Type 1 Diabetes

Pancreatic Hormones

• Insulin is a protein hormone enabling glucose entry into cells.
• Islet amyloid polypeptide (IAPP or amylin) affects appetite, gastric emptying, and the secretion of glucagon and insulin.
• Glucagon is a hormone that increases blood glucose by mobilizing glycogen stores.
• Somatostatin universally inhibits secretory cells.
• Gastrin stimulates gastric acid secretion.
• Pancreatic peptide's function is unclear.
• Glycogen is the storage form of glucose in the liver.

Diabetes Types

• Type 1 diabetes involves the loss of beta cells, resulting in no insulin production and is often diagnosed in youth.
• Ketoacidosis can occur due to a lack of insulin and increased fatty acids forming ketoacids, potentially leading to death in Type 1 diabetes.
• Type 2 diabetes is characterized by relatively reduced insulin secretion and a reduced response to insulin by tissue receptors.
• Type 3 diabetes has causes other than Type 1 or Type 2, such as drugs.
• Type 4 diabetes is gestational diabetes, affecting 4% of pregnancies.
• During gestational diabetes, the placenta and placental hormones create insulin resistance in insulin cell receptors.

Type 1 Diabetes

• Type 1 Diabetes used to be called Juvenile Diabetes as it was always discovered in youth
• This disease is characterized by the loss of insulin as a result of autoimmune destruction of the insulin producing beta cells in the pancreas

Insulin

• Human insulin has a molecular weight of 5808 and consists of 51 amino acids in two chains.
• Insulin is produced from proinsulin, which is composed of insulin + C-peptide.
• C-peptide is formed in equimolar amounts as insulin, but has no known function.
• Zinc forms crystals with insulin within the pancreas.
• 28 Units of insulin is equivalent to 1 mg of insulin.
• Insulin is a protein too big for PO, therefore must be administered via IV, IM, or SC.
• Insulin is measured and dosed in International Units (IU).
• Units used for insulin go back to the 1920s.
• When insulin was extracted from cow or pig pancreas the extract needed to be tested for insulin content
• The IU was based on the ability of a fixed amount of extract to reduce the fasting blood glucose of a rabbit by x mg/dL
• From the mid 1980's, cow and pig were no longer used to harvest insulin, being replaced by recombinant E. coli insulin from Lilly and Sanofi and yeast used by Novo Nordisk.
• These three companies produce 100% of the insulin used in the US.

Insulin Release

• Elevated glucose levels and increased intracellular ATP levels in beta cells lead to insulin release.
• ATP-dependent K channels close, reducing K outflow and depolarizing the beta cell.
• Beta cell potassium inside is 115 mmol/L and outside is 5 mmol/L.
• Depolarization of the beta cell opens voltage-gated Ca channels.
• Calcium flows into the cell, triggering insulin release.
• Beta cell calcium outside is 110 mmol/L and inside is 0.001 mmol/L.
• Secretagogue drugs stimulate insulin release by exploiting this mechanism.
• Secretagogue drugs are any drug that can stimulate the pancreas to release insulin, which are useless to type 1 diabetics
• Type 1 diabetics require insulin injections

Insulin Degradation (Biotransformation)

• Insulin is removed from the body by the liver and kidneys.
• Insulin has a short half-life of 3-5 minutes, necessitating multiple injections.
• The kidneys remove 35-40% of endogenous insulin, while the liver removes 60%.
• The percentages are reversed with injected insulin.

Insulin Receptors

• Insulin receptors are found in the membranes of most cells.
• The alpha site of the receptor is outside the cell and functions as the recognition site.
• The beta site of the receptor spans the membrane and contains a protein tyrosine kinase (TK) unit.
• Insulin binding activates TK inside the cell.
• Activated TK phosphorylates proteins, causing glucose transporters (GLUTs) to translocate to the cell membrane, facilitating glucose uptake.
• Insulin moves glucose into cells, preventing it from remaining outside where it cannot be used for energy and becomes toxic.
• Insulin's main function is to prime the cell membrane in order to allow glucose to enter the cell
• Insulin binds to the portion of the insulin receptor that is outside the cell membrane
• Activated tyrosine kinase phosphorylates cell membrane proteins, which alters the cell membrane and allows glucose to enter the cell
• The Glucose Transporters in the cell membrane are activated and take up glucose into the cell
• The glucose transporters are GLUT 1 through GLUT 5 depending on the tissue location

Endocrine Effects of Insulin:

• The liver inhibits glycogenolysis, inhibits conversion of fatty acids to keto acids, and inhibits conversion of amino acids to glucose
• The muscle increases protein synthesis and increases glycogen synthesis
• Adipose tissue increases triglyceride storage

Types of Insulin Preparations

• There are four main types of insulin preparations: rapid-acting, short-acting, intermediate-acting, and long-acting.
• Rapid-acting insulins have a fast onset and short duration of action.
• Short-acting insulins have a rapid onset of action.
• Intermediate-acting insulins are absorbed over a longer time period.
• Long-acting insulins have a slow onset of action.
• Most insulin in the US is available as a 10 mL vial with 100 Units/mL, also called the U100 vial

Insulin Therapy Goal

• The objective is to provide an insulin drug that aligns with an individual's food intake, lifestyle, and the severity of their condition.
• Regular insulin is the preferred choice when IV administration is needed.
• Long-acting insulins mimic normal basal control, also known as endogenous insulin levels.
• Rapid-acting insulins are used to meed mealtime needs.

Rapid-Acting Insulins

• Rapid-acting insulins are taken immediately before meals and last about 4-5 hours.
• Insulin lispro has reversed positions of lysine and proline on the beta chain.
• Insulin aspart involves aspartic acid replacing proline at beta position 28.
• Insulin glulisine replaces lysine with asparagine at beta 3 and glutamic for lysine at beta 29.
• Insulin lispro and insulin aspart may act within 15 minutes

Short-Acting insulins

• Short-acting insulins take effect within 30 minutes, peak at 2-3 hours, and last 5-8 hours.
• Regular insulin acts within 30 minutes after SC injection, with a typical dose of 5-15 Units.
• Regular insulin is the drug to use as an IV in a hospital setting
• Regular insulin is a zinc crystalline insulin.
• The only type given IV is regular insulin.

Intermediate Acting

• NPH is a neutral protamine Hagedorn insulin.
• Protamine prolongs absorption, preventing the formation of insulin into hexamers or dimers, known as isophane.
• Proteolytic enzymes remove protamine in the body, allowing insulin to be absorbed.
• NPH has an onset of 2-5 hours and a duration of 4-12 hours.
• NPH, also called insulin isophane, was founded by Hagedorn of Novo Nordisk which makes insulin
• This type of insulin is often premixed with regular, lispro, or aspart insulins
• Absorption variation is over 50% in patients; thus, it is used less frequently compared to other forms.
• Insulin glargine has two arginine molecules attached to the beta chain, with glycine replacing asparagine at the alpha 21 position.
• Insulin glargine precipitates in the tissues after subcutaneous injection, resulting in slow absorption with a peak in 4-6 hours.
• Insulin glargine is slowly absorbed into the system with an onset of action in about 0.5 to 1.0 hour and never mix with another insulin
• Insulin glargine requires a body pH of about 7.4 to precipitate.
• Insulin detemir has a terminal threonine dropped from beta 30 position and a fatty acid (myristic acid) added to terminal beta 29 lysine.
• Insulin detemir has a duration of action approximately 17 hours
• Insulin Degludec has insulin with hexadecanoic acid added and an onset of action of 30-90 minutes with a duration of action of more than 42 hours

Insulin Mixtures

• NPH requires several hours to reach therapeutic levels; therefore, it is mixed with rapid or short-acting insulins to allow both short and long actions.
• NPL is neutral protamine lispro.
• NPA is neutral protamine aspart.
• The insulin pen is the most widely used form for insulin administration by SC injection and many different mixtures are available, for example, 70% NPH insulin with 30% Regular insulin

Insulin Facts

• All insulin is made from recombinant DNA technology from E. coli or yeast.
• All insulin does not contain C-peptide.
• Almost all formulations contain 100 U/mL in the vial.
• The usual subcutaneous injection is 10 U/mL.

Diagnosis:

• A fasting blood glucose of 126 mg/dL or higher, which measures glucose not mannose, lactose, fructose, etc.
• Hemoglobin A1c measurement; where an enzyme attaches the required number of glucose molecules to a protein with Glycosylation
• However, when a protein is exposed to solutions of glucose, the glucose will start to attach to the protein non-enzymatically, which is Glycation
• Glycation will add anywhere from 10 to 999 molecules of glucose, depending on how much time the protein is exposed to the 1000 molecules of glucose
• Glycosylation will add the 10 molecules as determined by the enzyme
• The human red cell contains the protein hemoglobin, where the hemoglobin A1c is exposed to glucose in the blood as the red cells float around in the blood
• The HbA1c test measures how much glucose has been non-enzymatically added to this protein through glycation
• The red cell lasts in the blood about 90 days, so the amount of glucose non-enzymatically added is an average measure of how much glucose was in the blood on average over the last 90 days
• Recommended level of HbA1c is less than 5.7%, while values of over or equal to 6.5% are considered diabetes mellitus
• Recommended value for a fasting blood glucose is less than 100 mg/dL in the US and every where else in the world the blood glucose value is < 5.6 mMol/L not < 100 mg/dL.

Glucagon

• This is a hormone produced in the alpha cells in the pancreas
• Glucagon is a protein with a molecular weight of 3485 Da.
• Glucagon is a storage depot for glucose.
• Its major use as a drug is to inject it into patients who are in major hypoglycemic shock.

Benefits of Tight Glycemic Control

• Benefits of tight glycemic control are found on page 804 in Katzung.

Insulin Regimens

• Intensive insulin therapy is used for all Type 1 and some Type 2 diabetics.
• Total daily insulin requirements are approximately 0.55 times the patient's weight in kilograms.
• Most of a dose covers background or basal levels, while the remainder covers meals and snacks.
• The 0.55 calculation is approximate, and patients calculate insulin requirements based on carbohydrate consumption and target blood glucose levels.
• Conventional insulin therapy is commonly used for Type 2 diabetics.
• Conventional insulin therapy is often based on current blood glucose levels.

Special Uses

• Diabetic Ketoacidosis is a medical emergency typically caused by inadequate insulin, often in Type 1 diabetes.
• Diabetic Ketoacidosis is managed with regular human insulin IV at 0.1 IU/kg/h.
• Hyperosmolar Hyperglycemic Syndrome is mainly found in Type 2 diabetes.
• Hyperosmolar Hyperglycemic Syndrome is caused by certain drugs and dehydration and drugs that cause dehydration
• Hyperosmolar Hyperglycemic Syndrome's plasma glucose is over 600 mg/dL, and plasma osmolality is over 320 mmol/L.

Complications

• Hypoglycemia is the most common adverse drug reaction (ADR) of insulin therapy.
• Hypoglycemia often occurs due to inadequate carbohydrate consumption, excessive insulin dose, or unusual physical exertion.
• Treatment for hypoglycemia involves oral glucose (orange juice, glucose tablets, etc.).
• For unconsciousness or stupor, treatment is 20-50 mL of 50% glucose solution IV over 2-3 minutes.
• If IV access is unavailable, inject subcutaneous glucagon, followed by oral glucose when the patient wakes up.
• If neither IV nor glucagon is available, apply honey to the buccal cavity.
• Insulin allergy involves histamine release due to an immediate type reaction.
• Mast cells with IgE release histamine when insulin binds.
• Sensitivity is often due to non-insulin proteins in the preparation.
• The incidence of Insulin Allergy is greatly reduced due to human recombinant insulin.
• Immune insulin resistance involves low titers of IgG insulin antibodies neutralizing the insulin dose.
• Most patients develop some of these antibodies.
• Immune insulin resistance rarely leads to significant insulin resistance due to recombinant forms of insulin.
• Lipodystrophy at the injection site, found with animal source insulins, is rare today.
• Hypertrophy of subcutaneous fatty tissue can occur with human insulin if injected into the same site daily; therefore, injection sites should be changed.