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)