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Describe the mechanism of action of insulin on glucose and potassium transport.
- Insulin binds to nearby subunits of insulin receptors activates the tyrosin kinase enzyme. Tyrosin kinase enzyme will phosphorylate various insulin receptor substrates that then go on and activate other reactions inside the cell.
- These reactions include cellular utilization of glucose, as well as facilitating the transporting of glucose into cells. In addition, insulin also facilitate the cellular uptake of amino acids and several electrolytes, including potassium, phosphate, and magnesium.
Compare the general actions of insulin and glucagon on metabolism, storage, and mobilization of nutrients.
- Insulin is an anabolic hormone that is secreted in times of nutrient excess (after eating). The action of insulin is to promote cellular uptake & storage of nutrient (glucose, fats, and protein)
- Glucagon is a catabolic hormone secreted in times of nutrient deficits (between meals). It promotes the release of nutrients from tissue storage sites into the blood. It is responsible for keeping blood glucose level within normal if we have not eaten something for several hours. It helps to prevent hypoglycemia by mobilizing nutrients out of storage sites and into the blood.
Which tissues are insulin dependent and which tissues are insulin-independent?
- Insulin-dependent tissue: liver, muscle, adipose tissues--requires insulin for the cellular uptake of glucose
- Insulin-independent tissues: neurons, vascular endothelium, epithelial cells, RBCs--these are the cell types that are affected by the chronic complication of diabetes. When there’s episode of hyperglycemia, the excess blood glucose cannot get into the insulin-dependent tissue cell types, but it can get into the cells that are insulin-independent. These cells types get bombarded with high levels of glucose that they don’t need immediately to be involve in reactions that produce ATP. So the cells make a variety of abnormal products with the excess glucose.
Explain the effects of amylin and incretin hormones on glucose homeostasis.
- Amylin is a protein that lowers blood glucose level by suppressing glucagon secretion, it also suppresses appetite after eating, and slows gastric emptying. By slowing the emptying of the stomach into the intestine, that delays the absorption of nutrients that helps to decrease postprandial (after meals) glucose levels.
- Incretin hormone are secreted by cells in the GI tract in response to food intake. They help lower blood glucose level. It acts on the pancreas to increase insulin secretion from the beta cells in the pancreas, and they also decrease glucagon secretion from the alpha cells in the pancreas. The result of this is increase glucose uptake by the cells, because of the increase availability of insulin, and a decrease release of glucose from the liver (decrease release of hepatic glucose)
What's cause of type 1 diabetes?
- Genetic predisposition
- Present of certain environmental factors that lead to destruction of pancreas beta cells. Eventually decreasing insulin levels that then get to the point where the pancreas produce no insulin
What are the causes of type II diabetes?
- Insulin resistance-cells don’t respond normally to insulin
- Sometimes there’s an insulin secretory deficiency
- Some have normal or elevated insulin levels
- Reason they have insulin above normal is because the present of insulin resistance, cells don’t respond to insulin, so their blood glucose level remain elevated, and the elevated blood glucose keep stimulating the pancreas to secrete more insulin
What are some signs of type I diabetes?
- Long preclinical period where the insulin level are gradually decreasing as the beta cells are getting destroy.
- When there’s a critically low level of insulin, there’s an abrupt onset of clinical manifestations
- Individual prone to ketoacidosis
- Insulin dependent
- An individual don’t inherit type I diabetes, but rather inherit a predisposition in the form of certain types of self-antigens that are present on the pancreatic beta cells that interact with environmental factor, usually some type of a of virus that eventually leads to the destruction of beta cells.
- Immune infiltration of islets (insulitis)
What are some signs and symptoms of type II diabetes?
- Many are obese
- Obesity in either children or adults is associated with insulin resistance
- Strong genetic predisposition in inheriting certain characteristics that in combination with environmental factors, such as lack of exercise, diet, causing them to have high fat or glucose levels to become obese. The genetic and environmental are interrelated factor
Discuss gestational diabetes in regard to the risk factors for developing it and its prognosis.
- A form of glucose intolerance that elevates blood glucose level that’s first recognized during pregnancy, usually during the third trimester.
- After the pregnancy is over, the woman’s glucose level may normalize, they may remained elevated, or the woman’s glucose level may progress to the point where she’s diagnose with having chronic diabetes
- Occurs in about 2% of all pregnancies. 60% of women who develop gestational diabetes will develop chronic diabetes within 15 years of their gestation (pregnancy)
- Children that are born of woman who had gestational diabetes are at increase risk for developing diabetes themselves.
Explain how the fasting plasma glucose (FPG), glucose tolerance test (GTT), and glycosylated hemoglobin (hemoglobin A1c) are used in the diagnosis and follow-up of diabetes mellitus.
- Fasting plasma glucose (FPG) is greater than 100 but less than 126 mg/dL
- Glucose tolerance is where the individual is given a glucose load, usually a syrupy solution that contains about 75 g of glucose, and then their blood glucose level is monitored for several hours afterwards. Two hours after the individual ingest the glucose load
- If the plasma glucose is 140 mg/dL or higher, but less than 200 mg/dL, that indicates an abnormal glucose tolerance test
- If plasma glucose is greater than 200 mg/dL, that would be diagnostic of diabetes.
- 10-25% will convert to type II diabetes within 10 years
- Glycosylated hemoglobin-if glycosylated hemoglobin level increases, the person may be diagnosis for DM
What is the lowest fasting plasma glucose level that is considered to be diagnostic for diabetes mellitus?
The fasting plasma glucose is greater than 126 mg/dL
What is the target level for hemoglobin A1c for diabetic patients?
Hgb A1c goal for the individual patient is as close to normal (<6%) as possible without significant hypoglycemia.
How does an elevated glycosylated hemoglobin level affect oxygen delivery to tissues?
Glycosylated hemoglobin binds to oxygen more tightly, therefore unloads less O2 to cells. When there’s less O2 available to cells, cells become hypoxic.
Explain why a person with diabetes can have a high plasma glucose level but not be spilling glucose into the urine.
If GFR is decreased, as with diabetic nephropathy, the renal plasma threshold for glucose will be increase, and glucose will spill into the urine only when the plasma glucose is very high or not at all.
What is meant by the renal plasma threshold for glucose?
Plasma glucose level where the glucose would spilled into the urine
What does exercise decrease insulin requirements?
Exercise encourages glucose uptake into skeletal muscle cells, and it decreases the amount of insulin that’s needed to do that. Exercising skeletal muscles develop some form of hypoxia, which results in increase membrane permeability, and this facilitates glucose uptake.
Explain why hypoglycemia can develop in a diabetic patient.
Hypoglycemia can develop in a diabetic patient when they are receiving too much insulin or other drugs that lower blood glucose levels. Usual develop in individuals with type I diabetes that are treated with insulin.
Explain the pathophysiological basis for the signs and symptoms of hypoglycemia.
Glucose is the prefer nutrient for the neurons in the brain, so a lot of clinical manifestations that are present when a person has hypoglycemia are CNS alterations. S/S include pallor, tremor, anxiety, tachycardia, palpitations, diaphoresis, headache, dizziness, irritability, fatigue, poor judgement, confusion, visual disturbance, hunger, seizure, and coma.
How can hypoglycemia be prevented and how should it be treated?
- If the patient is conscious, administer a rapidly absorbed carbohydrate (candy, juice) followed by a more slowly absorbed form of carbohydrate (bread, crackers)
- If patient is unconscious, administer glucose IV or a subscutaneous injection of glucagon (takes 15-20 minutes because it needs to be absorbed and break down)
- Prevention is achieved with individualized treatment, blood glucose monitoring, and education
Explain the pathophysiological mechanisms responsible for the chronic complications of diabetes mellitus.
- Activation of polyol pathway. A pathway whereby glucose is converted to sorbitol. One sorbitol (sugar alcohol) is produced inside the cell, it does not diffuse out so it stays in the cell. Sorbitol is a solute so it attracts water. Sorbitol is produced because not all the glucose is entering the cells as needed immediately for energy, so the cells start making other products with it.
- As sorbitol accumulate in the cell, pulls water with it, and it causes cell swelling which can alter nerve function; changes in vision; etc.
- Formation of advanced glycosylation end products (AGE)
- Thickening of vascular walls
- Increased binding of LDLs to vascular endothelium
- Increased level of glycosylated gHb -> decreased uploading of oxygen to tissues
- Secretion of cytokines resulting in inflammation
- Decreased nitric oxide (vasodilator produced by the vascular endothelial cells) production resulting in vasoconstriction
- Oxidative stress due to hyperglycemia stimulation of NF-Kappa B
- Protein kinase C activation
- Interferes with signaling pathway resulting in insulin resistance
- Proliferation of vascular cells contributing to atherosclerosis
Why do the chronic complications primarily affect the insulin-independent cell types?
Insulin-independent tissues: neurons, vascular endothelium, epithelial cells, RBCs--these are the cell types that are affected by the chronic complication of diabetes. When there’s episode of hyperglycemia, the excess blood glucose cannot get into the insulin-dependent tissue cell types, but it can get into the cells that are insulin-independent. These cells types get bombarded with high levels of glucose that they don’t need immediately to be involve in reactions that produce ATP. So the cells make a variety of abnormal products with the excess glucose.
Describe the metabolic syndrome
A metabolic disorder in which insulin resistance contributes to hyperglycemia, increased plasma, triglycerides, decreased HDLs, hypertension, systemic inflammation, abnormal fibrinolysis, micro- and macro-vascular diseases
What's the diagnostic criteria for metabolic syndrome?
- Waist circumference > 31.5 inches in female or > 37 inches in male
- waist circumference > 31 inches in women or > 35 inches in men of Asian origin
- Triglycerides > 150 mg/dL
- HDL’s < 50 mg/dl in woman or < 40 mg/dl in men
- BP > 130/85 mm Hg
- Fasting plasma glucose > 100 mg/dl
How do abdominal obesity and increased fatty acid levels lead to beta cell dysfunction in the metabolic syndrome?
- Enlarged lipid folds adipocytes in abdominal obese individuals are hypoxic as a result of the adipocytes outgrowing their blood supplies as they enlarge with all the lipids it contain.
- As a result, some of the tissues becomes necrotic. The necrotic cells trigger an inflammatory response in the adipose tissue resulting in secretion of chemokines (chemotactic chemicals) that attract macrophages into the adipose tissues to clean up the cell debris from the necrotic adipose cells.
- Macrophages and inflamed adipocytes then secrete inflammatory mediators including TNF and IL6. These inflammatory mediators impairs insulin signaling pathways in cells, and this leads to cellular insulin resistance.
- Excess fat accumulate outside of adipose tissues at ectopic cites, so fat also accumulates in liver and muscle tissues, and that contributes to insulin resistance in those tissues.
What is the function of adiponectin and how is it related to the metabolic syndrome?
- Adiponectin is a cytokine (chemical signal) that actives nuclear peroxisome proliferator-activated receptors (PPARs). When they are activated, resulting in production of products that activate genes, these gene products that’s produced increase the oxidation of fatty acids for energy. They increase cellular sensitivity (responsiveness) to insulin.
- They also secrete normal level of leptin, which is a substance that suppresses appetite and helps to control body weight.
- Have anti-inflammatory properties
- Low levels of adiponectin are present in the metabolic syndrome
Explain the pathophysiological mechanisms involved in the following complications associated with pregnancy in diabetic women:
- Increase risk for miscarriage, stillbirth, due to damage to placental blood vessels due to vascular complications associated with diabetes
- Increase risk for cesarean section because the fetus may be too large to fit or pass safely through the pelvic area due to macrosomia
- Insulin resistance during pregnancy is caused by placental hormones including estrogen, progesterone and human placental lactogen (HPL)
- Polyhydramnios is a state of excessive amniotic fluid surrounding the fetus and increases the weight of the uterus. The maternal high glucose that can occurred in a diabetic woman, especially if it is not well controlled during pregnancy, will have episode of hyperglycemia
- Some of the mother’s high glucose gets transferred to the fetus, and some of the glucose that’s in the fetus circulation gets excreted by the fetal kidneys as glycosuria. That is a osmotic diuresis taking place in the fetus due to the increase excretion of glucose in the fetal urine.
- The fetal urine is what makes the amniotic fluid normally. In this case, because of the high glucose level being transferred from the mother to the developing fetus, and the fetus excreting the glucose in the urine which pulls water with it, it creates an excessively large amount of amniotic fluid.
- Macrosomia is a fetus with a very large body. Mother’s blood brings extra glucose to the fetus and the fetus makes more insulin to handle the extra glucose. As a result, the extra glucose gets stored as fat and fetus becomes larger than normal.
- Neonatal hypoglycemia can develop in newborn because of the hyperglycemia that might occur during fetal development because the fetus is getting the mother’s excess glucose, which stimulates the fetus pancreas to produce increase amounts of insulin. After delivery and the umbilical cord is cut, the fetus will still have an elevated insulin that was produced before delivery, but now the fetus is not receiving any of the mother’s excess blood glucose, the fetus is in a position of having an excessive amount of insulin, and this can lead to hypoglycemia.