1. DIABETES , THE WHOLE Story
M.Mashahit Fayoum University

2. Type 2 DM is an old disease….
….still need to be revised
First Description of Diabetes 1550 BC
This papyrus found in 1862
contains descriptions of various
diseases including a polyuric
state resembling diabetes
mellitus.
Treatment recorded was a 4
day course of a liquid extract of
bones, wheat, grain, grit, green
lead and earth.

3. Madhumeha
• Indian physicians around the same time
identified the disease and classified it
as madhumeha or honey urine noting that the
urine would attract ants.

4. táng niǎo bìng (糖尿病),
• The sweet urine symptom of diabetes is
evident in the Chinese name for
diabetes, táng niǎo bìng (糖尿病), meaning
"sugar urine disease". This name has also
been borrowed into Korean and Japanese.
The sweet urine symptom of diabetes is evident in the Chinese name for diabetes, táng niǎo bìng (糖尿病), meaning "sugar urine disease". This name has also been borrowed in

5. Description
• The first complete clinical description by
the Ancient Greek physician Aretaeus of
Cappadocia ”[3] Diabetes mellitus appears to
have been a death sentence in the
ancient era

6. Diabetes
250 BCE by the Greek Apollonius Of Memphis

7. Mellitus
• Added by Thomas Willis in the
late 1600s to separate the
condition from diabetes insipidus
The term "mellitus" or "from honey" was added by Thomas Willis in the late 1600s to separate the condition from diabetes insipidus which is also associated with frequent urina

8. • In 1776 Matthew Dobson confirmed that
the sweet taste comes from an excess of a
kind of sugar in the urine and blood.[5]

9. Hippocrates ?????
• Hippocrates makes no mention of it, which
may indicate that he felt the disease was
incurable. ; he commented that "life (with
diabetes) is short, disgusting and painful."[4]
• It was rare during the time of the Roman
empire with Galen commenting that he had
only see two cases during his career.[2]

10. Avicenna
• in The Canon of Medicine, "describing the
abnormal appetite and the collapse of sexual
functions," and he documented the sweet
taste of diabetic urine. Like Aretaeus before
him, Avicenna recognized a primary and
secondary diabetes. He also described
diabetic gangrene, and treated diabetes using
a mixture of many HERBS

11. Avicenna Also
• Avicenna also described diabetes insipidus
very precisely for the first time, though it was
much later that Thomas Willis differentiated it
from diabetes mellitus in a chapter of his
book Pharmaceutice rationalis (1674).

12. Hundreds and thousands Years
• Although diabetes has been recognized
since antiquity, and treatments of various
efficacy have been known in various regions
since the Middle Ages,
Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in various regions since the Middle Ages, and in legendfor much lon

15. The Islets of Langerhans
• 1869 by an anatomist named Paul Langerhans
•

16. Thanks Ants

17. The Ants and Minkowski
• The discovery of a role for the pancreas in
diabetes is generally ascribed to Joseph von
Mering and Oskar Minkowski, who in 1889
found that dogs whose pancreas
• was removed developed all
the signs and symptoms
of diabetes and died
shortly afterwards

18. • In 1910, Sir Edward Albert Sharpey-
Schafer suggested that people with diabetes
were deficient in a single chemical insulin,
from the Latin insula, meaning island, in
reference to the insulin-producing islets of
Langerhans in the pancreas

19. Joslin
• 1916
• Elliott Joslin, MD, publishes the first edition of
The Treatment of Diabetes Mellitus. A clinician
and educator, Joslin is one of the most
influential voices in diabetes care.

20. Is it related ??
• The First world War

21. The Ortho Surgeon
• The endocrine role of the pancreas in
metabolism, and indeed the existence of
insulin, was further clarified in 1921, when
Sir Frederick Grant Banting and Charles
Herbert Best repeated the work of Von Mering
and Minkowski, and went further to
demonstrate they could reverse
induced diabetes in dogs by giving them an
extract from the pancreatic islets of
Langerhans of healthy dogs.[8]

25. Leonardo AND ELEZABETH
• This led to the availability of an effective
treatment—insulin injections—and the first
patient was treated in 1922. The first successful
patient treated was a 14 year old boy that
weighed on 65 pounds. When he was given the
extract on January 23, his ketonuria and
glycosuria were almost eliminated. His blood
sugar levels dropped as low as 77%.

26. Mass Production
• Six more patients were treated in February of
1922 and quickly experienced an improved
standard of life. A pharmaceutical firm
named Eli Lilly and Company, with the
University of Toronto began the mass
production of insulin by the fall of 1923,
25,000 patients were being treated in Canada
and the United States.[10]

27. Nobel Prize
• For this, Banting and laboratory director John
MacLeod received the Nobel Prize in Physiology
or Medicine in 1923; both shared their Prize
money with others in the team who were not
recognized, in particular Best and Collip. Banting
and Best made the patent available without
charge and did not attempt to control
commercial production. Insulin production and
therapy rapidly spread around the world, largely
as a result of this decision. Banting is honored
by World Diabetes Day which is held on his
birthday, November 14.

29. ?????
•Other Nobel
Prizes related to
insulin

30. • The determination of the amino acid
sequence of insulin (by Sir Frederick Sanger,
for which he received a Nobel Prize). Insulin
was the first protein that the amino acid
structure was determined.[10]
• The radioimmunoassay for insulin, as
discovered by Rosalyn Yalow and Solomon
Berson (gaining Yalow the 1977 Nobel Prize in
Physiology or Medicine)[12]

31. Type-1 and -2
• The distinction between what is now known
as type 1 diabetes and type 2 diabetes was
first clearly made by Sir Harold Percival (Harry)
Himsworth, and published in January 1936.[11]
•

33. • Development of the long acting insulin NPH in
the 1940s by Novo-Nordisk.[2]
•

34. The Second World WAR
•SU
• First 1955.
• Second 1982
• third generations

35. Rachmiel Levine, discovers that
insulin works like a key,
transporting glucose into cells. 1949

36. • Becton Dickinson and Company begins
production of a standardized
insulin syringe designed and approved by the
American Diabetes Association

37. • 1950
• The ADA , and the U.S. Public Health Service
devise a meal planner that divides foods into
six groups, or “exchanges”, based on the
calories, carbohydrate, protein, and fat in each
serving of food.

38. TESTING
• 1953 Tablets for testing urine glucose become
widely available, and urine test strips appear over
the next few years. These options are simpler
than using Benedict’s solution, which must be
mixed with urine and heated over boiling water.
•
• 1964 The Ames Company introduces the first
strips for testing blood glucose by color code.
• 1970 The Ames Company introduces the first
glucose meter.

39. • 1955
• Sulfonylureas, oral medications that stimulate
the pancreas to release more insulin, are
available. New, more potent forms of these
drugs will become available later.

40. 1956
6/21/2015 40

41. • 1961
• Glucagon, a hormone produced by the
pancreas that raises glucose levels, is
introduced by Eli Lilly and Company as a
treatment for severe hypoglycemia.

43. The Thrifty Gene
• The thrifty gene hypothesis is an attempt to explain why people
from some populations are prone to diabetes.
The geneticist James V. Neel proposed the hypothesis, in 1962,
Thrifty genes are genes which enable individuals to efficiently
collect and process food to deposit fat during periods of food
abundance in order to provision for periods of food shortage (
famine).
• Individuals carrying the thrifty genes would thus better survive
times of food scarcity. However, in modern societies with a constant
abundance of food, this genotype efficiently prepares individuals
for a famine that never comes. The result of this mismatch between
the environment in which the brain evolved and the environment of
today is a widespread chronic obesity and related health problems
like diabetes.

44. Pancreatic transplantation
• 1966
• The first successful pancreas transplant is
performed at the University of Minnesota
Hospital.

45. • 1971
• Insulin receptors are discovered
on cell membranes. This discovery raises the
possibility that missing or defective insulin
receptors may prevent glucose from entering
the cells, thus contributing to the insulin
resistance of type 2 diabetes.

46. • 1974
• Development of the Biostator enabled
continuous glucose monitoring and closed
loop insulin infusion.
• Human Leukocyte Antigens (HLAs) are
discovered on cell surfaces. People with type 1
diabetes have specific patterns of HLA that are
associated with varying levels of risk for
diabetes.

47. • 1976
• The first insulin pumps were invented.
• 1978
• Portable insulin pumps are introduced and
researchers achieve normal blood glucose
levels in patients using them. But, due to their
large size, they are impractical at this time.

48. HbA1c
• 1977
• Boston researchers develop a test to measure
glycosylated hemoglobin (A1C). A1C testing
becomes the gold standard for measuring
long-term diabetes control.

49. Insulin production By E Coli
• 1978
• Researchers at the City of Hope National
Medical Center in Duarte, California, and
Genentech, Inc., in San Francisco, induce E.
coli bacteria to produce insulin identical to
human insulin.

50. • 1980
• Introduction of the basal-bolus concept
enabled "intensive insulin therapy" to be used
in the clinic to effectively treat people with
type 1 diabetes.

51. 1982
• Autoantibody is discovered and is found to be
associated with type 1 diabetes.
• 1984 The insulin molecule is identified to be a
target of autoimmune response in individuals
with type 1 diabetes.
• 1986 T1 diabetes --- autoimmune disease

52. 1988
• Dr Gerald Reaven's identification of the
constellation of symptoms now
called metabolic syndrome in 1988

53. • 1989
• American Diabetes Association releases its
first Standards of Care to guide physicians in
the treatment of diabetes.
• 1993
• The Diabetes Control and Complications Trial
(DCCT) TYPE -1
• 1998 UKPDS TYPE -2

54. Then
• ACCORD
• VADT
• ADVANCE
• STENO TRIALS
• OTHERS

55. • Mid-1990s
• The incretin hormone GLP-1 is discovered.
Incretin hormones are secreted from the gut
in response to food, and encourage the body
to produce insulin. Discovery of GLP-1 will
later lead to a new class of diabetes drugs that
can increase insulin secretion in response to
glucose, and even increase the amount of
beta cells in the pancreas.

56. • 1995
• The drug metformin becomes available in the
U.S. Metformin is a biguanide that prevents
glucose production in the liver.
•
• 1996
• The drug acarbose, becomes available in the
U.S. Acarbose is an alpha-glucosidase inhibitor
that slows digestion of some carbohydrates.

57. 1996
• the advent of insulin analogues which had
vastly improved absorption, distribution,
metabolism, and excretion
(ADME) characteristics which were clinically
meaningful based on this early biotechnology
development.

58. INSULIN ANALOGUES
• LISPRO 1996
• GLARGINE
• DETEMIR
• ASPART
• GLULISINE
• DEGLUDEC

59. • 2008
• The results of the ACCORD, ADVANCE and VADT
studies are published and presented at the
American Diabetes Association Scientific
Sessions. All three studies fail to show a benefit
of intensive glycemic control on cardiovascular
outcomes in people with type 2 diabetes who are
at high cardiovascular risk. The results from these
studies lead to clinical recommendations that call
for a more individualized approach for setting
glycemic goals and treatment targets.

60. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM: A Patient-Centered
Approach
1. PATIENT-CENTERED APPROACH
2. BACKGROUND
• Epidemiology and health care impact
• Relationship of glycemic control to outcomes
• Overview of the pathogenesis of Type 2 diabetes
3. ANTI-HYPERGLYCEMIC THERAPY
• Glycemic targets
• Therapeutic options
- Lifestyle
- Oral agents & non-insulin injectables
- Insulin
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

61. TZDs
• 1997
• Troglitazone, brand name Rezulin (Parke-Davis), is
approved by the FDA. It is the first in a class of
drugs known as thiazolidinediones, and it
improves insulin sensitivity in muscle cells. It is
eventually removed from the market due to liver
toxicity. Rosiglitazone also removed because it
leads to heart failure . pioglitazone, also facing
the same troubles.

62. 1998
• The terms “insulin-dependent diabetes”
(IDDM) and “non-insulin-dependent diabetes”
(NIDDM) had long been used to describe
different groups of diabetes patients. The
terms type 1 diabetes and type 2 diabetes are
now accepted to define diabetes by cause
rather than treatment. In addition, the fasting
glucose level for diagnosing diabetes is
lowered from 140 mg/dl to 126 mg/dl.

63. • 1998
• Repaglinide, (Novo Nordisk) is
developed. Repaglinide belongs to a class of
drugs known as meglitinides. They stimulate
insulin secretion in the presence of glucose.

64. Pre diabetes IGT, IFG
• 2002
• The American Diabetes Association defines
prediabetes as impaired fasting glucose (IFG)
and/or impaired glucose tolerance (IGT). IFG is
defined as a fasting blood glucose of 100-125
mg/dl, and IGT is defined as a glucose level from
140 mg/dl – 199 mg/dl two hours after
consuming a glucose-rich drink. Later, A1C levels
of 5.7% to 6.4% are also used to identify
individuals with prediabetes.

65. • 2005
• Exenatide, , is approved in the U.S. as a first-
in-class incretin mimetic (GLP-1) drug to treat
type 2 diabetes. An injectable drug, exenatide
works by increasing insulin production in
response to blood glucose levels.
• Then others as liraglutide ,,,

66. • 2006
• FDA approves (sitagliptin phosphate), the first in
a new class of drugs known as DPP-4 inhibitors
that enhance the body's ability to lower elevated
blood sugar. DPP-4 is an enzyme that naturally
blocks GLP-1 from working, so by inhibiting this
enzyme, GLP-1 works in the gut to promote
insulin secretion.
• Now we have sita- vilda- saxa- lina-allo gliptins
and others

67. • 2013
• FDA approves Invokana (Canagliflozin), the
first in a new class of drugs know as the SGLT-
2 inhibitors, for lowering elevated blood sugar
in patients with type 2 diabetes. SGLT-2
inhibitors block the activity of sodium glucose
transport proteins in the kidney, reducing
glucose re-uptake and increasing secretion of
glucose in the urine

68. • Novo nordisk press release Feb 2015
oral GLP-1RA Somaglutide

69. Guidelines 2006 -2015
6/21/2015 69

70. Add basal or intensify
insulin
Lifestyle intervention and metformin
Add sulfonylurea
(least expensive)
Add basal insulin
(most effective)
Add TZD
Add TZD
Add basal
insulin***
Add
sulfonylurea
If HbA1c ≥7%*
If HbA1c ≥7%
If HbA1c ≥7%
Intensive insulin + metformin +/− TZD**
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Nathan DM et al. Diabetologia 2008;51(1):8-11.
Intensify
insulin***
ADA/EASD Management Algorithm

71. ADA/EASD Consensus Algorithm for
Management of Diabetes
Diabetes Care. 2009, 32:193-203
At diagnosis:
Lifestyle
+
Metformin
Lifestyle+Metformin
+
Pioglitazone
(No hypoglycemia, edema,
CHF, bone loss)
Lifestyle+Metformin
+
Sulfonylurea
Lifestyle+Metformin
+
Intensive insulin
Lifestyle+Metformin
+
Basal Insulin
Lifestyle+Metformin
+
GLP1
(No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle+Metformin
+
Basal Insulin
Tier 2: less well-validated
therapies
Tier 1: Well-validated core therapies
Step 1 Step 2 Step 3
Amylin agonists, Glinides
DPP-4 inhibitors may be
appropriate in selected
patients
*Useful when
hypoglycemia is to be
avoided

73. IDF guidelines as of December 2011

74. IDF Treatment algorithm 2011
www.idf.org/treatment-algorithm-people-type-2-diabetes
IDF treatment algorithm for people with
type 2 diabetes developed 2011

75. HbA1c > 7%
HbA1c > 7%
ADA-EASD Position Statement (2012)
Antihyperglycaemic therapy for T2DM
Inzucchi SE et al . Diabetes Care 2012; April 19th online e-pub DOI:10.2337/dc12-0413
Metformin

76. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-ior
or
or GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime InsulinFigure 2. An -hyperglycemic therapy
in T2DM: General recommenda ons Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Insulin (basal)
+

79. Egyptian Diabetes Profile
Number of people with diagnosed diabetes
in 2013 is
7,687,100
http://www.diabetesatlas.org/map cited 10-5-2011

80. Type 2 diabetes is a major healthcare burden
Diabetes is a huge and growing problem, and the costs to
society are high and escalating
International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

81. Diabetes burden is not yet fully addressed…
175 million people with diabetes
are undiagnosed
International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

82. Prevalence* (%) estimates of diabetes (20-79 years), 2013
International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

83. Thank You

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