Download Endocrinology of the Pancreas and Diabetes Mellitus

Pancreatic Hormones
19
• Introduction to the pancreas, its cell types,
its hormones, its functional organization, its
venous output to liver and its regulation
• Overview of intermediary metabolism and
enzyme sites of major actions of insulin and
glucagon
• Pancreatic hormones, insulin, glucagon, SS
and PPY. Their structure, synthesis, related
peptides, secretion, regulation, receptors and
effects. Effect of exercise on insulin and on
its counter-regulatory hormones
• Regulation of pancreatic hormones, Diabetes
Mellitus, hypoglycemia, fasting, NIDDM
Introduction
Pancreas and its “story lines”
Insulin decreases glycemia while glucagon
increases it. As glycemia increases blood levels of
insulin decrease while those of glucagon decrease.
Page 1
Glucose
metabolism
Introduction
• Endocrine
pancreas
a bird’s eye view of metabolism
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Storage and utilization of biological fuels.
Introduction
• Endocrine
pancreas
a bird’s eye view of metabolism
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
Intraorgan flow of substrate and the competitive regulatory effects of glucose
and fatty acids that comprise the glucose–fatty acid cycle.
E
Storage and utilization of biological fuels.
Page 2
Introduction
• Endocrine
pancreas
effects of metabolic hormones
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
Effects of metabolic hormones on adipose tissue.
*Lipolytic effects of cortisol are permissive.
E
Storage and utilization of biological fuels.
Introduction
• Endocrine
pancreas
effects of metabolic hormones
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
Effects of metabolic hormones on skeletal muscle. *The stimulation of fatty
acid oxidation by growth hormone and cortisol are indirect and result from
increased fatty acid mobilization.
E
Storage and utilization of biological fuels.
Page 3
Introduction
• Endocrine
pancreas
effects of metabolic hormones
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Effects of metabolic hormones on the liver.
S
E
Storage and utilization of biological fuels.
Introduction
• Endocrine
pancreas
changes induced by fasting
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
Quantitative turnover of substrates in the basal state after
fasting for 24 hours. Follow the “ready available money”
E
Page 4
Introduction
• Endocrine
pancreas
changes induced by fasting
Glucose
GH
Insulin
• Intermediary
metabolism Glucagon
• Pancreatic
hormones
Cortisol
GH
GH
T3
• Diabetes
mellitus
Representative values for plasma glucose and
metabolic hormones during fasting. Values for
growth hormone are averaged over 24 hours.
The small decline in cortisol may reflect a
decrease in cortisol binding globulin.
Effects of 1 day of fasting on GH
secretion. A. Normal fed young man.
B,L,D indicate meal times. GHRH
(1μg/kg) was given intravenously at
the time indicated by the arrow. B.
GH concentrations in plasma in the
same subject after a 24-hour fast
Hormonal changes in the basal state after fasting for 24 h.
S
E
Introduction
• Endocrine
pancreas
changes induced by fasting
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Plasma concentrations of glucose in normal subjects and patients suffering from
isolated deficiency of GH during control days of normal food intake and while
fasting. Some GH-deficient patients were untreated and others were given 5 mg
of hGH per day (treated). The fast began after the collection of blood on day 2.
Hormonal changes in the basal state after fasting for 24 h.
S
E
Page 5
Introduction
changes induced by exercise
• Endocrine
pancreas
O2 consuption
Epi
Insulin
• Intermediary
metabolism
Nepi
• Pancreatic
hormones
Glucagon
• Diabetes
mellitus
exercise in minutes
Changes in sources of fuels utilized
during prolonged exercise at 30% of
maximal oxygen consumption.
exercise in minutes
Cortisol
GH
exercise in minutes
Changes in concentration of insulin and counterregulatory hormones during prolonged moderate
exercise. Values shown are means obtained for 8
young men exercising on a bicycle ergometer at
~50% of maximum oxygen consumption.
Hormonal changes in the basal state after fasting for 24 h.
S
E
Introduction
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
•
•
•
•
•
•
•
•
pancreas, main regulator of sugar metabolism
sugars from food digestion and from glycogen
endocrine (islets) & exocrine pancreas (acinar)
the islets of Langerhans (triads: , ß, , cells)
hormones: insulin, glucagon, SS, PPY
pancreatic endocrine secretion to portal vein
blood glucose decreased by insulin, SS, IGFs
blood glucose increased by glucagon, CAs,
glucocorticoids, GI hormones, GH, CRH, ACTH,
T3 / T4, Ang II, food (arginine).
The opposite direction of plasma insulin and
glucagon define the metabolic state
E
Page 6
Introduction
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Cytoarchitecture of a typical human pancreatic islet as revealed in
immunostained confocal scanning microscopic images. Endocrine
cells are closely but randomly associated with vascular cells. Most
insulin- (red), glucagon- (green), and somatostatin- (cyan) immunoreactive cells are in close proximity to vascular cells immunoreactive
for smooth muscle cell actin (blue). Endocrine cells are aligned along
the blood vessels in a random order.
Introduction
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
Plasma levels of glucose and insulin in relation to
meal intake. Glucose increases insulin secretion
E
Page 7
Introduction
• Endocrine
pancreas
glucose
• Intermediary
metabolism
• Pancreatic
hormones
gluconeogenesis
glycogen
• Diabetes
mellitus
S
Time course of the origin of glucose under fasting
conditions. Look at the intermediary metabolic paths.
E
Introduction
• Endocrine
pancreas
• Intermediary
metabolism
FUEL METABOLISM IN ANABOLIC AND CATABOLIC PHASES
State
anabolism
Hormones
insulin
Fuel Source
diet
glycogen synth.
triglycerid synth.
protein synth.
storage
depots
glycogenolysis
lipolysis
proteolysis
ketogenesis
glucagon
• Pancreatic
hormones
• Diabetes
mellitus
S
catabolism
insulin
glucagon
Process
An opposite direction in the profile of plasma insulin
and glucagon defines the individual’s metabolic state
E
Page 8
Metabolic pathways
• Endocrine
pancreas
glycogen
glycogen phosphorilase
glycogen synthetase
G-1-P
G-6-Pase
• Intermediary
metabolism
glucose
hexokinase
F-6-P
PFK
F-1,6-diPase
• Pancreatic
hormones
• Diabetes
mellitus
S
glucose
G-6-P
F - 1,6 -diP
transaminases
insulin
glucagon
epinephrine
glucocorticoids
triose
amino acids
pyruvate
proteins
Krebs
cycle
acetyl CoA
fats
JP’s colorful version indicating the main action site
of various metabolic hormones
E
Metabolic pathways
• Endocrine
pancreas
Glucose
Glycogen
Glycogenesis
• Intermediary
metabolism
Glycolytic
pathway
Glucokinase
• Pancreatic
hormones
Glycogen
synthetase
Glycogen
phosphorilase
• Diabetes
mellitus
S
Glycogenolysis
Hadley’s textbook version of the intermediary
metabolic pathway
E
Page 9
Introduction
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
1.
2.
S
LEFT: Effects of insulin on glucose metabolism in hepatocytes. Green arrows indicate
reactions that are increased, and dashed red arrows indicate reactions that are decreased.
RIGHT: Biochemical pathways of glucose metabolism in hepatocytes. Reactions that are
accelerated in the presence of glucagon are shown in green. Broken red arrows indicate
reactions that are inhibited by protein kinase A catalyzed phosphorylation. The hexosemono-phosphate shunt is indirectly inhibited. Roman numerals indicate substrate cycles.
Goodman’s textbook version of the intermediary
metabolic pathway
E
Metabolic pathways
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
some associations to remember for an
endocrine regulatory viewpoint
S
E
Page 10
Metabolic pathways
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
some associations to remember for an
endocrine regulatory viewpoint
S
E
Metabolic pathways
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Hormonal effects on FFA production. Epinephrine and norepinephrine stimulate hormonesensitive lipase through a cyclic AMP mediated process. Insulin antagonizes this effect by
stimulating cyclic AMP degradation. T3, cortisol, and growth hormone increase the response
of adipocytes to epinephrine and norepinephrine. Growth hormone also directly stimulates
lipolysis. Insulin indirectly antagonizes the release of FFA by increasing reesterification.
Growth hormone and cortisol increase FFA release by inhibiting reesterification.
some associations to remember for an
endocrine regulatory viewpoint
S
E
Page 11
Insulin and its counterregulatory hormones
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Interaction of hormones to maintain the blood glucose concentration.
Green arrows denote increase; red arrows denote decrease.
Insulin decreases blood glucose while all
counter-regulatory hormones increases it
S
E
Insulin and its counterregulatory hormones
• Endocrine
pancreas
Insulin infusion
Epi
• Intermediary
metabolism
• Pancreatic
hormones
Nepi
Glucagon
Glycemia
after the
injection
of …..
cortisol
+ glucagon
+ epinephrine
glucagon
+ epinephrine
Cortisol
epinephrine
glucagon
• Diabetes
mellitus
GH
control
Insulin decreases blood glucose while all
counter-regulatory hormones increases it
S
E
Page 12
Insulin and its counterregulatory hormones
hormone effects on fat metabolism in adipocytes
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Insulin
Epi + Nepi
GH
Cortisol
T3
hormone effects on glucose metabolism in muscle
Insulin
Epi + Nepi
GH
Cortisol
T3
Insulin decreases blood glucose while all
counter-regulatory hormones increases it
S
E
Insulin and its counterregulatory hormones
hormonal regulation of metabolism in liver
• Endocrine
pancreas
• Intermediary
metabolism
Insulin
glucagon
Epi + Nepi
GH
Cortisol
T3
hormonal effects on insulin secretion
and on target cells’ sensitivity to insulin
• Pancreatic
hormones
• Diabetes
mellitus
Insulin
glucagon
Epi + Nepi
GH
Cortisol
T3
Insulin decreases blood glucose while all
counter-regulatory hormones increases it
S
E
Page 13
Insulin and its counterregulatory hormones
control
• Endocrine
pancreas
fasting
plasma
glucose
GH-deficient
treated with
GH
• Intermediary
metabolism
normal
• Pancreatic
hormones
glucose
• Diabetes
mellitus
glycogen
GH-deficient
gluconeogenesis
days
Insulin decreases blood glucose while all
counter-regulatory hormones increases it
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
• it has 51 aa, 2 chains, 3 S-S bonds, C-peptide
• stimulates anabolism and favors energy
storage
• increases glycogen storage and inhibits both
glycogen breakdown and gluconeogenesis
• increases fatty acid synthesis and decreases
lipolysis and ketogenesis
• stimulates transport of glucose and of some
amino acids into striated muscle and adipose
tissue
• increases protein synthesis in liver, muscle,
adipose
• Like growth factors it has a growth promoting
effect
An overview of the main effects of
pancreatic insulin
S
E
Page 14
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Insulin secreted from the pancreatic ß cells
decreases blood glucose levels
S
E
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
An overview of the factors affecting insulin
signalling
S
E
Page 15
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Metabolic, hormonal, and neural
influences on insulin secretion.
An overview of the factors affecting insulin
signalling
S
E
Insulin
• Endocrine
pancreas
insulin
• Intermediary
metabolism
glucose
• Pancreatic
hormones
• Diabetes
mellitus
An overview of blood glucose stimulation
of insulin secretion and intracellular effects
S
E
Page 16
Insulin
A.- “Resting” beta-cell
B.- Glucose activated beta-cell
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Triggering of insulin secretion by glucose.
A. “Resting” beta cell (blood glucose < 100 mg/dl). ADP/ATP ratio is high enough so that ATP-sensitive
potassium channels (KATP) are open, and the membrane potential is about -70 mv. Voltage-sensitive
calcium channels (VSCC) and calcium-sensitive potassium channels (CSKC) are closed.
B. B. Beta cell response to increased blood glucose. Increased entry and metabolism of glucose
decreases the ratio of ADP/ATP, and KATP channels close. Voltage-sensitive calcium channels
(VSCC) are activated; calcium enters and stimulates insulin secretion. Mitochondrial metabolites
formed in response to glucose and calcium amplify secretion. Influx of calcium inhibits voltagesensitive calcium channels and activates calcium-sensitive and voltage-sensitive potassium
channels, thereby allowing the cell membrane to repolarize and calcium channels to close. Calcium
is extruded by membrane calcium ATPase. Persistence of high glucose results in repeated spiking
of electrical discharges and oscillation of intracellular calcium concentrations.
C. Effect of incretins (GLP-1 and GIP) on insulin release by beta cells (see next slide).
Insulin
B.- Glucose activated beta-cell C.- Incretins activated beta-cell
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Triggering of insulin secretion by glucose and by incretins.
B. Glucose (G). Increased entry and metabolism of G decreases the ratio of ADP/ATP, and KATP channels
close. Voltage-sensitive Ca channels (VSCC) are activated; Ca enters and stimulates insulin secretion.
Mitochondrial metabolites formed in response to G and Ca amplify secretion. Influx of Ca inhibits
voltage-sensitive Ca channels and activates Ca-sensitive and voltage-sensitive K channels, thereby
allowing the cell membrane to repolarize and Ca channels to close. Ca is extruded by membrane CaATPase. Persistence of high G results in repeated spiking of electrical discharges and oscillation of
intracellular Ca concentrations.
C. Major acute cellular actions of incretins. GLP-1 and GIP acting through GPCR activate AC to increase
intracellular cAMP). Cyclic AMP increases the activity of PKA or binds to a GTP exchange factor to
increase cytosolic Ca and enhance the effects of Ca on insulin secretion. KATP = ATP-sensitive
potassium channels; KV = voltage sensitive potassium channels: VSCC = voltage sensitive calcium
channels; RP = reserve pool of secretory granules; ER = endoplasmic reticulum.
Page 17
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Insulin release from pancreatic beta-cells
acts on its targets by binding to its receptor
S
E
Insulin
• Endocrine
pancreas
Cys residues
kinase
NH2
hydrophobic aa
Cys rich
• Intermediary
metabolism
•
ECF
membrane
• Pancreatic
hormones
ICF
EGF
• Diabetes
mellitus
JAK2
insulin
PDGF
COOH
•
GH
Prl
cytokines
ANP
The insulin
receptor contains
an intrinsic protein
kinase that
specifically
catalyzes the
phosphorylation of
tyrosine residues
on proteins
Cystein and its
thiol (SH) group
linking the aa to
another Cystein aa
may form part of a
binding cleft for
ligands
The insulin receptor is a one transmembrane domain tyrosine kinase receptor
S
E
Page 18
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Binding of insulin and its receptor in the ECF domain
causes phosphorylation of the receptor intra-cellular
domain and elicits a conformational change in its tyrosine
kinase portion, thus activating its enzyme activity.
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Binding of insulin and its receptor in the ECF domain
causes phosphorylation of the receptor intra-cellular
domain and elicits a conformational change in its tyrosine
kinase portion, thus activating its enzyme activity.
Page 19
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Binding of insulin and its receptor in the ECF domain
causes phosphorylation of the receptor intra-cellular
domain and elicits a conformational change in its tyrosine
kinase portion, thus activating its enzyme activity.
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
The main effect of insulin is on the Glut - 4
transporter. This is how insulin decreases
glycemia and increases glucose absorption
Page 20
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Confocal fluorescent microscope images of cultured mouse adipocytes that were
transfected with GLUT4 linked to green fluorescent protein and then incubated in the
absence (A) or presence (B) of insulin for 30 min. Insulin stimulation results in the
translocation of GLUT4 from intracellular storage sites to the plasma membrane.
The main effect of insulin is on the Glut - 4
transporter. This is how insulin decreases
glycemia and increases glucose absorption
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Effect of insulin on 6–phosphofructokinase enzyme, or how
insulin increses glycolysis
Effect of insulin on glycogen
synthetase enzyme, or how
insulin increases glycogenesis
S
E
Other effects of insulin are mediated by its
action on metabolic enzymes. This is how
insulin increases glycolysis & glycogenesis.
Page 21
Insulin
Main actions of insulin on metabolic
pathways. Notice the 3 main targets.
• Endocrine
pancreas
Organ
liver
• Intermediary
metabolism
ketogenesis
glycogen synthesis
fatty acid synthesis
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Net effect
glycogenolysis
gluconeogenesis
Chief mechanism
phosphorylase (glucose-dependent de-P)
PEPCK (transcriptional regulation)
FDPase-2 (enzyme dephosphorylation)
substrate (alanine) delivery from muscle
substrate (FFA) delivery from fat
glycogen synthase (enzyme de-P)
acetyl CoA carboxylase (transcription)
fatty acid synthase
muscle proteolysis
protein synthesis
glucose uptake
glycogen synthesis
multiple mechanisms
activity at multiple steps
recruit glucose transporter to cell surface
glucose uptake
glycogen synthase (enzyme de-P)
fat
hormone sensitive lipase (enzyme de-P)
delivery of tryglyceride from liver
lipoprotein lipase
lipolysis
triglyceride synthesis
Insulin suppress glucose production by inhibiting the flux
of gluconeogenic precursors (alanine, pyruvate, lactate,
glycerol), energy substrates (free fatty acids) and glucagon
secretion. All these suppress glucose release by the liver.
Insulin
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Simplified model of insulin signaling pathways. The insulin receptor proteins (IRS
1,2,3,4), Cbl, Shc, and the subunits of the insulin receptor are phosphorylated on
tyrosine residues by the insulin receptor kinase and serve as anchoring sites for
cytosolic proteins that form signaling cascades. Proteins shown in blue boxes are
serine/threonine kinases. Specific isoforms and/or subunits are not shown nor are the
relevant phosphatases. Shc = Src homology containing protein; Cbl = Cacitas B lineage
lymphoma protein; PI3K = phosphoinositol-3-kinase; PDK = phosphoinositide dependent
kinase; PKC = isoform of protein kinase C; PKB = protein kinase B; PDE =
phosphodiesterase; RAS = Ras oncogene, a small G-protein; mTOR = mammalian target
of rapamycin; GSK = glycogen synthase kinase; ERK = extracellular receptor kinase.
Page 22
Glucagon
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
• main counterregulator to insulin together
with catecholamines (Epi) & cortisol
• 29 aa, member of a related family peptides
that includes VIP, GIP, and secretin
• determines glycemia in postabsorptive state
by glycogenolysis and gluconeogenesis
• glucose, insulin and SS inhibit its release
• aa, exercise and CAs stimulate its release
• gene expression is restricted to cells in
islet and is negatively regulated by insulin
• glycentin, GI specific proteolytic processing
Glucagon release is the main counterregulatory hormone to insulin secretion
S
E
Glucagon
• Endocrine
pancreas
(-)
(+)
Glucagon
secretion
Glucagon
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Glucagon
Glucose
Blood glucose
Stimulatory and inhibitory
signals for glucagon secretion.
Glucagon secreted by the pancreatic alphacells increase blood glucose levels (glycemia)
S
E
Page 23
Glucagon
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
R
cell membrane
Gs AC
phosphodiesterase
ATP ----------> cAMP -----------> 5’AMP
inactive PKA ----------> active PKA
inactive PKb <----------> active PKb
glycogen
phosphorilase b <----->
glycogen
phosphorilase b
glycogen + Pi --> glucose - 1 - P
• Diabetes
mellitus
cell membrane
T
Glucose
blood
glucoserelease to blood
Glucagon release is the main counterregulatory hormone to insulin secretion
S
E
Glucagon
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
S
E
Glucagon’s main mechanism of action is through AC,
cAMP and PKA. Amplification is an important event in
the mechanism of action of glucagon (cascade).
Page 24
Glucagon
• Endocrine
pancreas
Organ
liver
• Intermediary
metabolism
Net effect
glycogenolysis
glycogen phosphorylase (cAMP-dep- P)
glycogenesis
glycogen synthase
(phosphorylation)
F - 1,6 - diPase
(phosphorylation)
pyruvate kinase
(phosphorylation)
substrate delivery, r eleasing inhibition of
carnitine palmytoil transferase, allowing
mitochondrial transfe r and FA oxidation
gluconeogenesis
• Pancreatic
hormones
Chief mechanism
glycolysis
ketogenesis
• Diabetes
mellitus
Main actions of glucagon on metabolic
pathways. Notice the single main target
S
E
Glucagon
• Endocrine
pancreas
insulin
glycemia
• Intermediary
metabolism
glucagon
Liver glycogen
• Pancreatic
hormones
Glucagon / Insulin
Liver glucose
• Diabetes
mellitus
Changes in insulin and glucagon in plasma and carbohydrate metabolism in normal subjects
following ingestion of a liquid meal rich in carbohydrate. Although secretion of both insulin and
glucagon was stimulated, insulin increased about twenty-fivefold while glucagon increased only
threefold so that the ratio of glucagon to insulin fell dramatically. Plasma glucose increased
transiently, but release of glucose from the liver fell precipitously, and liver glycogen increased.
Effect of large carbohydrate meal on blood glucose,
glucagon, insulin and liver glucose-related data
S
E
Page 25
Glucagon
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Effect of large carbohydrate meal (left) and arginine
infusion (right), on glycemia, glucagon and insulin
S
E
Glucagon
• Endocrine
pancreas
glycemia
• Intermediary
metabolism
glucagon
• Pancreatic
hormones
insulin
• Diabetes
mellitus
Changes in the concentrations of plasma glucose, immunoreactive glucagon (IRG),
and immunoreactive insulin (IRI) throughout the day. Values are the mean ± SEM (n =
4). (From Tasaka, Y., Sekine, M., Wakatsuki, M., Ohgawara, H., and Shizume, K. (1975)
Levels of pancreatic glucagon, insulin and glucose during twenty-four hours of the
day in normal subjects. Horm. Metab. Res. 7: 205–206.)
S
E
Effect of daily meals on glycemia, glucagon & insulin
Page 26
SS and PPY
• Endocrine
pancreas
• Intermediary
metabolism
• Pancreatic
hormones
• SS has 14 aa and 1 disulfide bond. It
was discovered and named for its GH
inhibiting activity. SS inhibits a wide
variety of endocrine and exocrine
secretory activities in the pituitary and in
the GI tract. In the pancreas, SS inhibits
insulin, glucagon, PPY and exocrine
secretion
• PPY release is largely neurally mediated.
Sensing of food in the CNS causes its
vagal-mediated secretion. Food in
proximal GI tract also stimulates its
release. PPY affects GI motility,
secretory activity of stomach, intestine
and pancreas
• Diabetes
mellitus
Somatostatin & Pancreatic Polypeptide Y
are two of the many GI peptides
S
E
Effect of exercise
glucose
• Endocrine
pancreas
• Intermediary
metabolism
glucose
insulin
glycogen
Epi
Nepi
lactate
glucagon
• Pancreatic
hormones
• Diabetes
mellitus
working
muscle
cortisol
GH
glycogen
glucose
lactate
nonworking
muscle
fuels consumed by leg muscles of man
during mild prolonged exercise
Contribution to O2 uptake in %
Exercise
(min)
40
80
120
240
Plasma
glucose
Plasma
FFA
Muscle
glycogen
27
41
36
25
37
37
50
67
36
22
14
8
Exercise decreases insulin and increases
all its counter-regulatory hormones
S
E
Page 27
Diabetes
• Endocrine
pancreas
•
•
•
• Intermediary
metabolism
• Pancreatic
hormones
•
•
• Diabetes
mellitus
•
hallmark of insulin hyposecretion and insulin resistance is
hyperglycemia in the fasting state
hyperglycemia, polyuria (diabetes = siphon), urine sweetens
(mellitus = honey), polydipsia
precise mechanism for the deleterious effect of high glucose is not
known. Whether from non-enzymatic glycation of proteins or from
regulatory effects of excess glucose, blood vessels are damaged,
resulting in turn in damage to the retina and kidney, and circulation
compromise to the heart, brain and extremities. Main morbidity
causes are blindness, renal failure, heart attack, stroke,
amputations
glucose tolerance test, diabetes mellitus, insulin deficit / resistance
insulin resistance: prereceptor resistance (autoantibodies, mutant
insulin), receptor resitance (decreased number and affinity, point
mutation, impaired kinase expression), & post-receptor resistance
(down regulation of Glut4 or autoantibodies of Glut2 transporters,
mutation of glucokinase gene, ßcell exhaustion as in GH abuse)
diabetic ketoacidosis, dehydration due to hyperglycemic diuresis,
negative nitrogen balance, tissue wasting, poor resistance to
infections, metabolic acidosis, fruity smell of ketosis in breath,
cardiovascular involvement, hyperglycemic vs hypoglycemic coma
Diabetes mellitus has been linked to every
step in the mechanism of action of insulin
S
E
Page 28
Diabetes
• Endocrine
pancreas
Diabetes Mellitus can be Type 1 or Type 2
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Idealized glucose tolerance tests in normal and diabetic subjects. Subjects are
given a standardized solution of glucose to drink and blood samples are taken
at the indicated times thereafter. An impairment of glucose disposition results in
a greater than normal and prolonged increase in blood glucose concentration.
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Diabetes
• Endocrine
pancreas
Diabetes Type 1 – beta cells do not make insulin
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Page 29
Diabetes
• Endocrine
pancreas
Diabetes Type 2 – insulin is not “seen” by target cells
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Diabetes
• Endocrine
pancreas
Diabetics have a “sluggish” response to glucose
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Page 30
Diabetes
• Endocrine
pancreas
Diabetes has been linked to every step in the
mechanism of action of insulin
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Diabetes
• Endocrine
pancreas
Diabetes has been linked to every step in the
mechanism of action of insulin
• Intermediary
metabolism
• Pancreatic
hormones
• Diabetes
mellitus
Diabetes is a good example of “pushing the
regulatory feedback envelope” in endocrinology
S
E
Page 31