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Diabetes Mellitus Overview and Treatments

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Diabetes Mellitus
Introduction

Disease in which the body doesnt produce or properly use insulin, leading to hyperglycemia.

According to Greek physician Aretaios- excessive drinking of water and excessive passing of urine.

Diabetes mellitus comes from the Greek word "diabainein" meaning "to pass through," and the Latin word "mellitus" meaning "sweetened with honey." Put the two words together and you have "to pass through sweetened with honey."

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Word Wide Overview

2006 WHO Diabetes criteria
Condition Normal Impaired fasting glycaemia Impaired glucose tolerance Diabetes mellitus 2 hour glucose mmol/l(mg/dl) <7.8 (<140) <7.8 (<140) 7.8 (140) 11.1 (200) Fasting glucose mmol/l(mg/dl) <6.1 (<110) 6.1(110) & <7.0(<126) <7.0 (<126) <7.0 (<126)

20.8 million in US ( 7% of population)

estimated 14.6 million diagnosed (only 2/3) Consists of 3 types: 1) Type 1 diabetes

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Carbohydrate Digestion

The digestion of carbohydrate. The complex polysaccharide starch is broken down into glucose by the enzymes amylase and maltase (secreted by the small intestine).

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Insulin Secretion
Panel 2. Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane, causing the calcium channel to open up allowing calcium ions to flow inward. The ensuing rise in levels of calcium leads to the exocytose release of insulin from their storage granule.

How Insulin Works

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Panel 3. Insulin binding to the insulin receptor induces a signal transduction cascade which allows the glucose transporter (GLUT4) to transport glucose into the cell. Insulin molecules circulate throughout the blood stream until they bind to their associated (insulin) receptors. The insulin receptors promote the uptake of glucose into various tissues that contain type 4 glucose transporters (GLUT4). Such tissues include skeletal muscles (which burn glucose for energy) and fat tissues (which convert glucose to triglycerides for storage).

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What goes wrong in diabetes?

The bodys response to blood sugar requires the coordination of an array of mechanisms. Failure of any one component involved in insulin regulation, secretion, uptake or breakdown can lead to the build-up of glucose in the blood.

Likewise, any damage to the beta cells, which produce insulin, will lead to increased levels of blood glucose.

Diabetes mellitus, commonly known as diabetes, is a metabolic disease that is characterized by abnormally high levels of glucose in the blood. Whereas nondiabetics produce insulin to reduce elevated blood glucose levels (i.e. after a meal), the blood glucose levels of diabetics remain high.

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What goes wrong in diabetes?

Multitude of Mechanism

1.

Insulin
Regulation Secretion Uptake or breakdown

2. Beta cells

Damage

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Action of Insulin
In general we can say that insulin favors anabolic reactions; glucagon, catabolic reactions. Put more simply, insulin favors storing energy and production of proteins while glucagon activates release of stored energy in the form of glucose or fatty acids. The actions of these two hormones on individual metabolic processes are summarized in the following table.

Carbohydrate Protein Fat Metabolism

Carbohydrate

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Facilitates the transport of glucose into muscle and adipose cells Facilitates the conversion of glucose to glycogen for storage in the liver and muscle. Decreases the breakdown and release of glucose from glycogen by the liver

Protein
A protein-rich meal leads to release of both insulin and glucagon. The latter stimulates gluconeogenesis and release of the newly formed glucose from the liver to the blood stream. The very moderate rise in insulin associated with the protein meal stimulates uptake of the sugar formed in the liver by muscle and fat tissue.

Stimulates protein synthesis Inhibits protein breakdown; diminishes gluconeogenesis

Fat Metabolism
Storage of triglycerides after a meal is dependent upon insulin-stimulated glucose uptake and glycolysis. Fat cells take up both fatty acids and glucose simultaneously. The fatty acids come from the action of lipoprotein lipase at

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Type I Diabetes
The total lack of insulin leads to two metabolic crises; a marked increase in the rate of lipolysis in adipose tissue and activation of hepatic gluconeogenesis in spite of high plasma glucose levels. The dramatically increased rate of lipolysis in adipose tissue follows the lack of insulin inhibition of hormone-sensitive lipase. The increase in fatty acids that results leads to a massive synthesis of ketene bodies in the liver. These then exceed the buffer capacity of the blood, leading to ketoacidosis. Excess acid is a potent poison for the brain. Coma and death follow ketoacidosis. Blood glucose levels

Low or absent endogenous insulin

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Type I Diabetes
cells that produce insulin are destroyed

results in insulin dependence commonly detected before 30

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Type II Diabetes
Blood sugar levels are dependent upon glucose uptake after meals and hepatic release of glucose between meals. The sugar released from the liver comes either from stored glycogen or production of glucose from lactate and amino acids. This production of glucose is largely responsible for stabilization of postprandial blood sugar levels. The hyperglycemia noted in type 2 diabetes partially results from lack of control over hepatic glucose formation due to resistance to insulin. It has recently become clear that part of this insulin effect occurs indirectly through insulin-sensitive receptors in the brain(more precisely, in the hypothalamus).

Insulin levels may be normal, elevated or depressed

Characterized by insulin resistance, diminished tissue sensitivity to insulin, and impaired beta cell function (delayed or inadequate insulin release) Often occurs >40 years

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Type II Diabetes

Type 2 diabetes has a stronger genetic basis than type 1, yet it also depends more on environmental factors. Sound confusing? What happens is that a family history of type 2 diabetes is one of the strongest risk factors for getting the disease but it only seems to matter in people living a Western lifestyle.

In contrast, people who live in areas that have not become Westernized tend not to get type 2 diabetes, no matter how high their genetic risk.

Obesity is a strong risk factor for type 2 diabetes. Obesity is most risky for young people and for people who have been obese for a long time.

Comparison of type 1 and 2 diabetes

Features Onset Age at onset Body habitus Ketoacidosis Autoantibodies Endogenous insulin Prevalence

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Type 1 diabetes Sudden Any age(mostly young Thin or normal Common Usually present Low or absent Less prevalent

Type 2 diabetes Gradual Mostly in adults Often obese Rare Absent Normal, decreased More prevalent

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication in patients with diabetes mellitus. . An autoantibody is an antibody (a type of protein) manufactured by the immune system that is directed against one or more of the individual's own proteins

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Testing
Fasting Plasma Glucose Test (FPG) - (cheap, fast)
fasting B.G.L. 100-125 mg/dl signals pre-diabetes >126 mg/dl signals diabetes

Oral Glucose Tolerance Test (OGTT) tested for 2 hrs after glucose Taking rich drink 140-199 mg/dl signals pre- diabetes >200 mg/dl signals diabetes

Glycated Hemoglobin tests 80 to 90 mg per 100 ml, is the normal fasting blood glucose concentration in

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Screening for Diabetes

Fasting Blood Glucose <110

Significance

Action

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Diabetes - Insulin

Discovered in 1921 by Banting and Best Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A)

A = 21amino acids B = 30 amino acids

A = 21amino acids B = 30 amino acids

Diabetes Insulin (synthesis, storage, secretion

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Produced within the pancreas by cells islets of Langerhans insulin mRNA is translated as a single chain precursor called preproinsulin removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin Within the endoplasmic reticulum, proinsulin is exposed to several specific end peptidases which excise the C peptide, thereby generating the mature form of Insulin Stored as granules

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Diabetes Insulin
(Biochemical Role)

Tyrosine Kinase receptors are the locks in which the insulin

key fits

Involved in signal transduction (insulin hormone being 1st messenger

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In the case of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulin

Type 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance. A number of treatment options may be employed.

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Pancreatic Hormones and Insulin Receptor Antagonists

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The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. Inside the pancreas are millions of clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are:

1. Beta cells, which secrete insulin and amylin 2. Alpha cells, which secrete glucagon; 3. Delta cells, which secrete somatostatin 4. Gamma cells, which secrete a polypeptide.

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Pancreatic Hormones

Insulin Amylin Glucagon Somatostatin Pancreatic Polypeptide

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Who need insulin medicine

Type I (insulin dependent) diabetes patients whose body produces no insulin. Type 2 diabetes patients that do not always produce enough insulin.

Treatment
subcutaneous injection

Insulin drug evolution

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Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

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Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin). Yeast is also used to produce insulin (1987).

Recombinant DNA technology has also made it possible to manufacture slightlymodified forms of human insulin that work faster or slower (Lantus) than regular human insulin.

Diabetes Oral Medications

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Sulfonylureas stimulate cells Biguanides improves insulins ability to move glucose Sulfonylureas and biguanide combination drugs BOTH Thiazolidinediones cells more sensitive to insulin Alpha-glycosidase inhibitors Block enzymes that help digest starches Meglitinides stimulate cells (dependant upon glucose conc.)

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Management of Diabetes Mellitus

Nutrition management Blood glucose monitoring Medications insulin or oral hypoglycemic agents Physical activity/exercise Behavior modification

Medical Nutrition Therapy

Balance food intake with insulin (or oral agents) and activity to achieve blood glucose levels as near normal as possible. Achieve and maintain normal lipid (cholesterol) levels

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Nutritional Management for Type I Diabetes

Consistency and timing of meals Timing of meals and administration of insulin Insulin plans should be designed to match the persons eating pattern Monitor blood glucose regularly

Nutritional Management for Type II Diabetes

Weight loss: 10-20# is sufficient Smaller meals and snacks Physical activity Monitor blood glucose and medications

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Nutrition Recommendations

Carbohydrate

60-70% calories from carbohydrates and monounsaturated fats

Protein Fat

10-20% total calories

<10% calories from saturated fat 10% calories from PUFA <300 mg cholesterol

Fiber Alcohol

20-35 grams/day

Type I limit to 2 drinks/day, with meals

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In Conclusion
2 major types of diabetes (3 with Gestational)

Type 1 => insulin dependant (5-10%) Type 2 => may treat with oral medication which may alter insulin production &/or sensitivity ; disease often succumbs to insulin dependence (>90%)

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References:

http://www.webmd.com/content/article/59/66840 http://hms.harvard.edu/public/disease/diabetes/diabetes.html http://focus.hms.harvard.edu/2005/May20_2005/immunology.shtml http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm http://www.cancure.org/insulin_potentiation_therapy.htm http://www.diabetes.org/about-diabetes.jsp http://www.diabetesnet.com/diabetes_treatments/sulfonylureas.php http://www.people.vcu.edu/~urdesai/sulf.htm http://en.wikipedia.org/wiki/Glucohexal http://www.drkoop.com/druglibrary/93/glucovance-warnings_precautions.html