Endocrine, Pancreas
direct action; beta cells
An increase in blood glucose level (above 4.5 mmol/l or 81mg/100mL) stimulates both synthesis and release of insulin by a _______ ________ on ______ _______.
endocrine; exocrine
Located partially behind the stomach in the abdomen, the soft, triangular pancreas is a mixed gland composed of both ____________ and ___________ gland cells.
tyrosine kinase
MoA of insulin: A disulfide bond connects the two α subunits, and each α subunit is connected to a β subunit by a disulfide bond. The β subunits have ___________ __________ activity.
gene transcription
MoA of insulin: Insulin also binds to elements in the nucleus, the Golgi apparatus, and the endoplasmic reticulum. Thus, insulin stimulates ________ _____________ as well, similar to the actions of somatomedins, IGF-1 and IGF-2. Very peculiar, similar to how GH works (i.e., via secondary action of somatomedins and IGF).
internalized; endocytosis
MoA of insulin: The insulin-receptor complex is ___________________ by its target cell by ________________. The insulin is degraded by intracellular proteases. The insulin receptor is either degraded by proteases, stored or recycled to the cell membrane to be used again.
cholinergic, adrenergic, peptidergic
What are the three types of neurons that provide innervation for the islets of langerhans?
gap junctions; venous blood flow; innervation by cholinergic, adrenergic, and peptidergic neurons
What are the three ways in which the islets of larger hans communicate with each other?
blood glucose concentration; ANS (PNS, SNS)
What are the two MOST important factors regulating insulin release?
BG concentration; autonomic nervous system
What are the two main factors affecting release of glucagon?
catecholamines via alpha 2 adrenergic receptors
What is the biggest/most important inhibitory regulator of insulin secretion (besides glucose)?
cholinergic (ACh) via PNS
What is the biggest/most important stimulatory regulator of insulin secretion (besides glucose)?
electrical contact
What is the purpose of gap junctions in the islets of langerhans?
glycogen; fat; protein
When the availability of nutrients exceeds the demands of the body, insulin ensures that excess nutrients are stored as ____________ in the liver, as _____ in adipose tissue and as __________ in muscle. These stored nutrients are then available during subsequent periods of fasting or exercise to maintain glucose delivery to the brain, muscle, and other organs.
gastrin; secretin; CCK; GIP
_________, __________, _____ and particularly ______ (from muscosal endocrine K-cells) stimulate insulin release directly. These effects may be physiologically important in dealing with a sudden surge in blood glucose following a meal.
delta cells
10% of the islet and secrete somatostatin; Somatostatin: a hypothalamic GH release-inhibiting hormone; May exert a localized paracrine action on other islet cells to influence both insulin and glucagon secretion (usually inhibitory).
diet, exercise, hypoglycemic agents
Type II diabetes preferred treatments:
somatostatin
A hypothalamic GH release-inhibiting hormone
BG concentration; AAs and FAs; ANS; cholecystokinin
What are four factors affecting release of insulin?
lipolysis; FAs; ketoacids; HSL; cAMP
Actions of glucagon: Increases blood fatty acid and ketoacid concentration: Stimulate _________ and mobilization of _____ (from triglycerides), resulting in increased levels of circulating ____________, acetoacetate and β-hydroxybutyrate. This effect is mediated by an increase in _____ activity (via elevation of _____) Inhibits fatty acid synthesis, which also shunts substrates toward gluconeogenesis. Increases blood amino acid concentrations via protein breakdown.
blood
Actions of insulin are to decrease glucose, fatty acid, ketoacid, and amino acid concentrations in the _______
activates; inhibits
Activated tyrosine kinase phosphorylates several other proteins or enzymes that are involved in the physiologic actions of insulin including protein kinases, phosphatases, phospholipases, and G proteins. Phosphorylation either ____________ or __________ these proteins to produce the various metabolic actions of insulin.
paracrine
Besides endocrine effects in the pancreas, there are a lot of ____________ effects
glucose transport
Decrease blood glucose concentration by: Increasing __________ ___________ into target cells such as muscle and adipose by directing the insertion of glucose transporters (GLUT 4) into the cell membranes.
glycogen synthase; glycogen phosphorylase
Decrease blood glucose concentration by: stimulation of glycogen synthesis in skeletal muscle, liver and adipose tissue by a direct increase in ________ _________ and simultaneously, a decrease in ________ ______________ activity which inhibit glycogenolysis (glycogen breakdown).
fluid; electrolyte; DKA
Disturbances of ______ and _______________ balance are present in type I DM: Causes ______: A form of metabolic acidosis caused by increased levels of ketoacids.
islet of langerhans
Endocrine cells of the pancreas arranged in clusters that produce pancreatic hormones. Compose 1-2% of the pancreatic mass.
GLUT4; GLUT1; GLUT2
Fat and muscle and cardiac tissue require insulin for glucose uptake because ________ transporters require insulin. Other tissues like the brain have ________ and ________, which do not require insulin (good, because brain can only use glucose)
GLUT4
For all intents and purposes, insulin is required to get glucose into the cells. Exercise increases _________ transporters, working like insulin, stimulating glucose uptake independent of insulin.
beta; muscle
GLUT-2 are specific for ______ cells, while GLUT-4 are specific for __________ cells
cAMP; protein kinase A
Glucagon and somatostatin may also influence insulin release indirectly (stimulation or inhibition respectively) by modulating the levels of intracellular ________. A rise in this and subsequent activation of _________ ________ ____, generally promotes exocytosis of insulin and vice versa.
alpha cells; hyperglycemic
Glucagon: Synthesized in pancreatic islet _______ ______ from larger preproglucagon precursor molecule and stored in the dense granules until it is secreted by the cells. Extremely potent ______________ agent. One molecule of this hormone can cause the release of 100 million molecules of glucose into the blood.
glycogenolysis; glycogen formation; gluconeogenesis
Glucagon: increases blood glucose concentration: Stimulates hepatic _______________; Inhibits ___________ ____________ from glucose; Increases _________________ by decreasing the production of fructose 2,6-biphosphate, which decreases phosphofructokinase activity. Thus, substrate is directed toward the formation of glucose. Amino acids are utilized for gluconeogenesis, and the resulting amino groups are incorporated into urea. (don't need to memorize enzymes)
indirectly
Growth hormone (GH), glucocorticoids and thyroid hormone may stimulate insulin release ____________ by increasing the blood glucose level.
98%
How much of the pancreas is devoted to exocrine function?
storage; mobilization; utilization
In contrast to insulin, which promotes _________ of metabolic fuels, glucagon promotes their ______________ and ______________.
abundance; starvation
In most respects, glucagon is the mirror image of insulin. Insulin: hormone of ____________ Glucagon: hormone of ______________
insulin; GLUT4
In the presence of __________, glucose uptake by these tissues is rapidly increased, due to the selective mobilization (and activation) of preformed glucose transporters (_______) from intracellular vesicles to the cell membrane.
insulin
Increases in blood glucose concentration rapidly stimulate the secretion of _________. Because of the preeminence of glucose as a stimulant, it is used to describe the mechanism of its secretion by the β cells.
downregulates
Insulin _________________ its own receptor by decreasing the rate of synthesis and increasing the rate of degradation of the receptor. Down-regulation of the insulin receptor is in part responsible for the decreased insulin sensitivity of target tissues in obesity and type II diabetes mellitus.
tyrosine kinase; ATP
Insulin binds to the α subunits of the tetrameric insuln receptor, producing a conformational change in the receptor. The conformational change activates ___________ ________ in the β subunit, which phosphorylates itself in the presence of _____.
metabolism; gluconeogenesis
Insulin decreases BG by: Increase in glucose _______________ (glycolysis) with a simultaneous decrease in liver _____________________. Key enzymes involved in glycolysis (conversion of glucose into pyruvate and lactate) including 6-phosphofructokinase and pyruvate kinase are stimulated by insulin
enzymes; PFK
Insulin decreases BG concentration by: Decreasing liver gluconeogenesis: Key ___________ involved in gluconeogenesis (formation of glucose from amino acids, lactate and glycerol) including pyruvate carboxylase and phosphoenolpyruvate carboxykinase are inhibited. Insulin inhibits this process also by increasing the production of fructose 2,6-biphosphate, which increases ____ activity.
amino acids; protein synthesis
Insulin decreases blood AA concentration: Stimulates the cellular active transport of plasma _______ ______ into muscle (thereby lowering blood amino acid levels). Stimulates muscle _________ ____________ directly, (anabolic action) while depressing protein breakdown.
ketoacid
Insulin decreases blood FA and ketoacid concentration: Inhibits ___________ (β-hydroxybutyric acid and acetoacetic acid) formation in liver because decreased fatty acid degradation means that less acetyl coenzyme A substrate will be available for the formation of ketoacids
fatty acids; HSL (hormone sensitive lipase)
Insulin decreases blood FA and ketoacid concentration: Prevents breakdown of ________ ______ (lipolysis) by inhibiting ____ activity in adipose cells, which will reduce the circulating levels of free fatty acids.
adipose cells; triglycerides; lipoprotein lipase
Insulin decreases blood fatty acid and ketoacid concentration: Stimulates uptake of glucose into ________ _______ and promotes the synthesis (lipogenesis) and storage of fatty acids in the form of ______________ in both adipose and hepatic tissues (the activity of the blood capillary enzyme ____________ ________, that facilitates the clearance of dietary fat from the plasma, is increased by insulin).
second messenger
Insulin doesn't work through a true _________ _______________ system; it works by activating an enzyme that phosphorylates or dephosphorylates proteins.
intracellular; extracellular
Insulin has both an ____________ and _______________ MoA as opposed to most hormones
Na+-K+ ATPase
Insulin increases potassium (K+) uptake into cells (at the same time that it promotes glucose uptake) By increasing the activity of the _____ ____ ________. This action of insulin can be viewed as protecting against an increase in serum K+ concentration. When K+ is ingested in the diet, insulin ensures that ingested K+ will be taken into the cells with glucose and other nutrients.
anabolic
Insulin is generally regarded as a/n __________ hormone
beta cells; proinsulin
Insulin is synthesized in the ____ _____ as a precursor molecule, ____________.
directly lower
Insulin is the only hormone with the ability to __________ ________ the blood glucose level.
high; K+ channels; depolarization; Ca2+
Insulin secretion: This ______ level of ATP then inhibits the activity of a special class of ATP-sensitive ____ __________ present in the β cell membrane, with a resultant cell ______________, influx of _______ and triggering of hormone release.
hyperpolarized; nonsecreting
Insulin secretion: With normal levels of intracellular ATP, these channels remain open, and thereby maintain the β-cell in a ________________ (________________) state.
insulin; C-peptide
Insulin synthesis: Following synthesis, the proinsulin is stored within cytoplasmic secretory granules, where the C-peptide is slowly cleaved by peptidase enzymes to yield ________ and ____________ molecules.
disulfide bridges; A chain
Insulin: Two ______________ ___________ (connecting peptides) link the A chain to the B chain, and a third disulfide bridge is located within the __ ________.
straight chains; A; B
Insulin: a peptide hormone consisting of two __________ ________, an ___ chain (21 amino acids) and a ___ chain (30 amino acids).
catabolic; raises; liver
It is a ___________ hormone that ________ the blood glucose concentration by affecting carbohydrate, protein, and fat metabolism in the ________, its major target organ.
want to maintain glucose for the brain; want to not inhibit glycogen breakdown in muscle for glucose use during exercise
It is important to inhibit insulin during exercise for these two reasons:
orally; intravenously
It is well known that an _________-administered dose of glucose releases more insulin than an ______________ administered one, indicating the important role of gastrointestinal factors (released during food ingestion) in enhancing insulin secretion.
arginine; leucine; AAs; FA
Large amounts of _____________, __________ and some other ____ derived from protein/amino acid ingestion are potent stimulators of insulin release. These effects are generally synergistic (mutually enhancing) with those of glucose. An increase in _____ levels also promotes the secretion of insulin.
alpha cells
Largest cell type, localized towards the outer margins of the islet; 20% of the islet and secrete glucagon
beta cells
Occupying the central area of the islet; 65% of the islet and secrete insulin
insulin
Only the GLUT-4 isoform however (uniquely expressed in skeletal muscle, cardiac muscle and fat cells), is regulated by _________.
alpha 2
Parasympathetic (vagal) nerve stimulation (acetylcholine) increases insulin secretion while the dominant effect of sympathetic nerve stimulation is to inhibit release; the latter is due to activation of _______ ___ on the β-cell membrane, leading to a decrease in intracellular levels of cAMP (activation of β-adrenoceptors by adrenergic agonists has the opposite effect). Cholinergic (Ach) stimulation increases intracellular levels of cAMP.
65-115 mg/dl
Plasma glucose is normally maintained within the range of 3.6 to 6.4 mmol/l (_____ ________, fasting)
polypeptide; peptides; exocrine; GI tract
Remaining cells of the islet of langerhans: secrete pancreatic ______________ or other __________; Functional role of these peptides are complex and are primarily involved in ____________ function of the ___ _______ (e.g., digestion and metabolism of food).
insulin
Secretion of somatostatin is inhibited by:
The ingestion all forms of nutrients (i.e. glucose, amino acids, and fatty acids); Several gastrointestinal hormones; Glucagon; Β-adrenergic agonists
Secretion of somatostatin is stimulated by:
insulin; glucagon
Somatostatin: Function is to modulate or limit the responses of ________ and _____________ to ingestion of food.
delta
Somatostatin: Secreted by the ______ cells of the islets of Langerhans in response to a meal, diffuses to the nearby α and β cells.
facilitated diffusion
Some tissues (e.g. liver, red blood cells and particularly brain cells) depend on __________ __________ only (via specific glucose transporter proteins) for glucose entry (insulin is not required) Therefore adequate blood glucose level is essential for their normal function.
membrane
Still is a membrane bound receptor, because insulin has a hard time getting across the membrane; however, unlike amino acid based hormones, insulin can actually get across the _____________
hyperkalemia
T1 DM also causes a shift of K+ out of cells, resulting in...
proximal tubule; ECF volume contraction
T1 DM: also causes glucosuria, polyurea, and thirst. The increased blood glucose concentration results in an increased filtered load of glucose, which exceeds the reabsorptive capacity of the _____________ __________. The nonreabsorbed glucose then acts as an osmotic solute in urine, producing an osmotic diuresis, polyurea and thirst. The polyuria produces _____ ____________ _______________ and hypotension.
receptor; alpha subunits; beta subunits
The action of insulin on target cells begins when the hormone binds to its __________ in the cell membrane. The insulin receptor is a tetramer composed of two ______ ________ and two _____ _________.
BG concentration, other islet hormones, GI hormones, AAs and FAs, some other hormones, ANS
What are six factors regulating insulin secretion?
insulin; glucagon
The delta cells may exert a localized paracrine action on other islet cells to influence both ___________ and _____________ secretion (usually inhibitory).
adenyl cyclase; Gs; cAMP
The effects of glucagon are mediated by specific membrane glucagon receptors (coupled to _________ __________) via a ___ protein that generate an increase in intracellular ________ levels. This will then activate protein kinases that phosphorylate various enzymes; the phosphorylated enzymes then mediate the physiologic actions of glucagon.
Vagus; ACh
The main PNS nerve in the pancreas is the _______ nerve and it releases _____
glucose-6-phosphate; glycogen
The majority of glucose is converted to ________________ then stored as _________
humoral
The regulation of insulin secretion is an example of a/n ____________ mechanism of hormone release
GLUT-2; increase; ATP
This stimulatory effect of glucose depends on its initial facilitated transport into the β cells (via the _________ carrier protein, Glucose Transporter), and subsequent metabolism to yield an __________ in intracellular levels of _____.
glucosuria; polyuria, thirst
Three effects of T1 DM:
gap junctions; insulin; innervation
Three ways in which they communicate with each other and thereby alter each other's secretion: ______ ____________ provide electrical contact Venous blood flow ____________ from β cells washes onto α and δ cells and visa versa _____________ by cholinergic, adrenergic and peptidergic neurons
simple; diffusion; intracellular glucose
Tissues such as skeletal, cardiac and adipose cells, glucose cannot penetrate the cell membrane by _________ (or facilitated) ____________ down its concentration gradient, and ______________ ___________ is consequently low.
insulin replacement
Treatment for T1 DM consists of ________ _____________ therapy, which restores the ability to store carbohydrates, fats, and proteins and returns the blood values of nutrients and electrolytes to normal.
exercise; caloric; weight; sulfonylurea; biguanide
Treatment for T2DM include: __________ (doesn't have to be high intensity, even around 50% VO2max and one single bout show an effect on insulin sensitivity) _______ restriction and ________ reduction, ___________________ drugs (e.g. tolbutamide or glyburide), which simulate pancreatic insulin secretion _____________ drugs (e.g. metformin), which up-regulate insulin receptors on target tissues.
BG concentration
Type I DM: Inadequate amounts of insulin can lead to serious metabolic consequences. Carbohydrate, fat and protein metabolism will be disturbed, leading to: Increased _____ __________________
insulin, diet, exercise
Type I diabetes preferred treatment:
beta cells; insulin
Type I diabetes: Caused by destruction of _____ _______, such that very little or no _________ production is present, often as a result of an autoimmune process.
insulin resistance; lipolysis; hyperglycemia
Type II DM: Some patients may, in fact, show a characteristic _________ ________________ (coupled with a high blood insulin level or hyperinsulinaemia, leading eventually to β-cell exhaustion) suggesting a defect in the action of insulin (particularly in stimulating muscle glucose uptake) at the receptor or postreceptor levels. The insulin resistance leads to an increase in the rate of ____________ and elevation in free fatty acid levels; this coupled with an increased liver glucose production and reduced glucose uptake, results in a significant ________________.
