Exam III Pancreas-PT1 DM Flashcards
Pancreas Physiology in a Nutshell- Exocrine Pancreas
Composed of acinar cells that secrete proenzymes needed for digestion:
- Trypsinogen
- Chymotrypsinogen
- Procarboxypeptidase
- Proelastase
- Kallikrenogen
- Prophospholipase
Proenzymes and enzymes are carried by Ducts to the duodenum where they are activated.
Pancreas Physiology in a Nutshell - Endocrine Pancreas
Composed of the islets of Langerhans that secrete:
- Insulin by B cells
- Glucagon by a cells
- Somatostatin by δ cells
- PP cells secrete pancreatic polypeptide
Overview of DM
DM is a group of metabolic disorders sharing common feature of hyperglycemia.
Hyperglycemia is diabetes caused by
- Defects in insulin secretion
- Insulin action
- Or most commonly, both
The Chronic hyperglycemia and associated metabolic dysregulation might cause:
-secondary damage in multiple organ systems, especially the kidneys, eyes. Nerves and blood vessels
Regulation of Glucose Homeostasis
After a meal -> Insulin in normal subjects:
- It decreases liver glucose production by decreasing both glycogenolysis and gluconeogenesis.
- It increases glucose intake by skeletal muscle and adipose tissue by translocating glucose transporters
Response to Hypoglycemia in Normal subjects
Counter regulatory hormones
Relation between insulin and glucagon
-In the earliest stages (within minutes)
–Decreased insulin
–increased glucagon
Behavioral defenses
-The initial symptoms of sweating, anxiety, palpations, hunger and tremor -> plasma glucose concentration falls below 55 mg/dL (3.1 mmol/L)
Responses to Hypoglycemia in Diabetes
Impairment of behavioral and counter-regulatory responses
HAAF
Nocturnal hypoglycemia
- Direct relationship between overnight blood glucose and the following morning level
- Causes of morning hyperglycemia are nocturnal growth hormone secretion and hyperinsulinemia
Exercise
-Increases glucose utilization by muscle can cause hypoglycemia in PTs with insulin-deficient diabetes
Hypoglycemia-Associated Autonomic Failure (HAAF) in Diabetes
HAAF definition:
- The clinical syndromes of defective glucose counter-regulation and hypoglycemia unawareness
- Hypoglycemia, even if asymptomatic, causes a vicious cycle of recurrent hypoglycemia
HAAF mechanism
-reducing the sympathoadrenal response to subsequent hypoglycemia due to:
–changes hypothalamic functions
–increase in cortisol
Glucose Transporters
The most important stimulus for insulin synthesis and release in Glucose itself
Glucose enters beta cells via the glucose transporter, GLUT2, which causes the release of insulin into the bloodstream to bind to insulin receptors
Glucose Utilization:
-Insulin stimulates glucose uptake by skeletal muscle and fat by GLUT4
Glucose transporters
Intestine, kidney: energy-dependent sodium/glucose co-transporters
Other cells: diffusion via GLUTs 1-5
GLUT2: Beta cells, liver; low-affinity; post-prandial action
GLUT3: All tissues; major transporter in neurons or CNS
GLUT4: skeletal muscle, fat cells, insulin stimulates translocation from cytosol to cell membranes
Metabolic actions of insulin
Effect of insulin on metabolism of:
- Glucose
- Fat: decrease lipolysis
- Protein: inhibits breakdown
Clinical Pearl: Measuring Glycemic Control
Clinical test to estimate blood glucose control:
-Measurement of glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin, or HbA1C)
A1C assy:
A1C reflects mean blood glucose over the entire 120-day lifespan of the red blood cell, but it correlates best with the mean glucose over the previous 8-12 weeks
Diabetes Mellitus Broad Classification
Type 1 diabetes:
-An autoimmune disease characterized by pancreatic B cell destruction and an absolute deficiency of insulin
Type 2 diabetes:
-Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic B cells (“relative insulin deficiency”)
DM 1
Definition: An autoimmune disease -> islet destruction by endogenous B-cell antigens
Genetic susceptibility
-HLA region
Autoimmunity:
-Islet cell autoantibodies (ICAs)
Environmental factors
Immunological Response in DM I
Immunologic response
- The antigen binds to MHC class II -> autoimmune injury to the pancreatic beta cells
- Costimulatory pathways that further increase T cell activation
Risk of DM I
- The measurement of islet autoantibodies
- The presence of two or more of these islet autoantibodies
Confirmed targets of autoantibodies in DM I:
Insulin
Glutamic acid decarboxylase
Insulinoma-associated antigens 2 (A & B)
AnT8 (zinc transporter)
2 or 3 = DM I
Time Course of DM I
Genetic Markers:
-Present from birth
Immune Markers:
First appear at the time of the environmental triggering events
Clinically evident type 1 diabetes does not occur until there has been a much greater loss of functioning beta cells
Spectrum of Diabetes Metabolic Abnormalities
Diabetic Ketoacidosis (DKA – Mostly DM I) & Hyperosmolar hyperglycemic state (HHS Mostly DM II) in PTs with uncontrolled diabetes:
- HHS: glucose exceeds 1000 mg/dL (56 mmol/L)
- Pathogenesis:
–Insulin deficiency and or resistance
–Glucagon excess
- Ketoacidosis formed by lipolysis -> synthesis of ketones from FFA in the liver
- Hyperglycemic crises are pro-inflammatory states -> Oxidative stress
Pathogenesis of Diabetic Ketoacidosis
DM II
Definition: Complex disease that involves an interplay of genetic and environmental factors and a pro-inflammatory state
NO evidence of an autoimmune basis
Characterized by hypoglycemia, insulin resistance, and relative loss in insulin secretion
Hyperglycemia itself can damage pancreatic beta-cell function and magnify insulin resistance, causing a vicious cycle of hyperglycemia
Definition of metabolic syndrome: Co-occurrence of metabolic risk factors for both DM II and CVD
Metabolic defects in DM II
Insulin resistance
Inadequate insulin secretion:
-Due to the genetic alteration affecting GLU-2 expression
Impaired insulin processing
-The processing of proinsulin to insulin in the in the beta cells is impaired in DM II.
Insulin Resistance
Definition: Broadly defined as a deficient biological response to normal insulin
**Leprechaunism (insulin-receptor mutations)
Major organs affected by Insulin Resistance
Major organs associated with insulin resistance:
-Liver, skeletal muscle and adipose tissue
Consequences of Insulin resistance:
- Failure to inhibit gluconeogenesis-> high fasting blood glucose levels
- Failure of glucose uptake and glycogen synthesis -> high post-prandial blood glucose level
- Failure to inhibit lipoprotein lipase -> FFAs -> amplify the state of insulin resistance
Fatty Acid-Mediated Insulin Resistance
Insulin resistance (IR) starts in the hypothalamus -> imbalance of satiety and hunger signals
Increased inflammation and IR in adipose tissue
Excess fat released in the blood and taken up by the liver and skeletal muscles -> lipotoxicity
Obesity and Insulin Resistance
Central Obesity:
-(Abdominal Fat) is often linked to insulin resistance
Inflammation
-Excess FFAs within macrophages and B cells can activate the secretion of cytokines
Free Fatty Acids (FFA):
-Excess FFAs damage B cell function-> decrease insulin secretion
Adipokines:
- Secreted into the systemic circulation by adipose tissue
- Deficiency of adipokines increased insulin resistance
