Watson L6-8 Flashcards
What was the history of diabetes?
- Ancient Hindu manuscripts > 2000y ago – described urine
- Sushruta – Hindu physician
400 BC – tasted urine and noticed sweetness due to sugar being present. First highlighted due to presence of flies. - ~250 BC – “diabetes” = “to syphon”
Who were the influential people who helped discover diabetes?
Thomas Willis, von Merking & Minkowski, Banting & Best.
What was the role of Thomas Willis?
He was physician to King Charles II. “Diabetes Mellitus” having the taste of urine – honey and sugar. 1869 – Langerhans describes some odd looking groups of cells in the pancreas – about 1-2 % of total cells labelled Islets of Langerhans.
What was the role of von Merking & Minkowski in diabetes?
They were actually studying lipid metabolism and suspected the pancreas played a role (through bile secretion). Removed dog pancreas. They removed the pancreas and had to leave town for a few days. On their return the dog was exhibiting all the symptoms of diabetes!
What was the role of the Banting and Best in diabetes?
Tied off the pancreas and collected accumulated “extract.” His professor told him that his attempts were futile. First isolation of “insulin.” A polypeptide hormone that controlled circulating levels of glucose.
How is insulin synthesised?
Synthesised in pancreatic beta cells as preproinsulin. Proteolytically cleaved to generate two chains joined by disulphide bonds.
What chain is insulin involved in?
Negative feedback chain.
What is the opposing hormone to insulin?
Glucagon. It is released by pancreatic alpha cells.
What are the two main forms of diabetes?
- Type 1 DM – Typically adolescent onset called “juvenile diabetes.” Catastrophic loss of mass with an absolute requirement for insulin.
- Type 2 DM – Typically maturity onset. May not require insulin and can be modified by diet and exercise.
What are the components of the glucose system?
Kir 6.2 an ATP gated inwardly rectifying K+ channel, KATP, L-type Ca2+ channel which is voltage dependent, GLUT-2 glucose transporter and hexokinase IV (glucokinase).
What is the structure of glucagon and what is its role?
Glucagon is a 29 aa peptide hormone with opposite actions of insulin and increase circulatory glucose. It increases gluconeogenesis (makes glucose from Acetyl CoA in liver) and increases glycogenolysis. Decreases lipogenesis (formation of fatty acids from Acetyl CoA).
How is glucagon released?
Glucagon release by a-cells is also controlled by ADP/ATP levels and glucose metabolism by mitochondria. Release of glucagon is triggered by low cellular glucose levels.
What do pancreatic islets contain?
Clusters of pancreatic alpha and beta cells. Pancreatic a produce hormone glucagon. Pancreatic b are the site of insulin production. Endocrine tissue release the hormones into the circulation by diffusion.
What is the beta cell function?
Glucose enters cells via GLUT-2. Glucose is phosphorylated by Hexokinase IV. G6P metabolised by mitochondria altering levels of ATP in the cell. ATP/ADP ratio act as sensor for circulating glucose levels. Increased ATP closes the K+ channel causing cell depolarisation. Collapse of membrane potential activates the voltage-sensitive Ca2+ channel. Influx of Ca2+. Ca2+ flux drives membrane fusion of secretory granules and release of insulin.
What is alpha cell function?
Alpha cells exhibit depolarisation/ triggering activity under conditions of low ATP. The K leakage current is low enough to trigger depolarisation. Paradoxically - blocking K channel with increased ATP actually reduces triggering.
How is the insulin signal induced?
Phosphorylation of insulin receptor activates serine/threonine kinases. Leads to phosphorylation of a series of insulin-receptor-substrates (IRS). Phosphorylation of IRS-1/ IRS-2 activates the phosphoinositol pathway. Leading to phosphorylation and activation of Akt (protein kinase B). Akt is the main mediator of metoblic actions of insulin. Akt signalling drives cytoskeleton rearrangements that lead to insertion/activation of high affinity transporter GLUT4. Increases uptake of glucose 20 fold. Uptake of circulating glucose by skeletal muscle and adipocytes. Reduces blood levels.
What are the effects of insulin?
In the liver
o Decreased gluconeogenesis
o Increased glycogenesis
o Decreased glycogenolysis
o Increase lipogenesis
In the pancreas
o Decreased glucagon
o Increased beta cell growth
In skeletal muscle
o Increase glucose transport
o Increased glycogenesis
In adipocytes
o Increased glucose transport
o Increased lipogenesis
o Decreased lipolysis
What is glycogenesis?
Synthesis of glucose polymer “animal starch”
What is glycogenolysis?
Breakdown of glycogen in the liver to release glucose when levels are too low.
What is lipogenesis?
In times of glucose sufficiency, acetyl CoA is used to synthesise fatty acids. These are esterified with glycerol to form triglycerides.
What is lipolysis?
In times of glucose depletion, the breakdown of triglycerides to produce free fatty acids (FFA).
What is the evolution of type two diabetes?
Includes loss of insulin sensitivity and/or loss of insulin production through beta cells. Early stages characterised by increasing blood glucose levels. Often asymptomatic. Insulin levels become abnormally high as pancreas responds to glucose. Later insulin levels progressively fall as b cell mass and productivity fall off and hyperglycaemia ensues.
