Pancreas Endocrine vs. Exocrine PPT Notes

**Pancreas** Endocrine vs. Exocrine **Insulin** - Secreted by the Beta cells in the Islets of Langerhans - Function: influences carbohydrate and lipid (and to some degree protein) metabolism -- primarily anabolism - Peptide hormone, therefore has a very short half life -- any insulin...

**Pancreas** Endocrine vs. Exocrine **Insulin** - Secreted by the Beta cells in the Islets of Langerhans - Function: influences carbohydrate and lipid (and to some degree protein) metabolism -- primarily anabolism - Peptide hormone, therefore has a very short half life -- any insulin secreted will be cleared in 15 minutes. **Synthesis** http://www.hanall.co.kr/DOC\_IMG/images/78A31FCF-D22E-4FD8-9093-52ED9F814518.jpg - Insulin mRNA is translated as a single chain precursor called *preproinsulin* - Removal of its single peptide during insertion into the endoplasmic reticulum generates *proinsulin* - *Proinsulin* is composed of an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide called the C peptide - Activation of insulin breaks off the C peptide, leaving the bonded A and B peptide chains to be released into circulation as *insulin*. - Due to the difficulties of measuring insulin in the blood, C-peptide measurements provide an alternative index of insulin secretion and residual β-cell function. - Low C peptide in T1 DM; a good test to differentiate between T1 and T2 - Recent research has demonstrated that C-peptide is important in slowing complications of diabetes mellitus.\*\* **Secretion** - Prompted by increased plasma levels of glucose, amino acids, & free fatty acids - Plasma glucose most potent trigger - Inhibited by low plasma glucose levels and high levels of insulin - Glucagon -- peptide hormone; produced by alpha cells of pancreas; will cause liver to convert stored glycogen to glucose to help maintain control of glucose levels - FYI - Other stimuli include GI hormones (gastrin, CCK, secretin) and parasympathetic stimulation **Action on Cells** - Receptors for insulin are on plasma membrane of almost all cells - CNS neurons very dependent on glucose but do not rely on insulin for glucose uptake. - Insulin receptors have two alpha subunits (bind to insulin) and 2 beta subunits (tyrosine kinase component) - Insulin binds to its receptor, which activates *tyrosine kinase* (similar to on/off switch) which in turn activates a number of intracellular enzymes (e.g., protein kinase B and MAP kinase) to stimulate the range of physiological effects - Binding of insulin to its receptor also directly stimulates glucose uptake via the tyrosine kinase pathway - *Glucose transporter proteins (GLUT4)* are required for facilitated diffusion of glucose into cells - Glucose is a large molecule that requires process of facilitated diffusion **General Physiological Effects** - Control of postprandial plasma glucose levels  - Insulin also inhibits glucose-producing pathways - Promotes glucose storage as glycogen - Glucose has strong osmotic pressure (attracts water) and needs to be converted into glycogen (low osmotic pressure) or cell will swell - The volume of the hepatocytes normally contains between 5% And 8% glycogen - Fatty acid synthesis and triglyceride formation - Helps to build fat and muscle - If someone has elevated insulin levels, what condition would result? metabolic syndrome; T2 DM; promote formation of fats/fatty acids and stored in adipose tissue - Transport of amino acids into cells and stimulates protein synthesis - Stimulates cellular growth and differentiation - Facilitates K+ transport into cells - Those with hypokalemia will not be able to use insulin well - The diffusion of glucose into the cell requires the presence of insulin and potassium (K+).   **Glucagon** - Secreted by the alpha cells in the Islets of Langerhans of the pancreas - Glucagon is the primary "counterregulatory" hormone that increases blood glucose levels in the plasma - Insulin antagonist **Secretion** - Glucagon release is primarily stimulated *in response to* decreased plasma glucose levels **Physiological effects** - Promotes glycogenolysis and gluconeogenesis to raise blood glucose levels, as well as lipolysis and ketogenesis - Ketones are being made when we break down fats **Summary of Insulin & Glucagon**  **Diabetes Mellitus** **Overview** *A group of disorders associated with alterations in insulin activity resulting in chronic glucose intolerance, as well as alterations in protein and lipid metabolism.* **Epidemiology** Risk higher among certain racial & ethnic groups - CDC data from 2018-2019 indicate that **14.5% of American Indians and Alaska Natives** have diabetes, with rates varying by region from 6.0% among Alaska Natives to 22.2% among American Indians in certain areas of the Southwest. - 7.4% of non-Hispanic whites, 9.5% of Non-Hispanic Asians, 11.8% of Hispanics, and 12.1 % of non-Hispanic blacks had diagnosed diabetes **Risk influenced by education level (indicator of SES)** - 13.4% of adults with \< HS education - 9.2% of adults who graduated from high school - 7.1% of adults who have \> high school education **Rates increasing in youth.** **Diagnostic Criteria** ***American Diabetes Association*** - HbA1c [\>] 6.5% - FPG [\>] 126 mg/dl (7.0 mmol/L); fasting is defined as no caloric intake for at least 8 hours) - 2-hr plasma glucose [\>] 200 mg/dl (11.1 mmol/L) during an OGTT - In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose [\>] 200 mg/dl (11.1 mmol/l) **Type 1 Diabetes Mellitus** **Autoimmune-mediated Type 1A DM -- most common** - β-cell destruction usually leading to absolute insulin deficiency - Appearance of autoantibodies and cytotoxic T cells that target the beta cells, insulin, and antigens on the cells in the pancreatic islets. **Causes** - [Genetics] - 18 areas of the genome have been identified as being involved - If someone has a parent or sibling with type 1A DM, their risk of developing the disease is around 10% - [Environmental Factors] - Viral infection - Diet - Other factors **Nonimmune-mediated Type 1B DM** - β-cell destruction usually leading to absolute insulin deficiency - No evidence of autoimmune disease - Most of these cases occur secondary to other diseases such as chronic pancreatitis and cystic fibrosis **Pathophysiology** **Destruction of pancreatic beta cells** - Destruction of 80-90% of the beta cells in the pancreatic islets leads to a clinically detectable decrease in insulin secretion. **Alpha cells are left unopposed leading to a relative glucagon excess** - Since the proportion of insulin to glucagon in the portal vein controls hepatic glucose and fat metabolism, the abnormal levels of both contribute to hyperglycemia. **Decreased glucose uptake into cells** - Leads to hyperglycemia - If glucose cannot enter the cells, then there is a risk of cell starvation. - Amino acid uptake into cells also requires insulin. With an insulin deficiency, the body can switch to using fatty acids as a fuel source (but not efficient like glucose and does not suffice long term) **Osmotic Diuresis** - *Recall -* The amount of glucose reabsorbed is limited by the number of carrier molecules in the membrane of the renal tubules. There is a level at which the carrier molecules can become saturated -- that point is called the *tubular maximum (Tm)* or renal threshold. - Individuals with diabetes who become hyperglycemic often exceed the Tm for glucose reabsorption in the kidneys. - Any glucose remaining in the filtrate will prevent water from being reabsorbed, thus causing diuresis. **Decreased potassium uptake into cells** - With an insulin deficiency, potassium isn't transported into the cell with glucose. - This leads to *hyperkalemia*. **Fat breakdown in adipose tissue** - Insulin deficiency stimulates the breakdown of fat (i.e. lipolysis) in the adipose tissue. - The process of fat breakdown liberates a molecule called a *ketone*. - Ketones are acidic molecules that will lower the pH of the blood. - FYI -- Insulin deficiency in combination with elevated cortisol causes the release of a lipase in the adipose tissue. The breakdown of triglycerides and liberation of fatty acids causes the formation of ketones (ketone bodies). **Type 2 Diabetes Mellitus** **Risk Factors** **Genetics** (genetic link much stronger for T2 than T1) - Multiple types of mutations have been identified including genes that code for: - Insulin synthesis - Insulin receptors - Cell responsiveness to insulin **Obesity (BMI \> 30)** - There is a relationship between the **chronic disease of obesity** and the **chronic disease of type 2 DM** - Approximately **80-90%** of individuals with Type 2 DM have BMI \> 25 - Obesity is associated with a **ten-fold increase** in the incidence of type 2 DM. - **Truncal obesity** has the highest correlation to the development of type 2 DM. **Age \> 40 years** - Type 2 DM generally affects individuals over age 40 - Incidence of type 2 DM is rising rapidly among adolescents and young adults. **Ethnicity** - There is an increased incidence of type 2 DM among **American Indian, Hispanic/Latino, Pacific Islander, and Black** populations. **Family History** - Studies have shown up to a 75% concordance rate of type 2 DM among identical twins and 95% concordance when it come to abnormal glucose metabolism. **Polycystic ovarian syndrome** - 7-fold increase in incidence of type 2 DM **Metabolic Syndrome** - Custering of at least 3 of 5 conditions - Central obesity - HTN - Elevated blood sugars - Prediabetes/diabetes - High serum triglycerides - Low HDL **Pathophysiology** **Hyperinsulinemia and insulin resistance** - High calorie diet (esp. carbs and sugars) leads to increased insulin secretion. - *Hyperinsulinemia* *=* chronically high insulin levels - When cells are exposed to high levels of a hormone, they will decrease the number of receptors they have for this particular hormone--a phenomenon called *receptor down-regulation*. - Eventually the individual has so few functional receptors that the cells are unable to respond to insulin. This condition is called *insulin resistance*. **Release of adipokines by adipose cells** - Individuals with more adipose tissue secrete more adipokines. - Adipokines have several normal physiological functions, but when present in high quantities, they stimulate insulin resistance. - Note: Increased secretion of glucagon also contributes to hyperglycemia **Decreased glucose uptake into cells** - Insulin resistance leads to decreased glucose uptake and *hyperglycemia*. - The clinical consequences of hyperglycemia in type 1 DM are the same in type 2 DM (osmotic diuresis, etc.) **Development of dyslipidemia** - As insulin resistance develop, lipid deposition in the adipose tissue decreases and lipolysis activity increases. - Upon diagnosis, most type 2 diabetics present with dyslipidemia (typically with low HDL and high triglycerides). - Clinical note: In most individuals, insulin resistance occurs for many years prior to the development of T2DM. This means that for many years, increasing quantities of lipids have been released into the plasma. **Beta cell destruction** - Complications associated with hyperglycemia and presence of adipokines can cause beta cell injury. - The pancreas is infiltrated by protein strands called amyloids which appear to destroy the pancreatic islets. **Chronic Complications of Diabetes Mellitus** **Pathophysiology** **Hyperglycemia & Nonenzymatic Glycosylation** - Nonenzymatic glycosylation is a process by which glucose binds to proteins, lipids, and nucleic acids. - With chronic or persistent hyperglycemia, glucose becomes irreversibly bound to these molecules in the RBCs, endothelial cells lining the blood vessels, and other tissues. - This binding forms complexes called *advanced glycosylation end-products (AGEs)*. - The formation of AGEs induces changes in cell structure and function, and can cause cell injury. - Hemoglobin glycosylation -- The HgbA1c test measures the buildup of glucose that has become irreversible bound to hemoglobin in the circulating RBCs - Clinical note: While normal glucose testing only provides an immediate evaluation of blood glucose levels, the HgbA1c test reflects glucose levels over the life span of an RBC (90 -- 120 days). If the HgbA1c is \> 7%, then the patient has not maintained glycemic control over the past 2 -- 3 months (normal range = 3 -- 5.6%). - Capillary basement membrane thickening - Leads to decreased gas exchange between the capillary and tissues. - Increased capillary permeability - Leads to edema which reduces oxygen delivery to the cells. - Arterial smooth muscle proliferation - Leads to thickening of arterial walls and eventually hypertension. - Production of oxygen free radicals - Cause endothelial cell injury and injury to cells in the tissues. - Inactivation of nitric oxide (NO) - Vasoconstriction of the arteries leads to hypertension. - Promotion of coagulation - Promotes clot formation in capillaries causing ischemia and veins leading to DVT. **Shunting of Glucose to the Polyol Pathway** - Use of glucose via the polyol pathway occurs in tissues that do not use insulin for glucose transport (eg: neuronal cells) - Hyperglycemia causes more glucose to be shunted through this pathway in these tissues. - Glucose is converted to sorbitol, which increased osmotic pressure in these cells - The consequence is cellular swelling that leads to cell injury. - The consequences of shunting large amounts of glucose via the polyol pathway include: - **\*\*\*Cataracts in the lens of the eyes leading to decreased visual acuity and blindness.\*\*\*** - Disruption of neuron/nerve conduction leading to neurological problems - Swelling and stiffening of the RBCs which can lead to premature hemolysis **Inappropriate Protein Kinase C Activation** - Protein kinase C is an enzyme that has a number of biochemical functions in the body including phosphorylation of ATP. - Large quantities of activated protein kinase C: - Promotes insulin resistance - Increases capillary permeability - Increases basement membrane thickening - Promotes vasoconstriction **Microvascular Disease** - *Effects of capillary injury (primarily vasoconstriction and clotting)* - *All **three** mechanisms related to chronic hyperglycemia cause injury to the microvasculature (i.e., arterioles & capillaries).* - Formation of AGEs - Shunting glucose through the polyol pathway - Protein Kinase C activation **Retinopathy** - Caused by retinal ischemia -- vessel thickening and clotting - Infarcts of nerve layer of the retina - Sometimes see retinal detachment or hemorrhages - The consequence of retinal ischemia is loss of visual acuity and eventually blindness. In some cases there is retinal detachment, probably due to loss of tissue integrity. - Neovascularization and retinal detachment increase the risk of hemorrhages. **Nephropathy** - *Mechanisms of renal glomerular & tubular destruction are unknown* - See intraglomerular hypertension, basement membrane thickening, and glomerulosclerosis - Proteinuria/alubuminuria (first clinical sign), then develops into chronic renal failure (CRF) and eventually ESRD - Recall: consequences of CRF include: - Increased plasma creatinine, decreased CrCl, etc - HTN from fluid retention - Anemia d/t to decreased erythropoietin secretion - Hyperkalemia & metabolic acidosis - Eventually multi-organ/system failure **Atherosclerosis** - Endothelial injury is caused by the accumulation of AGEs in the endothelial cells - Dyslipidemia facilitates the deposition of LDLs in the wall of the arteries which eventually develops into the atherosclerotic plaque - *Clinical Consequences include:* - Coronary artery disease - Myocardial ischemia leading to heart failure - Myocardial infarction - Cerebral infarct (stroke) - Renal arterial stenosis leading to chronic renal failure - Intestinal vascular insufficiency - Peripheral arterial disease leading to skin ulceration - Peripheral arterial disease leading to gangrene and amputation **Neuropathies** - Pathophysiology involves shunting of glucose via the polyol pathway which in neurons leads to neuronal swelling. - Accumulation of AGEs and activation of protein kinase C (PKC) also leads to neuronal injury. **Results in:** - Ischemia of peripheral neurons - Axonal degeneration - Demyelination of neurons - conduction velocity of neuron is impaired **Clinical Consequences** - [Sensory ] - Sensory neuropathies manifest as decreased sensation (numbness) often accompanied by tingling and burning (paresthesias). In most cases, sensory neuropathies manifest bilaterally and most frequently in the lower limbs. - [Motor] - Decreased conduction velocity causes significant impairment in motor coordination. This manifests with gait disturbances and in impairments of other activities that require coordination. Decreased motor activity to skeletal muscles leads to disuse atrophy and muscle weakness. - [Autonomic] - Diabetic neuropathy can affect all aspects of autonomic function. As examples, parasympathetic dysfunction can lead to bowel alterations such as diarrhea and constipation. Sympathetic dysfunction manifests with orthostatic hypotension because the baroreceptor reflex activity is impaired. **Increased Risk of Infection** - Vascular complications discussed previously lead to decreased perfusion to the tissues in the skin which causes tissue death and skin break down. - Impaired vision and decreased sensory perception increase the risk that the diabetic will fail to notice wounds or infections, especially on their feet. - Pathogenic bacteria (and fungi) thrive in the hyperglycemic environment. More glucose = more food = rapid growth and colonization! - Decreased perfusion to infected wounds (caused by micro- and macrovascular disease) decreases the number of WBCs available to fight the infection. - Hyperglycemia and DM is also associated with impaired WBC function, although the mechanism is not clear.