Integration of Metabolism, Diabetes, Fasting, and Starvation Flashcards
The integration of energy metabolism across organ systems is controlled primarily by the actions of the pancreatic hormones
Insulin and Glucagon
When food is available in abundance, responding changes in the circulating levels of these hormones allow the body to store energy in the forms of
Glycogen and FAs
Represents the most common disruption that occurs in this complex system of hormones, enzymes, and metabolites in humans
Diabetes Mellitus
There are two fundamental sorts of diabetes, type 1 is known as
Insulin-dependent diabetes (IDDM)
Type 2 diabetes is classified as
Insulin-independent diabetes (NIDDM)
A polypeptide hormone produced by the B- cells of the Islets of Langerhans, clusters of cells that comprise about 1% of the pancreas
Insulin
Insulin is one of the most important hormones coordinating the utilization of
Fuel
The metabolic effect of insulin are
Anabolic
Composed of 51 amino acids arranged in two polypeptide chains, designated A and B (proteolytically processed from a single primary translation product)
Insulin
These A and B polypeptide chains are linked together by two
Disulfide bridges
The insulin molecule also contains an intra-molecular disulfide bridge between amino acid residues
6 and 11
The B-cells of the pancreas release both the mature insulin and the processing by-product
C-peptide
Human insulin has the same potency as pig insulin, which is similar in structure to the human hormone and has been used in the past for treatment of
Diabetes
Insulin secretion by the B-
cells of the Islets of Langerhans of the pancreas is closely coordinated with the release of
Glucagon by a-cells
The most important glucose-sensing cells in the body
Pancreatic Beta-cells
Ingestion of glucose or a carbohydrate-rich meal leads to a rise in blood glucose, which is a signal for increased
Insulin secretion
Causes a transient rise in plasma amino acids levels, which in turn induces the immediate secretion of insulin
Ingestion of protein
Insulin secretion is stimulated by the gastric peptides
-release following the ingestion of food
Secretin and Incretins
Cause an anticipatory rise in insulin levels in the portal vein before there is an actual rise in blood glucose
Secretin and Incretins
This may account for the fact that the same amount of glucose given orally induces a much greater secretion of insulin than if given intravenously
The anticipatory rise
Decreased when there is a scarcity of dietary fuels, and also during periods of trauma
Synthesis and release of insulin
Trauma effects on insulin secretion are mediated primarily by
Epinephrine
Has a direct effect on energy metabolism, causing a rapid mobilization of energy-yielding fuels, including glucose from the liver and fatty acids from adipose tissue, via a receptor and signal transduction mechanism
Epinephrine
Able to override the normal glucose-stimulated release of insulin
Epinephrine
Thus, in emergency situations, the sympathetic nervous system largely replaces plasma glucose concentration as the controlling influence over
Insulin secretion
Glucose transport into most insulin responsive tissues, for example, skeletal muscle and adipocytes, increases in the presence of
Insulin
Promotes the recruitment of glucose transporters from a pool in intracellular vesicles to the cell membrane
Insulin
Depends on both the abundance of glucose transporters and their activation, probably by phosphorylation of transporters in the membrane
Glucose Transport
Hepatocytes, erythrocytes, the nervous system, and the cornea have
Insulin-dependent glucose transport
In the liver, brain, cornea, intestinal mucosa, renal tubes and the red blood cells, glucose transport is not sensitive to
Insulin
Leads to significant changes in carbohydrate metabolism, including increased glycolysis, increased glycogen synthesis, and decreased gluconeogenesis
Intravenous administration of insulin
Adipose tissue metabolism patterns respond within minutes to the administration of
Insulin
This results in a marked increase in
FA synthesis
Insulin decreases the level of circulating fatty acids by inhibiting the activity of
Hormone-sensitive lipase
Insulin acts primarily by countering the stimulation of adenylyl cyclase by
Epinephrine and Glucagon
Simultaneously, insulin increases the transport and metabolism of glucose, providing which three substrates for FA synthesis?
Acetyl CoA, Glycerol-3-phosphate, and NADPH
Lastly, insulin stimulates the entry of amino acids into cells and contaminant
Protein Synthesis
Like other peptide hormones, insulin binds to specific, high-affinity receptors present in the cell membranes of specific tissues, including
Liver, muscle, and adipose
Has very few insulin receptors, the functions of which are unclear
The brain
For glucose metabolism, the signaling cascades caused by insulin influence which three enzymes?
Glucokinase, PFK-2/FBP-2, and Pyruvate kinase
For glycogen metabolism, the signaling cascades caused by insulin influence which two enzymes?
Glycogen synthase and Glycogen phosphorylase
For fatty acid metabolism, the signaling cascades caused by insulin influence which
two enzymes?
Acetyl CoA carboxylase and Hormone sensitive lipase
Enzyme expression is regulated at the level of mRNA synthesis while enzyme activity is regulated at the level of
Phosphorylation/dephosphorylation
Eventually, the insulin:insulin receptor complex enters the cell by
Pinocytosis
Ultimately degraded in the lysosomes and the receptor is recycled back to the membrane
Insulin
A polypeptide hormone, secreted primarily by the a-
cells of the pancreatic islets
Glucagon
Opposes many of the actions of insulin
-The counter regulatory hormones
Glucagon, epi, cortisol, and GH
Most importantly, acts to maintain blood glucose levels by activation of hepatic glycogenolysis and gluconeogenesis
Glucagon
Composed of 29 amino acids arranged in a single polypeptide chain
Glucagon
The a-cell is responsive to a variety of stimuli that signal
actual or potential
Hypoglycemia
Specifically, glucagon secretion is increased by:
Low blood glucose, Amino acids, and Epi
The primary stimulus for glucagon release
Low blood sugar
During an overnight or prolonged fast, elevated glucagon levels prevent
Hypoglycemia
Amino acids derived from a protein-containing meal stimulate the release of both
Glucagon and insulin
Elevated levels of circulating epinephrine produced by the adrenal medulla, and/or epinephrine produced by direct enervation of the pancreas, stimulate the release of
Glucagon
Thus during periods of stress, trauma or vigorous exercise, newly elevated epinephrine levels can override the inhibitory effect on the
a-cell of circulating
Insulin and Glucose
In these situations, regardless of the concentration of blood glucose—glucagon levels rise in anticipation of increased
Glucose utilization
Glucagon secretion is markedly decreased by
Elevated Blood Sugar
The intravenous administration of glucagon leads to an immediate rise in
Blood sugar
This results from alterations in carbohydrate metabolism that lead to an increase in
Glycogenolysis and gluconeogenesis
Promotes the oxidation of fatty acids in a number of tissues, as a preferred energy source
Glucagon
Stimulates the formation of ketone bodies from acetyl CoA
Glucagon
Glucagon also stimulates
Hormone sensitive lipase
Glucagon increases the uptake of amino acids by the liver resulting in the increased availability of a variety of carbon skeletons for
Gluconeogenesis
Results in a decrease in the plasma levels of amino acids
Glucagon
Glucagon binds to high affinity receptors on the cell membrane of target cells such as the
Hepatocyte or adipocyte
There are no glucagon receptors in
Muscle tissue
Glucagon binding results in activation of adenylyl cyclase in the plasma membrane. This causes a rise in
cAMP
This increase in cAMP in turn activates
cAMP-dependent protein kinase
This cascade of activities results in the phosphorylation-mediated activation or inhibition of key regulatory enzymes involved in
Carbohydrate and lipid metabolism
Classified as roughly the 2-4 hour period following ingestion of a balanced meal
Absorptive state
During this interval there occurs a transient increase in plasma glucose, amino acids, and triacylglycerol, the latter primarily as components of
Chylomicrons
The elevated insulin:glucagon ratio, and the ready availability of circulating substrates, makes the 2-4 hours following ingestion of a meal an
Anabolic Period
May result from an inability to obtain food, the desire to lose weight rapidly, or to clinical situations in which an individual cannot eat because of trauma
Starvation
Not one disease, but rather is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by a relative or absolute deficiency in insulin
Diabetes
An excess of glucagon aggravates metabolic alterations caused by inadequate release of
Insulin
Constitute 10% to 20% of the many million diabetics in the United States
Insulin-dependent diabetes mellitus (IDDM)
Individuals with IDDM require insulin to avoid life-threatening
Ketoacidosis
IDDM is characterized by an absolute deficiency of insulin caused by massive autoimmune attack on the
Pancreatic Beta-cells
The islets of Langerhans then become infiltrated with activated
T-lymphocytes
The islets of Langerhans become infiltrated with activated T-lymphocytes, leading to a condition called
Insulitis
IDDM symptoms typically appear
-when 80-90% of B-cells have been destroyed
Abruptly
At this point the pancreas can no longer respond adequately to ingestion of glucose, and patients reqire
Insulin therapy
The most common form of the disease, afflicting approximately 80% of the diabetic population in the United States
Non-insulin-dependent Diabetes Mellitus (NIDDM)
Diagnosis is based most commonly on the presence of fasting hyperglycemia—that is, blood glucose concentration of greater than 140 mg/dL persisting several hours after a meal
NIDDM
Having said that, it is also correct that some individuals with NIDDM do have noticeable symptoms of
Polyuria and polydipsia
The disease does not involve viruses or autoimmune antibodies, but rather “insulin resistance” in peripheral tissues
NIDDM
The metabolic alterations observed in NIDDM are milder than those described for the insulin-dependent form of the disease and are thought to be due to a combination of which two factors?
Dysfunctional B-cells and Insulin resistance
