DIABETES , THE WHOLE Story M.Mashahit Fayoum University

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.

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.

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 into

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

Diabetes

250 BCE by the Greek Apollonius Of Memphis

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 urination.

• In 1776 Matthew Dobson confirmed that

the sweet taste comes from an excess of a kind of sugar in the urine and blood.[5]

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]

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

Avicenna Also

• Avicenna also described diabetes insipidusvery 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).

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 longer, pathogenesis of diabetes has only been understood experimentally since about

The Islets of Langerhans

• 1869 by an anatomist named Paul Langerhans

•

Thanks Ants

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

• 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

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.

Is it related ??

• The First world War

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 Meringand 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]

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%.

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]

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. Bantingand 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.

?????

•Other Nobel Prizes related to insulin

• 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]

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]

•

• Development of the long acting insulin NPH in

the 1940s by Novo-Nordisk.[2]

•

The Second World WAR

•SU• First 1955.

• Second 1982

• third generations

1949Rachmiel Levine, discovers that

insulin works like a key, transporting glucose into cells. 1949

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

• 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.

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.

• 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.

1956

6/21/2015 40

• 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.

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.

Pancreatic transplantation

• 1966

• The first successful pancreas transplant is performed at the University of Minnesota Hospital.

• 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.

• 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.

• 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.

HbA1c

• 1977

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

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.

• 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.

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

1988

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

• 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

Then

• ACCORD

• VADT

• ADVANCE

• STENO TRIALS

• OTHERS

• 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.

• 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.

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.

INSULIN ANALOGUES

• LISPRO 1996

• GLARGINE

• DETEMIR

• ASPART

• GLULISINE

• DEGLUDEC

• 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.

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]

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.

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.

• 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.

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.

• 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, exenatideworks by increasing insulin production in response to blood glucose levels.

• Then others as liraglutide ,,,

• 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 gliptinsand others

• 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

• Novo nordisk press release Feb 2015

oral GLP-1RA Somaglutide

Guidelines 2006 -2015

6/21/2015 69

Add basal or intensify insulin

Lifestyle intervention and metformin

Add sulfonylurea(least expensive)

Add basal insulin (most effective)

Add TZD

Add TZDAdd 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

ADA/EASD Consensus Algorithm for

Management of DiabetesDiabetes 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-validatedtherapies

Tier 1: Well-validated core therapies

Step 1 Step 2 Step 3

Amylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected patients

*Useful when hypoglycemia is to be avoided

IDF guidelines as of December 2011

IDF Treatment algorithm 2011

www.idf.org/treatment-algorithm-people-type-2-diabetes

IDF treatment algorithm for people with type 2 diabetes developed 2011

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

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-i

or

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-RA Mealtime Insulin Figure2.An -hyperglycemictherapyinT2DM:Generalrecommenda ons Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Insulin (basal)

+

Egyptian Diabetes Profile

Number of people with diagnosed diabetes in 2013 is

7,687,100

http://www.diabetesatlas.org/map cited 10-5-2011

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

Diabetes burden is not yet fully addressed…

175 million people with diabetes are undiagnosed

International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

Prevalence* (%) estimates of diabetes (20-79 years), 2013

International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

Thank You

References[ ]

– Jump up^ Ripoll, Brian C. Leutholtz, Ignacio. Exercise and disease management (2nd ed.). Boca Raton: CRC Press. p. 25. ISBN 978-1-4398-2759-8.

– ^ Jump up to:a b c d e f g h i editor, Leonid Poretsky, (2009). Principles of diabetes mellitus (2nd ed.). New York: Springer. p. 3. ISBN 978-0-387-09840-1.

– Jump up^ Dallas, John (2011). "Royal College of Physicians of Edinburgh. Diabetes, Doctors and Dogs: An exhibition on Diabetes and Endocrinology by the College Library for the 43rd St. Andrew's Day Festival Symposium"

– Jump up^ Medvei, Victor Cornelius (1993). The history of clinical endocrinology. Carnforth, Lancs., U.K: Parthenon Pub. Group. pp. 23–34. ISBN 1-85070-427-9.

– Jump up^ Dobson, M. (1776). "Nature of the urine in diabetes". Medical Observations and Inquiries 5: 298–310.

– ^ Jump up to:a b Patlak M (December 2002). "New weapons to combat an ancient disease: treating diabetes". The FASEB Journal 16 (14): 1853. doi:10.1096/fj.02-0974bkt.PMID 12468446.

– Jump up^ Von Mehring J, Minkowski O. (1890). "Diabetes mellitus nachpankreasexstirpation". Arch Exp Pathol Pharmakol 26 (5–6): 371–387. doi:10.1007/BF01831214.

– Jump up^ Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (November 1991). "Pancreatic extracts in the treatment of diabetes mellitus: preliminary report. 1922". CMAJ145 (10): 1281–6. PMC 1335942. PMID 1933711.

– Jump up^ Bryan, Jenny (2004). Just the Facts Diabetes. Chicago, Illinois: Heinemann Library a division of Reed Elsevier Inc. p. 7. ISBN 1-4034-4600-8.

– ^ Jump up to:a b Anatomy and Physiology: The Unity of From and Function. Saladin Sixth Edition. New York, N.Y. 2012 by McGraw- Hill Companies, InC

– Jump up^ Himsworth (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types". Lancet 227 (5864): 127–30. doi:10.1016/S0140-6736(01)36134-2.

– Jump up^ Yalow RS, Berson SA (July 1960). "Immunoassay of endogenous plasma insulin in man". The Journal of Clinical Investigation 39 (7): 1157–75. doi:10.1172/JCI104130.PMC 441860. PMID 13846364.

– Jump up^ The Diabetes Control And Complications Trial Research Group (September 1993). "The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group". The New England Journal of Medicine 329 (14): 977–86. doi:10.1056/NEJM199309303291401. PMID 8366922.

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