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Diabetes Mellitus Types I & II

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1 Diabetes Mellitus Types I & II
James Bresnahan, MS1 Robert Gyory, MS1

2 Introduction How does your body make use of glucose from the food you eat? What is the difference in etiology between type 1 and type 2 diabetes? How does this affect treatment? What is the homeostatic balance between insulin, glucose, glucagon, and stress hormones? How does this differ between nonaffected individuals vs. type 1 diabetics vs. type 2 diabetcs? Why does high blood glucose cause other complications? What are some psychosocial considerations regarding diabetes?

3 -Glucose is your body’s main source of energy
-Glucose is your body’s main source of energy. As you ingest food, complex carbohydrates (such as bread, pasta, potatoes, etc.) are broken down into smaller sugars (disaccharides) and finally monosaccharides (glucose, fructose, and galactose). -Glucose is the most common, therefore it is the most important to regulate. -Glucose can be stored as Glycogen in muscles, liver, and fat. -Glucose is also distributed and utilized by tissues throughout the blood stream.

4 I thought T1DM is about insulin?
Glycogen is a good form of storage. It’s condensed, easily broken down, and its byproducts are used efficiently to make energy. I thought T1DM is about insulin? α-1,6-linkage -Complex chemical reactions take place within cells to turn glucose into glycogen. In order to understand these you need at least a basic concept of organic chemistry and biochemistry, I don’t expect you to know the molecular pathway of glycogen formation. -However, the role of glycogen is very important. You should know this. Glycogen allows glucose to be stored in a very compact way. You can see that compared to free floating glucose in the cell or in the blood stream, this big bulky glycogen molecule renders glucose in a stable formation. The formation of glycogen makes metabolism more efficient. It allows for the short term storage of your most important body fuel. When glycogen stores are depleated, as such by people who run marathons and high intensity cardiovascular exercise, this is what it means to “hit a wall.” When your glycogen stores are depleted, you have to look to other energy sources for fat, such as fat and muscle (extreme cases). Imagine how quickly your body would run out of energy if you weren’t able to efficiently store glycogen and had to rely only on the amount of glucose present in your blood before turning to fat. This is part of our evolutionary adaptation. α-1,4-linkage

5 Without insulin… -Insulin is a peptide hormone released by the pancreas (next slide). When insulin receptors are bound to, there is an upregulation of glucose receptors on the cell membrane. This upregulation allows glucose to enter the cell and be used for a variety of things Stored as glycogen Converted to fat Used for glycolysis, etc.

6 How do you get Type 1 “Diabeetus?”
No!! T1DM is AUTOIMMUNE. Destruction of Pancreatic B-islet cells. What about T2DM? Ask Rob.. If you take nothing else from this lecture, PLEASE, understand that Type 1 Diabetes, or “Juvenile Diabetes” is AUTOIMMUNE in nature. Your own body attacks your own body.

7 What are B-Islet cells? How are they destroyed?
Genetic predisposition Environmental stimuli Lead to antibodies that attack pancreatic Beta cells Diagnosis is bimodal with peaks at 4-6 years and years 3M:2F?? 23.6 per 100,000 per year. The actual destruction of B-islet cells has a variety of components. There is a genetic “predisposition” This means that T1DM is not technically “genetic” In cases of identical twins where one has T1DM, in only 30% of cases the other twin develops T1DM within 10 years. 65% by the age of 60. The chance of “inheriting” this from your parents is even less. 1-4% when mother is affected; 3-8% when father is affected. Therefore, this is not something we can classify as being Autosomal recessive, dominant, co-dominant, sex-linked, etc. This indicates that T1DM is influenced by a number of genes and epigenetic factors. Epigenetic means that other environmental, social, or biological cues outside of strictly your genes control for the expression or repression of certain genes that may affect the presentation of T1DM. Common factors may or may not include (some of these are controversial): Different viruses are thought to have similar shapes to B-islet cells Possible Vitamin-D deficiency Early exposure to cows milk High birth weight Higher socioeconomic status? Many of these are simply correlation links with unknown origins. Basic Pathway to develop T1DM: Genetic predisposition. Something triggers the immune system that attacks B-islet cells After a period of time all B-cells are destroyed and the patient presents as T1DM. General facts: Diagnosis is bimodal (4-6 and peaks) Diabetes is the ONLY autoimmune disorder that is even closely significantly severe in Men, in fact, 3:2 ratio of males to females. This is really odd since most autoimmune disorders are heavily favored in females. This is probably due to some unknown epigenetic reason. Prevalence: 23.6 per 100,000 per year in the USA. Varies between countries. Highest? Finland. Lowest? Asia (China specifically)

8 What are the general effect
What is most important to understand here is that in untreated diabetes, blood glucose continues to rise Since your cells cannot access the glucose in the blood, they BEGIN TO STARVE. Your cells look for energy from other sources (lipids first) The breakdown of lipids create ketone bodies, which are ACIDS. Ketone bodies decrease blood pH. Cells are vastly dehydrated (Glucose is transported with sodium, water follows sodium into cells). This causes increased heart rate and low blood pressure (both due to low blood volume). Think of the heart and circulatory system as a closed unit. As volume (water) leaves to attempt to hydrate cells and dilute urine, you have to pump hard, and faster to get the blood throughout the body since there is less of it. Since there is less blood, the blood pressure is decreased. There is also increased respiratory rate, as the body attempts to blow off CO2 (an attempt to raise the blood pH). This can lead to cardiac arrest if not addressed. Also, ketoacids are converted between acetoacetate and acetone, so there is often a smell of acetone on patients with severely untreated diabetes. - This is called DIABETIC KETOACIDOSIS.

9 Clinical Presentation
-T1DM is usually diagnosed before ketoacidosis, but not always. -Can you name the reason for all of these symptoms? Polydipsia: You’re dehydrated! You’re body is trying to increase blood volume. Polyuria: This water can’t rehydrate the blood fast enough because it can’t get into the cells. It’s also pulled into the renal tubules and excreted in an attempt to dilute the urine. Polyphagia: You’re cells are starving! They’re trying to get more energy, so you get hungry, which causes blood gluocse to rise even more since T1DM isn’t an input problem, it’s a UTILIZATION problem. Your cells can’t utilize the sugar that is present. Weight Loss: When you can’t utilize glucose as a fuel source, your body starts to convert fats to fuel, so you lose weight. This is the basis of the Atkin’s diet. It’s also why this diet is very dangerous, as ketone bodies are harmful. Fatigue: You can’t properly utilize glucose as energy! You’re body is no longer efficient. Anything below fatigue deal more with diagnosis. Side note: Anyone with autoimmune diseases usually have increased frequency of infection due to a decreased immune system.

10 How do you treat T1DM?  Future? -REGULAR blood glucose monitoring
-T1DM must test their blood glucose on a regular basis. It is suggested that they test before every meal and 2 hours after each meal. Insulin injections Usually ~3 injections/day. Combination of short acting and long acting insulin. Required to stay on a VERY strict diet. Breakfast, Lunch, Dinner, and snacks must be approximately the same amount of carbohydrates AND at the exact time every day. Think about the typical diagnosed age of T1DM (4-6 or 10-14), what problems might this lead to with these age groups? One is very young, the other is just starting to gain some freedoms. Insulin Pump Therapy Insulin is loaded into a medical device. This device is programmed by patients and physicians to deliver continual insulin to meet basal metabolic needs, hence this is called a basal rate of insulin. Insulin is inject by pump based on how much the user tells the pump to give at each meal. This is not a cure, patients still need to calculate many ratios that vary not only between patients but also at different times of the day. The insulin pump gives the patient more freedom, but it is still difficult and requires constant monitoring. New technology has lead to integrated insulin sensors. These still need to be calibrated every few hours and are actually quite painful. There is a lot of research going on in this field to decrease the number of times needed to test each day and focus on continual glucose monitoring.  Future?

11 How do Endocrinologists monitor their diabetic patients over long periods of time?
-Hemoglobin A1C (Hb A1C) measures glycated hemoglobin over a longer period of time ( days, which is the lifespan of a red blood cell.) -Glycated hemoglobin (Hb A1C) forms by a nonenzymatic reaction between hemoglobin and glucose. The key to this procedure is that once a hemoglobin is glycated, it cannot convert back to regular hemoglobin. So, while the occurance of it happening aren’t very likely, it is irreversible, which means it will stay glycated for the entire lifetime of the cell. -The amount of glycated hemoglobin is a direct measurement of the average amount of glucose in the blood. If there is more glucose, there is more glycated hemoglobin. This can give patients an “average glucose level” over days. T1DM get HbA1C tests every 3 months. T2DM is usually less frequent.

12 So, high glucose is bad, what about low glucose?
-Low blood glucose is FAR more detrimental in terms of short term problems. -Diabetic coma due to Neuroglycopenia - Glucagon is released by a-cells in RESPONSE to b-cells not making insulin (a sign of high BG.) If B-cells are destroyed, a-cells can’t release glucagon. Low blood sugar is far more detrimental to Type 1 diabetics. It can lead to loss of consciousness, ataxia, and eventually coma. This can happen very fast. Neuroglycopenia means the brain isn’t getting enough glucose to function properly. Excess insulin cannot signal for glucagon. Glucagon stimulates Glycogen  glucose in the liver. - Glucagon is released by a-cells in RESPONSE to b-cells not making insulin (a sign of high BG.) If B-cells are destroyed, a-cells can’t release glucagon. This is a major fault with current treatments in diabetics.

13 Future ways to monitor T1DM?
Take into consideration different ethical issues ranging from cost of supplies/equipment to the mental demands of current T1DM patients.

14 Diabetes Mellitus Type II

15 But first, a biochemical interlude: Downregulation vs. Upregulation
Adapted from the common domain of Cornell University

16 The mechanism of DM II is a complex sequence of biochemical processes
Diet high in fat and carbohydrates + sedentary lifestyle  highly elevated plasma [glucose] Chronically ↑ plasma [glucose]  chronic overstimulation of β cells and chronic hypersecretion of insulin Chronic hypersecretion of insulin  down regulation of insulin receptors on adipocytes and skeletal muscles

17 Down regulation of insulin receptors exhibits a number of negative consequences
↓ glucose uptake by cells ↓ glucose for cells to use for energy ↑↑ plasma [glucose] Can cause relatively minor symptoms or serious DM I type symptoms Adapted from the University of Arizona Dept. of Biological Sciences

18 What are the consequences of decreased glucose for cellular energy?
Cells begin to burn fats for energy. Can cause pH problems (DKA) Inefficient fuel source leads to fatigue, low energy, etc. *Important: Glucose uptake is severely decreased, but not nonexistent as in DM I

19 What are the consequences of elevated plasma [glucose]?
DM Type I Symptoms e.g. polyuria, polydypsia, glycosuria, etc. Hypertrophy of β cells Extremely chronic hyperstimulation can lead to β cell destruction Leads to insulin dependence Beta cells stained in green

20 What are the symptoms of Type II diabetes mellitus?
Some patients may be asymptomatic for many years Others experience lighter versions of many of the symptoms of diabetes mellitus I Rarely, DKA and other complications can occur such as hyperosmotic coma Why do these symptoms differ from DM I when their mechanisms of pathogenesis are so similar?

21 How is DM II diagnosed? Chronically high fasting plasma [glucose]
Elevated glycated hemoglobin pattern (HbA1C) In difficult cases, insulin immunoassay

22 Treatments for DM II are widely variable
For most people, diets lower in fats and carbohydrates coupled with exercise will correct the down-regulation of insulin receptors Others need medications such as biguanides and sulfonylureas (e.g. metformin) to decrease endogenous glucose production Severe cases in which beta cells have been destroyed will need to supplement with insulin ‘insulin dependent’ diabetes

23 Biguanides versus sulfonylureas
Metformin Phenoformin Buformin Proguanil Sulfonylureas Carbutamide Tolbutamide Chlorpropamide Acetohexamide And others….

24 The prognosis and sequelae of DM II are very similar to DM I
In well controlled diabetics, there are very few resulting problems With poor control, however: Poor circulation  vascular disease and cardiovascular problems Neuropathy Other metabolic dysfunctions If a person controls their condition well, they can either live an asymptomatic life or go into remission altogether With poor control, however: Myocardial infarction, stroke, blindness, amputation, degenerative brain disorders, renal failure, death

25 Diabetes mellitus II is one of the most preventable disease in our society
Obesity is the number one predictor of DM II Healthy diet and plenty of exercise are needed Patient education!!! Prior patient knowledge about the various genetic and medical factors that can increase DMII predisposition

26 Systemic Insulin Regulation

27 How do hormones and other factors regulate insulin?

28 The following hormone pathways work to help regulate the action of insulin
Epinephrine and cortisol inhibit insulin and increase secretion of glucagon in the pancreas HPA axis Growth hormone directly acts on the pancreas to cause glucagon secretion Glucagon inhibits insulin secretion and causes biochemical effects that are opposite those of insulin

29 Other friends that you’ve met throughout the year that effect insulin secretion
Thyroxine and T3 Norepinephrine Low ATP And others ↑ insulin secretion High ATP Somatostatin Leptin

30 Learning objectives for this lecture
Review the biochemistry, pathology, and medical treatments of diabetes mellitus 1 and 2 Provide a general overview of biochemical dysfunction, resulting metabolic derangement, compare and contrast the risks and sequelae, and discuss the treatments for both diseases and why treatments are specific to only one disease and not the other Discuss the utility of HbA1c measurement as a method of monitoring treatment efficacy Discuss patient, doctor, and psychosocial issues surrounding diabetes mellitus Discuss the prevalence of diabetes mellitus, long term risks to patients, and cost of care issues Discuss quality of life issues Discuss the importance of primary prevention in diabetes mellitus 2

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