carbohydrate.
Apollinaire Bouchardat
1809-1886
1889
Removal of the Pancreas Produced Diabetes
Mellitus in Dogs
Von Mering studied the role of the pancreas in fat
digestion.
Joseph von Mering
1849-1908
Minkowski, a skilled surgeon, removed the pancreas
The dog showed extreme thirst and excessive
urination…. symptoms of diabetes.
Sugar was found in the urine.
Implantation of a pancreatic fragment temporarily
reduced the appearance of sugar in the urine
Oskar Minkowski
1858-1931
1895
Sharpey Schafer Proposes That Pancreatic Islets
Secrete an Anti-Diabetic Factor
Ligation of the pancreatic duct results in destruction
of most of the pancreas, but not diabetes.
Edward Sharpey Schafer
1850-1935
Removal of the pancreatic remnant results in
diabetes.
Transplantion of the remnant reversed diabetes for as
long as the remnant survived.
Proposed that islet tissue produce a substance that
he called insuline
1901
Eugene Opie Discovers Severe Destruction of the Islets of
Langerhans in Pancreata of Deceased Diabetic Patients
Eugene Opie
1873-1971
.
Drawing of an Islet of a patient
who died of diabetes
1910
Allen Introduces “Starvation Treatment”
Considered the best therapy for diabetics before the
introduction of insulin.
Restricted calorie intake to 1000 calories per day.
Frederick Allen
1879-1964
Diet was rich in fat and protein with only 10 grams of
carbohydrate per day.
1916
Joslin Publishes The Treatment of Diabetes Mellitus,
Joslin was the first physician to specialize in diabetes treatment and
management.
Advocated diet and exercise to control symptoms including Allen’s
“starvation diet”.
Elliot Joslin
1869-1962
Advocated patient education enabling patients to take control of
their disease.
Became the foremost authority in treatment and management of
diabetics.
Championed tight control of glucose to minimize complications.
Early Efforts to Find the Pancreatic Antidiabetic Factor
1906
Extract of calf pancreas “Acomatrol” injected into dying
comatose patient showed improvement despite severe side effects and
died days later after the supply of acromatrol ran out.
George Zuelzer
1870-1949
1915-1919 aqueous extracts administered to diabetics at Rockefeller
definitively proved that a substance from the pancreas lowered blood
sugar.
Israel Kleiner
1885-1966
1916
Paulescu Prepares “Pancreine”, an Active Extract of
Bovine Pancreas
Pancreine lowered blood glucose in diabetic dogs.
Nicolae Paulescu
1869-1931
Call to military service in World War I prevented completion
of experiments.
Experimental results were published in June of 1921 including
a statement that toxic side effects made pancreine unsuitable
for humans.
Pancreine was patented in April 1922
1922
The Discovery of Insulin
Frederick G. Banting
1891-1941
Charles Best
1899-1978
In early 1923, just one year after the first test
injection, insulin became widely available and
by the fall 25,000 patients were treated in the
United States and Canada.
John Macleod
1876-1935
James B. Collip
1892-1965
First Patients Successfully Treated with Insulin
Leonard Thompson
1908-1935
Elizabeth Hughes Gossett
1907-1981
Jim Havens
1900-1960
1923
Nobel Prize Awarded to Banting and McCleod
Banting shares prize money with Best
McCleod shares prize money with Collip
1923
Kimball and Murlin Isolate a Blood Glucose-Raising
Substance Contaminating Insulin Preparations
They name this glucose agonist Glucagon
John R Murlin
1874-1960
Injection of glucagon to dogs and rabbits results in a
rapid increase in blood glucose concentration
1926
Abel Crystallizes Insulin
Found that the substance isolated was a protein
Insulin was the first large molecule with hormonal activity.
John Jacob Abel
1857-1938
Deflected interest away from glucagon contaminant
1936
Harold Himsworth
1905-1993
Himsworth Distinguishes Between the Two Types of
Diabetes Mellitus
1942
Homemade Insulin
1940 Eva and Victor marry in Prague and flee to
Shanghai to escape the Nazis.
1941 Eva develops diabetes and obtains insulin from
local pharmacy.
Eva Saxl
1921-2002
1942 Japan closes off Shanghai-Eva runs out of Insulin
Victor and Eva prepare insulin from water buffalo
pancreas following Banting and Best protocol as
described in a physiology text book.
1942-1945 Eva and Victor’s insulin saves 400 diabetics
in Shanghai ghetto.
1947 Saxyls emigrate to the United States and Eva
begins career as advocate for diabetes treatment
and therapy.
Victor Saxyl
~1915-1968
1948
The Hyperglycemic Glycogenolytic Factor (Glucagon)
is Present in Pancreatic Alpha Cells and Gut Mucosa
Injection of glucagon stimulates hepatic
glycogen breakdown and increased plasma
glucose concentrations.
Christian DeDuve
1917-2013
Glucagon is present in extracts of pancreas
prepared after destruction of insulin-secreting
cells, i.e. the Alpha cells.
Glucagon is also present in the lining of the
small intestine.
Earl Sutherland
1915-1974
1949
Levine Discovers that Insulin Facilitates the
Entry of Glucose into Cells
Insulin
Rachmiel Levine
1910-1998
galactose
concentration
minutes
1951-53
Frederick Sanger
1918-2013
Sanger Describes the Complete Amino Acid
Sequence of Insulin
1957
Eli Lilly Scientists Describe the Amino Acid
Sequence of Glucagon
1960
Berson and Yalow Develop the Radioimmunoassay for Insulin
Fasting plasma insulin concentrations are higher in recently
diagnosed maturity onset diabetics than normal controls.
Insulin secretion increases in both groups in response to
a glucose challenge.
Solomom Berson
1918-1972
Plasma insulin concentrations increase faster in normal
subjects than in diabetics, but increase twice as much overall
in diabetics and remain elevated long after they return to
baseline in normal subjects.
Rosalyn Yalow
1921-2011
1965
David Kipnis
1927-2014
The Incretin Effect on Insulin Secretion
1967
Donald Steiner
1930-2014
Discovery of Proinsulin
1971
Jesse Roth
1934-
Discovery of Insulin Receptors on the Cell Membrane
1975
Insulin and Glucagon Are a Bihormonal Metabolic Regulator
Insulin
Roger Unger
1924-
Blood
Glucose
Glucagon
1977
Hemoglobin A1C Becomes the Gold Standard for
Measuring Long-term Diabetes Control.
~Valine + glucose = Hemoglobin A1c
Hemoglobin A (beta chain)
(Hb A1c)
1978 Human insulin successfully produced in bacteria
1982 Recombinant human insulin approved for human treatment
1982-1998
Type I Diabetes is an Autoimmune Disease
1986
The Product of the Glucagon Gene (Proglucagon) Contains
Several Bioactive Molecules Embedded within its
Structure
158
1
Graeme Bell
1950-
Glucagon
Proglucagon
30 33
1
GRPP
Pancreatic
 Cells
GLP-1
61 69 72
GLP-2
158
78
Glucagon
Principal Glucagon-like Fragment
69
1
Glicentin
Intestinal
K Cells
1
30 33
GLP-1
69
GRPP
Oxyntomodulin
158
114 125
78
GLP-2
Actions of the Incretin Hormones Glucose-Dependent Insulinotropic
Peptide (GIP) and Glucagon-like Peptide 1 (GLP1)
Studies on the Actions of the Glucagon-Like Peptide (GLP1)
Have Produced New Therapy
GLP1 and GIP are rapidly destroyed by the enzyme dipeptidyl peptidase-4 (DPP-4
2005
Exenatide (Byetta) is a GLP-1 mimetic derived from exendin,a closely related
hormone (53% homologous) found in the saliva of the Gila monster.
2006
JANUVIA (sitagliptin phosphate), the first in a new class of drugs that inhibit
DPP-4 and prolongs the presence of GLP-1 in the blood.
Pharmacologic Agents for Treatment of Diabetes
1942 Sulfonyl ureas stimulate insulin secretion.
1995 Metformin is a biguanide that prevents glucose production in the liver.
1996 Acarbose is an alpha-glucosidase inhibitor that slows digestion of some carbohydrates.
1997 Thiazolidinediones improve insulin sensitivity in muscle cells
1998 Repaglinide stimulates insulin secretion in the presence of glucose.
2013 Invokana blocks the activity of sodium glucose transport protein in the kidney,
reducing glucose re-uptake and increasing excretion of glucose in the urine.
20?? Glucagon receptor antagonists;