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Pancreas Function: Insulin, Glucagon, and Blood Glucose Regulation, Exams of Nursing

University of WestminsterNursing

An in-depth exploration of the endocrine role of the pancreas, focusing on the functions of insulin and glucagon, their secretion, and the regulation of blood glucose levels. Topics include the differences between type 1 and type 2 diabetes mellitus, the role of incretins, and the impact of free fatty acids on insulin sensitivity.

Typology: Exams

2023/2024

Available from 03/19/2024

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Endocrine Pancreas & Diabetes Mellitus
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1. Pancreas An organs in the abdominal cavity with two roles. The
first is an exocrine role: to produce digestive enzymes
and bicarbonate, which are delivered to the small intestine
via the pancreatic duct. The second is an endocrine role:
to secrete insulin and glucagon into the bloodstream to
help regulate blood glucose levels. It is located behind
the stomach, between the spleen and the duodenum.
Blood supply: anterior lobe = superior mesenteric artery.
Posterior lobe = branches of the celiac artery. Pancreatic
islets receive - about 10% of pancreatic blood flow, but
only represent about 1% pancreatic mass.
2. Islets of Langer-
hans Cell clusters in the pancreas that form the endocrine
part of that organ. Alpha cells = secrete glucagon. Beta
cells = produce insulin. Delta cells = secrete somatostatin
(and gastrin). Pancreatic polypeptide (PP) = exerts GI
effects - stimulation of secretion of gastric and intestinal
enzymes. Inhibition of intestinal motility. Innervation: PNS
- stimulates pancreatic hormonal secretion. SNS - inhibits
pancreatic hormonal secretion.
3. Ā±Cells Cells that produce glucagon in order to raise blood sugar
levels.
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  1. Pancreas An organs in the abdominal cavity with two roles. The first is an exocrine role: to produce digestive enzymes and bicarbonate, which are delivered to the small intestine via the pancreatic duct. The second is an endocrine role: to secrete insulin and glucagon into the bloodstream to help regulate blood glucose levels. It is located behind the stomach, between the spleen and the duodenum. Blood supply: anterior lobe = superior mesenteric artery. Posterior lobe = branches of the celiac artery. Pancreatic islets receive - about 10% of pancreatic blood flow, but only represent about 1% pancreatic mass.
  2. Islets of Langer- hans Cell clusters in the pancreas that form the endocrine part of that organ. Alpha cells = secrete glucagon. Beta cells = produce insulin. Delta cells = secrete somatostatin (and gastrin). Pancreatic polypeptide (PP) = exerts GI effects - stimulation of secretion of gastric and intestinal enzymes. Inhibition of intestinal motility. Innervation: PNS - stimulates pancreatic hormonal secretion. SNS - inhibits pancreatic hormonal secretion.
  3. Ā±Cells Cells that produce glucagon in order to raise blood sugar levels.
  1. Ā²Cells Cells which secrete insulin in order to lower blood sugar levels. Their dysfunction is an essential component in the development of overt diabetes. Early change: beta cell function increases = compensatory measure to counter insulin resistance and maintain euglycemia = beta cell compensation. Cell morphology: beta cell hyperplasia = in prediabetic state. Compensation can occur for years. Progressively: beta cells are unable to adapt to long-term demands of peripheral insulin resistance --> state of rela- tive insulin deficiency. Cell morphology: beta cell atrophy = correlates with the progression of clinical diabetes.
  2. Ā“Cells Cells in the pancreas that secrete somatostatin.
  3. Pancreatic Polypeptide (PP) Pancreatic cells that exert GI effects through stimulation of secretion of gastric and intestinal enzymes. Inhibition of intestinal motility. Secreted by the gamma cells of the islets.
  4. C-Peptide The amino acid sequence removed from proinsulin to leave insulin. The presence of this indicates endogenous generation of insulin (will only be present in T2DM, not T1DM). Degraded and excreted in the kidney. Longer half-life than insulin, measurable. Helps identify the caus- es of hypoglycemia.

A glucose transporter found in adipose tissue and muscle that responds to glucose concentration in peripheral blood with low Km. Function: facilitate glucose uptake postpran- dially. Effected by: exercise = drives GLUT4 to the cell surface. It does not function until target cell is bound to insulin.

  1. GLUT2 A low-affinity (high Km) glucose transporter in hepato- cytes and pancreatic cells that serves as the glucose sensor for insulin release.
  2. Insulin Sensitivi- ty
  3. Insulin Resis- tance An index of how responsive the cells are to insulin binding. It is affected by multiple factors: age, weight, abdominal fat
    • adipocytes release hormones that are altered in obesity, result in impaired insulin sensitivity, and physical activity. A subnormal biological response to normal insulin con- centrations is implicated in numerous diseases. It is af- fected by obesity, hypertension, heart disease, and T2DM. Failure of target tissues to respond to insulin --> highly associated with obesity.
  4. SGLT- 2 Symporter found in the PCT of the kidney that trans- ports sodium ions and glucose for re-uptake. Medications (-flozins) that are inhibitors of this channel are used in the treatment of T2DM.

  1. Amylin A hormone synthesized by pancreatic B cells that con- tributes to glucose control during the post-prandial peri- od. It is co-secreted with insulin in response to nutrient stimuli. Released at much lower levels that insulin (1 mol- ecule per 100 insulin). Effect: regulates blood glucose con- centration by delaying gastric emptying and suppressing glucagon secretion after meals. Another function: satiety effect which reduces food intake. Other: produces amyloid deposits in pancreatic islets in most patients with T2DM of long duration --> may contribute to beta cell dysfunction. It has an antihyperglycemic effect.

  2. Glucagon A protein hormone secreted by pancreatic endocrine cells that raises blood glucose levels; an antagonistic hormone to insulin. It raises blood glucose. It stimulates glycogenol- ysis in the liver, gluconeogenesis in the kindyes and lipoly- sis in adipose tissue, and stimulates lipolysis --> ketogenic effect caused by the metabolism of free fatty acids in the liver. The presence of glucose inhibits its secretion. Secre- tion increases with: low glucose levels, sympathetic stim- ulation promotes glucagon release (i.e. hypoglycemia). Secretion is inhibited: high glucose levels, insulin levels, somatostatin, and high levels of circulating fatty acids suppress its secretion. The major target hormone for this hormone is the liver -- the liver will release its glucose stores.

  4. GLP- 1 Glucagon-like peptide 1. Produced in the small intestine after a meal. Binds to its receptors in target tissues, lo- cated in: pancreatic beta cells, gastric mucosa, kidney, lung, heart, skin, and immune cells. Main effect: stimu- lates glucose-dependent insulin release from pancreatic islets. Functions: slows gastric emptying (early satiety?), promoting hepatic glucose secretion, acts on the brain and inhibits appetite + induces weight loss, inhibits glucagon secretion, protects beta cells from destruction and stim- ulates beta cell growth. It is broken down by DPP-4. Its medications (-glutides), used in the tx of T2DM, promote weight loss and improves insulin response to GLP-1.

  5. DPP- 4 Enzyme that inactivates and breaks down incretins. Both GIP and GLP-1 are important in reducing serum glucose levels. Medications (-gliptins) - which are inhibitors of this

    • increase the activity of incretins in amplifying insulin production from beta cells. They improve glycemic levels and lower A1C.

  6. Ghrelin A hormone whose name is derived from growth hor- mone-releasing peptide. Ability to bind + activate GH sec- retagogue + stimulate GH-releasing peptide. Produced by endocrine cells in the gastric mucosa (in fundus) + Ī¼cells in the islets. Action: stimulates GH secretion directly in the pituitary, induces gastric emptying + acid secretion, regulates appetite + energy balance (via neurons in the hypothalamus). May play an essential role in maintaining

glucose levels during starvation + energy balance. Unclear full role of pancreatic ghrelin.

  1. Neuroglycopenia Deficiency of sugar that interferes with normal brain activ- ity.
  2. Obesity A state of increased body weight, caused by adipose tissue accumulation, that is of sufficient magnitude to pro- duce adverse health effects.
  3. Body Mass Index (BMI) A measure of body fat that is the ratio of the weight of the body in kilograms to the square of its height in meters. *Underweight: < 18.5 kg/m^2, Healthy weight: 18.5-24.9 kg/m^2, Overweight: 25.0-29.9 kg/m^2, Obese:

    30 kg/m^2.* Pathogenesis: caloric intake > caloric ex- penditure. Severe genes have been identified - genes that encode molecular components of the physiologic system that regulates energy balance. Key players = LEP gene, and its product leptin.

  4. Leptin A hormone produced by adipose (fat) cells that acts as a satiety factor in regulating appetite. Basal conditions: circulating levels correlate with fat mass. Levels decrease after weight loss. Decreasing levels of this inform the brain of diminishing fat storage --> negative energy bal- ance. Results in compensatory effect on appetite + ener- gy expenditure with the goal: replenish stores. This role is best understood from the phenotype of rare cases of humans with complete leptin deficiency --> hyperphagia, impaired immune function --> obesity; these patients will have weight loss with analogue administration of this hor- mone. Main point: decreased leptin levels signal the brain of a "negative balance" --> behavior of consuming food
  1. Dyslipidemia Abnormally elevated cholesterol or fats (lipids) in the blood. Obesity is associated with this characterized by: increased levels of VLDL cholesterol, triglycerides, total cholesterol, and decrease in HDL cholesterol.
  2. Diabetes Mellitus A group of metabolic disorders characterized by hyper- glycemia. Hyperglycemia in diabetes results from: defects in insulin secretion or action (or both). Complications of chronic hyperglycemia and the metabolic abnormalities of diabetes are often associated with secondary damage in multiple organs - kidneys, eyes, nerves, and blood ves- sels.
  3. > 6.5% What is the HbA1c to dx an individual as diabetic?
  4. Prediabetes Impaired glucose metabolism in which blood glucose con- centrations fall between normal levels and those consid- ered diagnostic for diabetes; includes impaired fasting glu- cose and impaired glucose tolerance, not clinical entities in their own right but risk factors for future diabetes and cardiovascular disease. Fasting plasma glucose between 100 - 125 mg/dL, 2 hour plasma glucose between 140 - 199 mg/dL (during an oral glucose tolerance test), and HbA1c level between 5.7% and 6.4%.
  5. Type 1 Diabetes Mellitus Diabetes caused by a total lack of insulin production; usu- ally develops in childhood, and patients require insulin re- placement therapy to control the disorder. Key pathogenic features: pancreatic beta-cell destruction, absolute defi- ciency of insulin. *Strongest association with class II MHC

(HLA-DR3/DR4) genes.* Antibodies against beta cell anti- gens (including insulin and beta cell enzyme glutamic acid decarboxylase). Clinical presentation: polydipsia, polyuria, polyphagia, weight loss, and fatigue. Severe cases can lead to ketoacidosis.

  1. Type 2 Diabetes Diabetes in which either the body produces insufficient Mellitus insulin or insulin resistance (a defective use of the insulin that is produced) occurs; the patient usually is not depen- dent on insulin for survival. Most common is adult onset, but prevalence is increasing in children and adolescents. Accounts for about 90 - 95% of all cases. Key pathogenic features: peripheral insulin resistance, inadequate secre- tory response by the pancreatic beta cells. Clinical presen- tation: polyuria, polydipsia, fatigue, recurring infections, visual changes, neuropathy. Secondary risk factors: CAD, peripheral artery disease, cerebrovascular disease.

  2. Excess Free Fat- Inverse correlation between fasting FFAs and insulin sen- ty Acids sitivity. Increase in FFAs --> decrease in insulin sensitivity. Decrease in FFAs --> increase in insulin sensitivity.

  3. Inflammation A localized physical condition in which part of the body becomes reddened, swollen, hot, and often painful, es- pecially as a reaction to injury or infection. In diabetes, it has emerged as an important contributor to pathogen- esis of T2DM. Adipose tissue contains adipocytes + in- flammatory/immune cells (macrophages + lymphocytes

    • adipocytes). As adipocyte lipid stores increase --> in- crease in FFAs release + proinflammatory adipokines --> recruitment of macrophages to adipose tissue which then become activated, resulting in: peripheral insulin resis- tance and beta cell dysfunction. Activated macrophages release cytokines (TNF-alpha, IL-6, NO) that: decrease insulin sensitivity, further promotes release of proinflam- matory cytokines + release of more FFAs. Creates a pos- itive feedback loop that maintains chronic state of local inflammation and insulin resistance.

  5. Hyperosmolar Hyperglycemic State (HHS)

  6. 1.) Formation of advanced glyca- tion end prod- ucts (AGEs) 2.) Activation of protein kinase C 3.) Disturbances in polyol path- ways

  7. Advanced Glyca- tion End Prod- ucts (AGEs) pain, acetone odor on the breath. Hyperkalemia despite total body potassium depletion. Rare but deadly metabolic state is more common in the elderly with type 2 DM. HHS is characterized by hyper- glycemia and severe dehydration without ketoacidosis. Clinical presentation: glycosuria + polyuria due to extreme glucose elevation. Severe volume depletion, increased serum osmolarity, intracellular dehydration, loss of elec- trolytes (including potassium), neurologic changes - stu- por. What are the three distinct metabolic pathways involved in the pathogenesis of long-term complications of diabetes? Derivatives of glucose-protein and glucose-lipid interac- tions that are linked to aging and chronic diseases. Occur as a result of non-enzymatic reactions between intracellu- lar glucose-derived precursors and the amino acid groups of proteins. Rate of production is greatly accelerated by hyperglycemia. They bind to a specific receptor (RAGE) which is expressed on inflammatory cells (macrophages and T cells), endothelial cells, vascular smooth muscle (and RBCs - glycated hemoglobin, or A1C). Detrimental effects: release of cytokines and growth factors. Genera- tion of ROS in endothelial cells. Increased procoagulant activity on endothelial cells and macrophages. Enhanced proliferation of vascular smooth muscle cells and synthe- sis of the extracellular matrix.

  1. Protein Kinase C Intracellular protein kinase that leads to numerous down- stream effects: production of proangiogenic molecules (VEGF) --> implicated in neovascularization seen in di- abetic retinopathy. Production of profibrogenic molecules (TGF-beta) --> excess deposition of ECM and BM mater- ial.
  2. Polyol Pathway Hyperglycemia leads to an increase in intracellular glu- cose which is then metabolized by the enzyme aldose reductase --> sorbitol, a polyol, and then eventually to fructose. This occurs in tissues that do not require in- sulin for glucose transport. This leads to depletion of glu- tathione reductase (GSH), which is an important anti-ox- idant mechanisms in the cell. When you deplete GSH --> the cell is more susceptible to oxidative stress. This promotes glucose neurotoxicity, which promotes diabetic neuropathy.
  3. Charcot Joint Bone and joint destruction secondary to a neuropathy and loss of sensation. Location: primarily at foot/ankle. Due to long-term diabetes.