Download Metabolism

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Metabolic syndrome wikipedia , lookup

Hypoglycemia wikipedia , lookup

Fluorescent glucose biosensor wikipedia , lookup

Blood sugar level wikipedia , lookup

Artificial pancreas wikipedia , lookup

Diabetes in dogs wikipedia , lookup

Transcript
Metabolism
The Absorptive State
Anabolic Pathways
Fat
Muscle
protein
Hormone-sensitive
lipase – inactive
Stored fat
glycogen
Lipoprotein
lipase active
Urea,
NH3
Liver
TAG
Fatty acids
Transaminase
Keto
acids
Amino Acids
glycogen
Glucose
Chylomicrons
Insulin is the dominant hormone of the
absorptive state
• Secreted by beta cells of the pancreatic
Islets of Langerhans
• Secretion stimulated by:
– Increased plasma glucose
– Increased plasma amino acids
– Neuronal and hormonal signals from gut (GIP,
CCK, vagal efferents)
Secretion inhibited by epinephrine and
sympathetic efferents
Islets are multifunctional
Alpha cells: glucagon
Beta cells: insulin
Delta cells: somatostatin
The Endocrine Pancreas
Cell
Type
Product
Stimuli
alpha
glucagon
Decreased plasma glucose,
Increased liver glycogen
Increased plasma amino acids in breakdown and
gluconeogenesis
the absence of increased
plasma glucose; Alpha
adrenergic input
beta
insulin,
several
related
peptides
Increased plasma glucose,
increased plasma amino acids,
duodenal signals, vagal
efferents; inhibited by adrenergic
input
delta
somatostatin (?) Plasma levels rise after a
mixed meal; possibly involved in
modulating or terminating
absorptive phase responses
Effects
For most cells: Increased
glucose uptake (GLUT2
transporter); increased
amino acid uptake
Converts intestine to
secretory state; inhibits
gastric secretion; inhibits
secretion of insulin,
glucagon and other gut
peptides
Insulin Effects
• Increased uptake of glucose and amino acids by
most cell types
• Stimulates glucose oxidation – glucose is the
major source of energy during the absorptive
state
• Favors protein synthesis, fat deposition, and
glycogen storage in liver and muscle
• Genomic effects promote growth (in primitive
vertebrates, insulin is the growth hormone)
Glucose-tolerance test
If glucose levels remain high or
have not returned to baseline
after 3 hours, a failure of glucose
homeostasis is indicated
150
microU/ml
Plasma insulin
10
microU/ml
150 mg%
Plasma glucose
75
mg%
2
1
Glucose meal after
12 hour fast
hours
3
Islet responses to pure carbohydrate and
pure protein meals
Diabetes mellitus
• Type I “juvenile onset”:
– insulin production low or absent, functional beta cells
are lacking – incidence about 1/600 in European
populations; 1/10,000 in east Asia. Genetic
predisposition + autoimmune response to infection
may be involved
• Type II “adult onset”:
– insulin production may be normal or almost normal;
plasma glucose may be within normal range in fasting
but homeostatic defect shows up in glucose tolerance
test. Multiple causes are likely, including insulin
receptor pathology or “insulin resistance”; obesity is a
strongly predisposing factor.
Consequences of untreated or inadequately
treated type I diabetes mellitus
• Metabolic acidosis due to fat breakdown with
production of ‘ketone bodies’: acetone,
acetoacetate, beta OH butyrate.
• Küssmaul breathing (respiratory
compensation)
• Vascular, retinal and neural pathologies – largely
traceable to protein glycosylation - can use
hemoglobin glycosylation as a measure of
plasma glucose levels over previous 30 days or
so.
Roles of Glucagon
1. Maintenance of blood glucose during
fasting
2. Protection of blood glucose during
absorptive period for meals high in
protein but low in carbohydrate;
otherwise, insulin release would cause
blood glucose levels to fall dangerously.
Plasma Lipoproteins
type
origin
chylomicrons intestine
fate
Storage in fat; oxidation by muscle;
leftovers are IDL or ‘chylomicron
remnants’ which mediate lipid transport
to the liver for metabolism to FFA
VLDL
Liver, intestine, during
fasting
IDL
Result from action of
lipoprotein lipase on
CM and VLDL
Taken up by liver or converted to LDL
by apoprotein transfer in plasma
LDL
Formed from VLDL by
apoprotein donation
from HDL
Cholesterol-rich - broadly targeted to
most cell types, including the liver; this
is the main route of delivery of
cholesterol from liver to rest of body
HDL
Secreted by liver
Accelerate clearance of TAG from
plasma and regulate plasma
cholesterol by promoting return of
cholesterol to liver
Metabolism
Postabsorptive State
Transition to the postabsorptive state
• Most metabolic changes during the
postabsorptive state can be initiated simply by a
drop in insulin levels.
• However, a drop in plasma nutrient levels will
cause an increase in sympathetic outflow and an
increase in glucagon secretion.
• Growth hormone is an important component of
the endocrine picture in fasting because, in the
absence of net nutrient uptake, it contributes to
mobilization of fat and protein.
Catabolic pathways during the
postabsorptive state
Glucosesparing
Metabolic priorities in the postabsorptive state
• Protect plasma glucose for brain energy metabolism – Glucose sparing – most cell types can convert from
metabolizing glucose to metabolizing keto acids
• Draw on fat stores –
– Activate ‘hormone-sensitive’ lipase and ketogenesis in
liver
• Mobilize labile protein component of muscle, providing
amino acid substrate for gluconeogenesis
Endocrine Protection of Plasma Glucose in fasting
Hormone
Source
Glucagon
Delta cells Decreased
of
plasma
pancreas glucose,
increased
plasma amino
acids
Mobilization of glucose from liver
glycogen; increased lipolysis;
opposes insulin
Epinephrine
Adrenal
medulla
Decreased
plasma
glucose
Mobilization of glucose from liver
glycogen; increased glycogen
breakdown in muscle (muscle doesn’t
export glucose)
Stress, drop in
plasma
glucose
Permissive for epinephrine and
glucagon (low levels); increased
lipolysis, glycogen breakdown and
protein breakdown (high levels).
Cortisol
Adrenal
(glucocorticoid) cortex
Growth
Hormone
Anterior
pituitary
Stimuli
Effects
Promotes protein turnover and
lipolysis
Typical whole-body energy reserves
Substance
Turnover
(gm/day)
Reserve on
hand (gm)
Duration
Glucose
(glycogen in liver
and muscle)
250
400
<2 days
Amino acids
150
(labile protein in
muscle)
6,000
1-2 weeks
Fatty acids
(Adipose tissue
and liver)
10,400
4-6 weeks
100
Stored nutrients and control of
appetite/metabolism
• A ‘normal’ individual can survive about two
months without caloric input; an obese person
might survive for up to a year.
• The average woman gains 11 Kg between ages
of 25 and 65. This corresponds to a daily error
of 350 mg of food/day versus a 20 ton total
intake over this time span.
• An extra ½ slice of bread/day would result in a
gain of 20 Kg over 10 years.
• Conclusion: the nutrient store is both huge and
closely regulated.
Leptin is a hormonal measure of the total mass of
body fat and is an important metabolic regulator
• Leptin is secreted mainly by adipose cells
• Leptin receptors are expressed in areas of the
hypothalamus involved in hunger and satiety
• Leptin affects the body’s energy budget in two major
ways:
– Suppresses hunger
– Increases basal metabolism
• Leptin also promotes inflammation and can worsen
autoimmune disease
• Leptin is the signal that couples attaining a threshold
level of body fat with the onset of menarche in pubertal
girls
Evidence for the role of leptin in fat mass
regulation
• Administration of leptin causes loss of body fat
• Mutations of the leptin gene or the leptin receptor cause
obesity
• In most obese humans, plasma leptin levels are above
the normal level – suggesting that obesity is
accompanied by decreased sensitivity to the leptin signal
Ghrelin is a hormonal signal from stomach to
hypothalamus that says “I’m empty”
• Administration of ghrelin increases food intake and body
mass
• Ghrelin levels in plasma of obese humans are depressed
relative to those of lean individuals
• Ghrelin enhances learning and memory – so animals
learn most readily when they are hungry.
• Centrally, ghrelin serves as a signal from the
hypothalamus to the anterior pituitary to release growth
hormone (GHrh - it is one of a family of releasing
hormones)