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Diabetes : 'dia' = through - 'betes' = to go

Diabetes : 'dia' = through - 'betes' = to go. 1500 B.C . Ancient Egyptians had a number of remedies for combating the passing of too much urine (polyuria).

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Diabetes : 'dia' = through - 'betes' = to go

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  1. Diabetes: 'dia' = through - 'betes' = to go 1500 B.C. Ancient Egyptians had a number of remedies for combating the passing of too much urine (polyuria). Hindus in the Ayur Veda recorded that insects and flies were attracted to the urine of some people, that the urine tasted sweet, and that this was associated with certain diseases. 1000 B.C. The father of medicine in India, Susruta of the Hindus, diagnosed Diabetes Mellitus (DM). Early Greeks had no treatment for DM, latter Greeks like Aretaeus, Celsus and Galen described DM. Celsus described the pathologic condition "diabetes"

  2. Diabetes: 'dia' = through - 'betes' = to go 1798 A.D. John Rollo certifies excess sugar in the blood. 1889 A.D. Mehring and Minkowski produce DM in dogs by removing the pancreas. 1921 A.D. Banting and Best find insulin is secreted from the islet cells of the pancreas.

  3. Diabetes is a disease that is the 5th leading cause of death in the USA

  4. 23.6 Million Americans have Diabetes (8% pop) More have pre-diabetes

  5. There are two (or 3) different types of diabetes and the diseases are very different

  6. There are three categories of diabetes mellitus: Insulin-Dependent Diabetes Mellitus (IDDM) [also called "Type 1" diabetes] and Non Insulin-Dependent Diabetes Mellitus (NIDDM) ["Type 2"] Inherited Forms of Diabetes Mellitus (MODY)

  7. There are three categories of diabetes mellitus: IDDM (also called Type 1 diabetes) is characterized by little (hypo) or no circulating insulin; most commonly appears in childhood. It results from destruction of the beta cells of the islets. The destruction results from a cell-mediated AUTOIMMUNE ATTACK of the beta cells. What triggers this attack is still a mystery IDDM is controlled by carefully-regulated injections of insulin. (Insulin cannot be taken by mouth)

  8. Inhalable insulin was introduced in mid-2006 The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed. Once it has been absorbed, it begins working within the body over the next few hours. Diabetics still need to take a longer acting basal insulin by injection. It has been concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective."[\ In October 2007, Pfizer announced that it would be discontinuing the production and sale of Exubera due to poor sales. Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics. PFIZER LOSS = 2.8 billion

  9. For many years, insulin extracted from the glands of cows and pigs was used. However, pig insulin differs from human insulin by one amino acid; beef insulin by three. Although both work in humans to lower blood sugar, they are seen by the immune system as "foreign" and induce an antibody response in the patient that blunts their effect and requires higher doses. Two approaches were taken to solve this problem:

  10. There are three categories of diabetes mellitus: Two approaches have been taken to solve this problem: Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. This approach is expensive, so now the favored approach is to Insert the human gene for insulin into E.coli and grow recombinant human insulin in culture tanks. Insulin is not a GLYCOPROTEIN so E. coli is able to manufacture a fully-functional molecule (trade name = Humulin). Yeast is also used (trade name = Novolin). Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.

  11. Each cell has thousands of proteins. In many cases a missing or defective protein has no effect

  12. Inherited Forms of Diabetes Mellitus • Some cases of diabetes result from mutant genes inherited from one or both parents. • Examples: • mutant genes for one or another of the transcription factors needed for transcription of the insulin gene . • mutations in one or both copies of the gene encoding the insulin receptor. • These patients usually have extra-high levels of circulating insulin but defective receptors. • The mutant receptors • may fail to be expressed properly at the cell surface or • may fail to transmit an effective signal to the interior of the cell.

  13. Diagnostic Diabetes: diagnosing maturity-onset diabetes of the young (MODY)

  14. Diagnosing MODY • What is MODY? • Different types of MODY- Glucokinase MODY- Transcription factor MODY • Separate from Type 1, Type 2 and genetic syndromes

  15. MODY (inherited) MODY is caused by a change in a single gene.  6 genes have been identified that account for 87% of MODY:  HNF1-a Glucokinase HNF1-b HNF4-a IPF1   Neuro D1 MOST ARE TF’s that modulate insulin transcription Important to diagnose MODY

  16. Diabetes in Young Adults (15-30 years) Type 2 Type 1 MODY MIDD 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 Age of diagnosis

  17. Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members Off insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis Must be diabetes in one parent (2 generations) and ideally a grandparent or child ( 3 generations) Diagnostic criteria for MODY • Early-onset diabetes • Not insulin-dependent diabetes • Autosomal dominant inheritance • Caused by a single gene defect altering beta-cell function, obesity unusual Tattersall (QJM 1974)

  18. The Genetic Causes of MODY MODY 75%Transcription factors 11%MODY x 14%Glucokinase(MODY2) 3%HNF4 3%HNF1 <1%IPF1 <1%NeuroD1 69%HNF1(MODY3) Frayling, et al Diabetes 2001

  19. Transcription factor (HNF-1a) Glucokinase Normal Two subtypes of MODY Glucokinase and Transcription factor 20 16 12 Glucose (mmol/l) 8 . . 4 0 0 20 40 60 80 100 Age (yr..) Pearson, et al Diabetes 2001

  20. Glucokinase and Transcription factor diabetes MODY Transcription factormutations Glucokinasemutations (HNF-1, HNF-1b, HNF-4) Onset at birthStable hyperglycemiaDiet treatmentComplications rare Adolescence/young adult onsetProgressive hyperglycemia1/3 diet, 1/3 other, 1/3 InsulinComplications frequent

  21. MODYDiagnostic Genetic Testing: why do it? • Makes diagnosis : defines monogenic and defines subtype • Differentiates from type 1 • Helps define prognosis • Helps family counselling • Helps treatment decisions

  22. Inherited Forms of Diabetes Mellitus a mutant version of the gene encoding glucokinase, the enzyme that phosphorylates glucose in the first step of glycolysis. Mutant version of insulin gene TFs mutations in the gene encoding part of K+channel in the plasma membrane of the b cell. The channels fail to close properly causing the cell to become hyperpolarized and blocking insulin secretion. mutations in several mitochondrial genes which reduce insulin secretion by b cells. These diseases are inherited from the mother as only her mitochondria survive in the fertilized egg. While symptoms usually appear in childhood or adolescence, patients with inherited diabetes differ from most children with NIDDM in having a history of diabetes in the family and not being obese.

  23. Inherited Forms of Diabetes Mellitus MODY GENES like Mutant glucokinase insulin gene TFs K+channel of the b cell. IR some mitochondria genes

  24. Of 20+ million Americans with Diabetes, only 10% have typeI diabetes

  25. Most diabetics Have Type II diabetes T2DM or NIDDM

  26. 90% of diabetics in industrialized nations have Type II diabetes

  27. Type II diabetes Defined by insulin resistance insulin resistance-inability to respond to insulin

  28. Hyperglycemia causes retinopathy, neuropathy, and nephropathy

  29. Type II diabetes-patients are insulin resistance so can’t get glucose into cells

  30. How do you get high blood glucose? Glucose comes from the food you eat and is also made in your liver and muscles. Your blood carries the glucose to all the cells in your body. Insulin controls glucose disposal into fat and skeletal muscle The pancreas releases insulin into the blood. Insulin helps the glucose from food get into your cells. If your body doesn't make enough insulin or if the insulin doesn't work the way it should, glucose can't get into your cells. It stays in your blood instead. Your blood glucose level then gets too high, causing pre-diabetes or diabetes.

  31. Type II diabetes research related to adipocytes

  32. Adipocytes accumulate lipid accumulate lipid insulin sensitive insulin sensitive Endocrine functions Endocrine function

  33. Most patients with Type II diabetes are obese > 85%

  34. Strong link between T2DM and Obesity

  35. Many diseases due to loss or defect of one protein Sickle Cell Anemia Huntington’s Disease Type I Diabetes MODY

  36. Many diseases due to loss or defects in many proteins Heart Disease Cancer Type II Diabetes

  37. Very hard to cure diseases that have multiple proteins defective

  38. What is pre-diabetes? Pre-diabetes is a condition in which blood glucose levels are higher than normal but are not high enough for a diagnosis of diabetes. People with pre-diabetes are at increased risk for developing type 2 diabetes and for heart disease and stroke. The good news is if you have pre-diabetes, you can reduce your risk of getting diabetes. With modest weight loss and moderate physical activity, you can delay or prevent type 2 diabetes and even return to normal glucose levels.

  39. How does Exercise work Exercise results in an increase in GLUT4 vesicles moving to the PM The effect is independent of insulin The effects of insulin and exercise are additive. Exercise, even in the absense of WEIGHT LOSS can reduce blood glucose levels and increase insulin sensitivity

  40. What are the signs of diabetes? being very thirsty urinating often feeling very hungry or tired losing weight without trying having sores that heal slowly having dry, itchy skin losing the feeling in your feet or having tingling in your feet having blurry eyesight may have had one or more of these signs before you found out you have diabetes. Or may have had no signs at all. A blood test to check your glucose levels will show if you have pre-diabetes or diabetes.

  41. A1C, also known as glycated hemoglobin or glycosylated hemoglobin, indicates a patient's blood sugar control over the last 2-3 months. A1C is formed when glucose in the blood binds irreversibly to hemoglobin to form a stable glycated hemoglobin complex. Since the normal life span of red blood cells is 90-120 days, the A1C will only be eliminated when the red cells are replaced; A1C values are directly proportional to the concentration of glucose in the blood over the full life span of the red blood cells.

  42. A1C values are not subject to the fluctuations that are seen with daily blood glucose monitoring. The A1C value is an index of mean blood glucose over the past 2-3 months but is weighted to the most recent glucose values. Values show the past 30 days as ~50% of the A1C, the preceding 60 days giving ~25% of the value and the preceding 90 days giving ~25% of the value. This bias is due to the body's natural destruction and replacement of RBC. Because RBCs are constantly being destroyed and replaced, it does not take 120 days to detect a clinically meaningful change in A1C following a significant change in mean blood glucose.

  43. WHY IS IT SO HARD TO TREAT NIDDM

  44. Medications for NIDDM Many types of diabetes pills can help people with T2DM lower their blood glucose. Each type of pill helps lower blood glucose in a different way. Sulfonylureas- stimulate your pancreas to make more insulin.Biguanides decrease the amount of glucose made by your liver.a glucosidase inhibitors slow the absorption of the starches you eat.

  45. Medications for NIDDM Thiazolidinediones TZDs-make you more sensitive to insulin. Meglitinides -stimulate your pancreas to make more insulin.D-phenylalanine derivatives -help your pancreas make more insulin quickly.Combination oral medicines put together different kinds of pills.

  46. Gila monsters are one of only two venomous lizards in the world, the other being the closely related beaded lizards

  47. A fairly new diabetes treatment from Eli Lilly and Amylin that is extracted from the saliva of the Gila monster received approval from the Food and Drug Administration in April 2005 Byetta, which was co-developed by both companies, improves blood sugar control in patients with type 2 diabetes. The drug, developed from a compound in the toxic saliva of a rare lizard found only in the Southwest U.S. and Mexico. Came on Market in June of 2005 Used in patients who aren't getting enough insulin through oral medication

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