REB 8. Insulin Flashcards
What is the major characteristic of Diabetes Mellitus?
elevated fasting blood glucose levels - hyperglycaemia
What are the 3 types of Diabetes Mellitus?
[1] Type I - insulin deficiency
[2] Type II - insulin resistance (around 95%)
[3] Gestational Diabetes - 5% of all pregnancies
If Diabetes Mellitus is unmanaged overtime, what can it lead to?
[1] Nerve Damage (Neuropathy) [2] Renal Failure (Nephropathy) [3] Heart Attacks [4] Blindness (Retinopathy) [5] Strokes [6] Vascular Damage (Macroangiopathy) - leads to amputation
Where is insulin secreted? What is its primary function and what are its major targets?
- secreted by beta cells of islet of Langerhans in pancreas
- primary function is to facilitate uptake of glucose into body cells
- adipose tissue and skeletal muscle are major targets of insulin
Which cells do not require insulin for glucose uptake?
- brain cells
- liver cells
- kidney cells
What are the 3 major cell types in the Islets of Langerhans? Which one is the most prevalent?
[1] alpha cells - 20%
- secrete glucagon
[2] beta cells - 75%
- produce insulin
[3] gamma cells - 5%
- secrete somatostatin
What are some characteristics of the Islets of Langerhans?
- 1 to 3 million islets per adult pancreas (1 to 2% of mass)
- highly vascularized (allows secreted hormone good access to circulation)
- innervated by sympathetic and parasympathetic neurons
- nervous signals modulate secretion of insulin + glucagon
What are the functions of Somatostatin on the gastrointestinal system and anterior pituitary gland?
Gastrointestinal System:
- suppresses release of insulin + glucagon (pancreatic hormones)
- suppresses release of gastrin, cholecystokinin (gastrointestinal hormones)
Anterior Pituitary:
- inhibits the release of growth hormone (GH) and thyroid stimulating hormone (TSH)
What is the function of glucagon?
it opposes role of insulin and raises glucose levels - by enhancing gluconeogenesis and glycogenolysis
How is insulin synthesized/coded for? List the steps
[1] synthesized in beta cells
[2] mRNA translated as single chain precursor - Preproinsulin
[3] removal of the signal peptid by endopeptidases in the rough endoplasmic reticulum
[4] proinsulin has 3 domains:
(a) amino-terminal B chain
(b) carboxy-terminal A chain
(c) connecting peptide or C peptide (it is cleaved off - no physiological function)
[5] mature insulin has 2 unbranched peptide chains - linked by 2 disulphides
What are the 3 prohormone convertase enzymes involved in insulin processing?
[1] PC2
[2] PC3
[3] Carboxypeptidase E
then, insulin + C-peptide are packaged into golgi into secretory granules
What are the steps/procedure for insulin release?
[1] Glucose enters the cells through GLUT2 transporter
[2] Glucose is metabolized by the glucokinase enzyme (glucose to glucose-6-phosphate)
[3] this generates ATP (the ATP/ADP ratio increases)
[4] the increased ATP leads for the closure of ATP-sensitive K+ channels
[5] there is a decreased K+ efflux (potassium stays in cell) and this depolarises cell membrane
[6] there is the opening voltage-sensitive Ca2+ channel and the calcium ions enter the cells
[7] the increased intracellular calcium ions triggers the release of insulin-containing secretory granules
- insulin is released!
What may be a possible cause of hypoglycaemia? (general answer)
hyperinsulinism - high insulin levels
What are some causes of hypoglycaemia from excess endogenous insulin production/secretion?
[1] Insulinomas
- insulin secreting pancreatic tumours
[2] Congenital Hyperinsulinism
- genetic defects
What are some causes of hypoglycaemia that is not from endogenous insulin (from an external source)?
[1] Drug-Induced Hyperinsulinism (e.g. Sulfonylurea type 2DM treatment)
[2] Hypoglycaemia due to exogenous (injected) insulin
What are the 2 main forms of congenital hyperinsulinism?
[1] Transient Neonatal Hyperinsulinism
- may be due to premature births
- usually resolves itself in a few days or months
[2] Focal or Diffuse Hyperinsulinism
- due to genetic defects
- there are 3 types of this form of hyperinsulinism all dependent on a genetic mutation
What are the 3 types of genetic mutations that may occur leading to focal/diffuse hyperinsulinism?
[1] KATP channel disorders (mutations SUR1 Kir6.2 proteins in channel results in inappropriate insulin secretion)
[2] Glucokinase gain-of-function mutation (the “glucose-sensing enzyme” instructs the beta-cell to secrete insulin when there is a lower blood glucose than normal)
[3] Hyperammonaemic Hyperinsulinism (HI/HA) gain of function mutation glutamate dehydrogenase
- beta cells secrete insulin when an increase ATP/ADP ratio triggers amino acid breakdown + formation of alpha-ketoglutarate
- more insulin is secreted
What are some regulators of insulin release? (first name the 3 main categories)
[1] Nutrients
- Glucose
- Amino Acids (leucine, isoleucine, alanine + arganine)
[2] Paracrine Hormones
- Glucagon
- Somatostatin
[3] Gastrointestinal Hormones (Incretins)
- Gastric Inhibitory Polypeptide (GIP)
- Glucagon Like Peptide (GLP)
What are incretins?
Incretins are hormones produced in the small intestine during a meal that enter the vasculature and trigger insulin release by pancreatic beta cells
Where is glucagon synthesized? [3]
[1] Pancreas - Pancreatic Alpha Cells [2] Intestine - Intestinal Neuroendocrine L-Cells [3] Brain
When is glucagon secreted? What triggers glucagon to be secreted?
[1] Low Blood Glucose
[2] Low Insulin - low insulin means low blood glucose
[3] Rise in Amino Acids after a protein meal (stimualates glucagon)
[4] adrenaline + noradrenaline
What is the function of glucagon? What does it do?
[1] activation of hepatic glycogenolysis
- breakdown of glycogen
[2] activation of hepatic gluconeogenesis
- glucose is created
What is the precursor for glucagon (which undergoes tissue-specific post-translational processing)?
Proglucagon
Proglucagon is converted into what in the pancreatic alpha-cells?
[1] Glucagon
[2] Glicentin-Related Pancreatic Peptide
[3] MPF
Proglucagon is converted into what in the intestinal neuroendocrine L-cells?
[1] Glucagon Like Peptide-I (GLP I)
[2] GLP II (biologically inactive)
[3] Glicentin
What are the functions of Glucagon Like Peptide I?
- potent stimulator of insulin secretion
- stimulates somatostatin release for delta-cells of pancreas
- inhibits glucagon from alpha cells
What are the functions of Glicentin?
- stimulator of insulin secretion
- inhibits gastric acid secretion
- regulates gut motility
What are the... [1] Rapid [2] Intermediate [3] Delayed principal actions of insulin?
[1] increases transport of glucose, amino acids and K+ into insulin-sensitive cells
[2]
- stimulates entry of amino acids + protein synthesis
- inhibits protein degradation
- activates glycolysis + glyocogen synthesis
- inhibits glycogenolysis + glucose-Genica enzymes
[3] increase in mRNAs for lipogenic + other enzymes
What is the receptor type for insulin receptors? How many subunits are they made up of? Explain the characteristics of the subunits.
Receptor Type: Tyrosine Kinase It has 2 subunits: [1] Alpha Subunit - extracellular part - contains the insulin-binding domain
[2] Beta Subunit
- transmembrane domain
- ATP Binding + Tyrosine Kinase Domains
*note: they are bonded by disulfides bonds
What bond is between the alpha and beta subunit in the insulin receptor?
A disulfide bond
When insulin binds to the insulin receptor what happens?
[1] autophosphorylation of the tyrosine on the beta subunits
[2] the activated receptor phosphorylates intracelullar proteins (e.g. IRS-1)
[3] signal pathways are activated
- has an influence on gene expression, metabolism and growth
[4] insulin then degraded by lysosomes
What is the mechanism by which insulin facilitates glucose entry into both muscle and adipose tissue?
[1] after the insulin binds to the receptors, this causes the fusion of vesicles with the plasma membrane
[2] the fusion of vesicles then allows for the insertion of glucose transporters (GLUT4)
[3] when receptors are no longer occupied, they are recycled back into the cytoplasm
Which glucose receptors are required for the brain and liver?
TRICK QUESTION
the brain and liver do not require insulin for glucose uptake
- they use a non insulin-dependent transporter (GLUT2 + GLUT3)
Which glucose transporter is responsive to insulin and is in adipose tissue and striated muscle (skeletal + heart)
GLUT4
What type of tissue are the GLUT4 receptors in?
[1] adipose tissue
[2] striated muscle (skeletal + heart)
How is circulating insulin broken down? What is the half-life for insulin?
- insulinase in the liver and kidneys break down circulating insulin
- the half life of insulin is 4 to 6 minutes
(degradation ensures that the insulin level is modulated)
What are some disorders due to hypoglycaemia (excess insulin)?
[1] Insulinoma
[2] Persistent Hyperinsulinaemia and Hypoglycaemia in Infancy
- ATP-sensitive K+ channels on beta cells are closed
- glucokinase/glutamate dehydrogenase (gain of function mutation)
What is a disorder of hyperglycaemia/insufficient insulin?
Diabetes Mellitus
What are the 3 types of diabetes mellitus?
[1] Type I Diabetes
- beta cell destruction (mostly immune mediated)
- absolute insulin deficiency
- onset most common in childhood and early adulthood
[2] Type II Diabetes
- most common type (95%)
- various degree of beta cell dysfunction and insulin resistance
- associated with obesity and overweight
[3] Gestational Diabetes Mellitus
- transient condition associated with pregnancy
- can increase risk of mother developing type II
Compare the times of onset between Type I and Type II diabetes.
Type I diabetes has a rapid onset.
Type II has a slow onset.
What are the classical symptoms of Type I diabetes?
[1] increased thirst (polydipsia) [2] increased urination (polyuria) [3] glycosuria [4] weight loss with increased appetite [5] fatigue [6] nausea [7] vomiting [8] diabetes ketoacidosis
What are the classical symptoms of type II diabetes?
[1] increased thirst (polydipsia) [2] increased urination (polyuria) [3] glycosuria [4] increased appetite [5] fatigue [6] blurred vision [7] slow-healing infections [8] impotence in men
What is diabetes ketoacidosis and how can it result?
Diabetes Ketoacidosis: uncontrolled diabetes may result in ketoacidosis (diabetic coma)
Steps:
- when body cannot make insulin, the body cannot use glucose and breaks down fats for energy
- when fats are broken down, ketones are produced in liver
- if levels of ketones cannot be excreted in urine, they build up in blood which can lead to ketoacidosis
What are the symptoms of ketoacidosis?
- shortness of breath
- breath that smells sweet
- nausea and comforting
- very dry mouth
Why is plasma glucose concentration increased in diabetes Mellitus?
- insulin regulates uptake of glucose
- without insulin, glucose cannot be transported into the cells (the body interprets this as a lack of glucose)
- gluconeogenesis, glycogenolysis and lipolysis resulting in increased blood glucose
Why do patients with diabetes Mellitus have glycosuria?
- normally, 100% of the glucose that is filtered is reabsorbed
(glucose reabsorption involved transport proteins) - in hyperglycaemic people, the filtered glucose can exceed the capacity that the kidney tubules can reabsorb glucose (this is because the transport proteins become saturated)
- result is glucose in urine
- glucose draws water in the urine by osmosis
- so hyperglycaemia causes a diabetic to produce a high volume of glucose-containing urine (polyuria)
