Metabolism
The Absorptive State
Anabolic PathwaysMuscle
Liver
Amino Acids
GlucoseChylomicrons
Fat
glycogenKeto acids
protein glycogen
Fatty acids
TAGUrea, NH3
Stored fat
Lipoprotein lipase -active
Hormone-sensitive lipase – inactive
Transaminase
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 Effects
alpha glucagon Decreased plasma glucose,
Increased plasma amino acids in the absence of increased plasma glucose; Alpha adrenergic input
Increased liver glycogen breakdown and gluconeogenesis
beta insulin, several related peptides
Increased plasma glucose, increased plasma amino acids, duodenal signals, vagal efferents; inhibited by adrenergic input
For most cells: Increased glucose uptake (GLUT2 transporter); increased amino acid uptake
delta somatostatin (?) Plasma levels rise after a mixed meal; possibly involved in modulating or terminating absorptive phase responses
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
Glucose meal after 12 hour fast
Plasma insulin
Plasma glucose
hours
75 mg%
10 microU/ml
321
If glucose levels remain high or have not returned to baseline after 3 hours, a failure of glucose homeostasis is indicated
150 microU/ml
150 mg%
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 Lipoproteinstype origin fate
chylomicrons intestine Storage in fat; oxidation by muscle; leftovers are IDL or ‘chylomicron remnants’ which mediate lipid transport to the liver for metabolism to FFAVLDL 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
Glucose-sparing
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 Stimuli Effects
Glucagon Delta cells of pancreas
Decreased plasma 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)
Cortisol
(glucocorticoid)
Adrenal cortex
Stress, drop in plasma glucose
Permissive for epinephrine and glucagon (low levels); increased lipolysis, glycogen breakdown and protein breakdown (high levels).
Growth Hormone
Anterior pituitary
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
(labile protein in muscle)
150 6,000 1-2 weeks
Fatty acids
(Adipose tissue and liver)
100 10,400 4-6 weeks
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)