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Integration of biochemical and
physiologic effects of insulin
on the control of blood glucose
concentrations
June 1st, 2004
Definition and Clarification of
Terms
• Action: the primary effect of hormone, usually its
binding to a specific receptor
• Effect: interaction between the hormonereceptor complex and an effector system.
– an experimental observation made either in vitro or in
vivo, it can be molecular, biochemical, or physiologic.
• Function: an inference that is made according to
its physiologic effects that result from increasing
or decreasing the blood level of the hormone.
=> it may not be possible to distinguish each of
these sections since they overlap
Figure 12.1
Action
• Binding of insulin to the external component of
its receptor results in activation of the internal
component (tyrosine kinase)
• This leads to phosphoylation of tyrosine
residues of phophatidyl-inositol 3-kinase, which
as a result is activated.
• This kinase then phosphorylates and activates a
number of other enzymes, resulting in what can
be described as biochemical effects.
Biochemical Effect
1.
2.
3.
4.
5.
MAP-kinase mediates the growth-promoting effects of
insulin by phosphorylating transcription factors
Rribosomal S70 kinase → Stimulation of protein
synthesis
Phosphorylation and inhibition of glycogen synthase
kinase-3 → Glycogen synthesis in muscle and adipose
Phosphorylation and increase in the activity of acetylCoA carboxylase → increases lipid synthesis and
controls fatty acid oxidation
Stimulation of glucose transport by translocation of
glucose transporter protein from an intracellular store
to the plasma membrane in muscle and adipose tissue
Physiologic Effects
- muscle, liver, adipose tissue • Stimulation by insulin
–
–
–
–
–
–
Glycolysis
Glycogen synthesis
Lipogenesis
Specific and general protein synthesis
Uptake of TG from blood into adipocyte
VLDL synthesis and secretion by the liver
• Inhibition by insulin
–
–
–
–
–
Gluconeogenesis
Glycogen breakdown
Lipolysis
Fatty acid oxidation
Protein degradation
Effects on glucose metabolism in
muscle
• Glycolysis by increasing
– Glucose transport
– Activities of hexokinase and 6-phophofructokinase
• Stimulation of these two enzymes is of fundamental
metabolic importance
– When glycogen store in muscle is replete, the glucose taken up
is converted to lactate to maintain enhanced glucose utilization.
– Lactate produced and released by muscle is taken up by liver
and converted to glycogen
→This allows glucose to be converted to a glyconeogenic
precursor when muscle glycogen store is replete, and
functions as a temporal buffer for glucose.
The Cori cycle (fig. 12.2)
The Cori cycle (fig. 12.2)
• Dynamic buffer of lactate in which its
concentration remains relatively constant both in
the tissues and in the blood stream
• Lactate can be used by tissues whenever
required for oxidation but also for anabolic
purposes
• Lactate is converted to pyruvate, which is a
precursor for acetyl-CoA, which has many
important anabolic functions in the body.
=> Thus, the maintenance of the blood glucose
level via the Cori cycle provides the condition for
anabolism.
Glycogen synthesis
• Glycogen synthase is the key regulating enzyme
for glycogen synthesis and is activated by insulin
• The process of glucose transport and glycogen
synthase do not respond to insulin in a
quantitatively identical manner.
– If the effect of insulin on glycogen synthesis is very
small, almost all of the increased glucose entering the
muscle could be converted to lactate (after a meal).
– If the process of glycogen synthesis is very sensitive
to insulin, almost all of the increased glucose that
entered muscle would be converted to glycogen (after
exercise).
The importance of Adipose tissue
• Adipocytes secrete a large number of hormones
and cytokines that can affect energy
homeostasis and the sensitivity of tissue to
insulin.
• The role of the adipose tissue
– Buffering the level of fatty acids in the circulation in
the postprandial period
• by regulation of the release of NEFA into the circulation
• according to the conditions of feeding or fasting through a
change in the activity of hormone-sensitive lipase.
– Changes the rate of triacylglycerol clearance through
a change in lipoprotein lipase via the effect of insulin.
The glucose-fatty acid cycle
(Fig.12.3)
The glucose-fatty acid cycle
(Fig.12.3)
• The control of glucose utilization by insulin
– A decrease in NEFA via the inhibition of adipose tissue lipolysis
– A specific decrease in the rate of fatty acid oxidation via an increase in
malonyl-CoA
=> Marked increase in the rate of glucose utilization by muscle.
• Lipotoxicity in T2DM
: If insulin is unable to regulate hormone –sensitive lipase
→ the impairment of the buffering action of the adipose tissue
→ chronic exposure to very high concentrations of NEFA and TG in all
tissues
→ impair insulin action on the liver and muscle / toxic effect on the islet
beta-cells
• Overall, Insulin effect on blood glucose levels is:
– Regulation of the plasma and intracellular levels of NEFA >> increase of
glucose utilization or decrease of endogenous glucose production.
“ hyperfattacidemia”
Effects on endogenous glucose
production
• Liver glycogen provides an immediately available
reserve of glucose to maintain the blood glucose
concentration (such as during short periods of
hypoglycemia, starvation, or exercise).
• The rates of synthesis and breakdown of liver glycogen
are regulated by glycogen synthase and phosphorylase,
respectively
• The control mechanism of glycogen synthesis depends
on:
– In the liver, changes in intracellular glucose concentration
– In muscle, blood concentration of insulin and factors that change
the insulin sensitivity of this tissue, such as the amount of
glycogen already stored in muscle.
Gluconeogenesis
(Fig. 12.4)
Gluconeogenesis
(Fig. 12.4)
• Complex, branched pathway only in the liver and kidney cortex
Control by variations in the concentrations of the precursors and of
the end product (glucose) or by hormones.
• Precursor: lactate, glycerol, alanine, glutamine
– Lactate:
• 1/3 from RBC, kidney medulla, retina,
• 2/3 from small intestine, skin, SM, adipose tissue
– Glycerol:
• triacylglycerol hydrolysis from adipose tissue.
• Important in prolonged starvation and T2DM
• If precursors ↑, glucose-6-phosphate was converted to glycogen
=> endogenous glucose production remained unaltered
(Autoregulation of glucose production).
• NEFA in liver → gluconeogensis ↑
• Insulin to decrease lipolysis in the adipose tissue decreases NEFA
to liver, decreasing the gluconeogenesis
Role of the Kidney
• Gluconeogenesis in kidney is important in conditions of
starvation or acidosis (such as in uncontrolled diabetes
or renal failure)
• Recently, kidney may also be important in the
postabsorptive state, contributing as much as 20 %
(range 5-28%) to the total endogenous glucose
production.
• Substrate: lactate, glutamine, glycerol
• Insulin effect
– by intrarenal effects (insulin increases lactate uptake)
: Insulin → NEFA ↓ in plasma → renal glucose production ↓
Insulin, Amino acid metabolism,
and protein synthesis (Fig. 12.5)
Insulin, Amino acid metabolism,
and protein synthesis (Fig. 12.5)
• The roles of insulin
– In muscle, insulin increases protein synthesis and decreases
protein degradation to favor the anabolic process
– Increase in the rate of gluconeogensis in the liver
• A provocative suggestion is that insulin inhibits
gluconeogenesis is not so much for deceasing glucose
formation but for maintaining the plasma concentrations
of amino acids within the normal range.
• Any lactate that will be produced by the insulin-mediated
increase in glucose utilization could be used for anabolic
processes.
Sensitivity of glucose utilization
to insulin (fig 12.6)
• Glucose intolerance: caused by resistance of the
tissues to the effects of insulin
• If insulin sensitivity increased in one or more
skeletal muscles, the increased entry of glucose
into the body after a meal could achieved in the
absence of a marked change of the blood insulin
concentration
• The blood glucose level would be controlled by
changes in insulin sensitivity at the tissue level
rather than by a change in the secretion of
insulin from the pancreas (the plasma insulin
concentration)
Sensitivity of glucose utilization
to insulin (fig 12.6)
Substrate cycle and sensitivity to
insulin
E1
E2
• Substrate → A
E3
B →
Product
E4
: Produced when a nonequilibrium reaction in the forward direction
of a pathway is opposed by another nonequilibrium reaction in the
reverse direction of the pathway.
• Advantages
– They do not change the properties or characteristics of the enzymes
catalyzing the reactions in the pathway
– Sensitivity can be varied quickly, effectively, and transiently with the
substrate cycles
• A large number of substrate cycles
– Glycogen/glucose-1-phosphage, fructose-6-phosphate/fructose
bisphosphate, TAG/NEFA
The greater the rate of cycling, the higher
is the sensitivity in control (Table 12.1)
E1
E2
• Substrate → A
E3
B →
E4
Product
Figure 12.7
• After a meal, hormonal or nervous stimulation of
substrate cycles is necessary to provide sufficiently
sensitive metabolic control mechanisms
• The considerable loss of energy as heat, which is the
consequence of this control mechanism, has an
important role in weight control
• Two of the factors known to relate energy storage and
expenditure to the rate of cycling are the insulin and
leptin
– Leptin has been shown recently to increase the rate of the
TAG/NEFA cycle.
– Increases in the levels of insulin and leptin after a high energy
intake
• Regulate the rates of glucose utilization
• Increase metabolic rate and hence facilitate the loss of extra energy
to the environment as heat
Factors affecting the sensitivity of muscle
to insulin
• Insulin-like Growth Factor-1
• Adenosine
• Glycogen levle
Insulin-like Growth Factor-1
– Structural homology to proinsulin
– Bound to a large binding protein, as a reservoir
– Smaller binding proteins (IGFBP-1) transfer IGF-1 from the blood to the
interstitial fluid
=> they can influence glucose uptake by muscle and hence may play an
important role in glucose homeostasis
• Regulation of IGFBP-1 by insulin
– Insulin reduces the plasma IGFBP-1
– Increase of IGFBP-1 reflects the decrease in insulin during an overnight
fast
– After a meal or OGTT, IGFBP-1 decrease by insulin
• Injections of IGF-1 lower the blood glucose by increasing glucose
utilization
• No evidence of an acute effect of IGF-1 on endogenous glucose
production
• In muscle, IGF-1 stimulates the rate of glucose utilization
(transport, phosphorylation, conversion to lactate,
glycogen synthesis, not glucose oxidation) independent
of insulin.
:These effects of IGF-1 are mediated via its own
receptors.
• In the plasma membrane, IGF-1 stimulates glucose
transport by increasing the translocation/activity of
GLUT-4 and GLUT-1
• The effects of IGF-1 to increase the rate of glucose
metabolism in muscle may be more important than that
of insulin alone.
• The reason is that the increase in the sensitivity to
insulin caused by such factors would permit better
utilization of glucose with less insulin
Adenosine
• Changing the adenosine concentration in
adipocytes or soleus muscle in vitro
demonstrates the following:
– In adipose tissue, adenosine increases the
sensitivity of lipolysis to insulin
– In muscle, it decreases the sensitivity of
glucose utilization to insulin
=> In vivo the overall effect of insulin could
depend on local changes in adenosine
concentration.
Glycogen level
• The rates of glucose uptake and glycogen
synthesis are influenced by the level of glycogen
within the muscle
• Glycogen ↑: these processes are insensitive to
insulin
• The advantage of this effect is that if the content
of glycogen in one muscle is high, glucose
would be directed to muscles in which the
glycogen content is low, thus ensuring that these
muscles would be provided with glucose to
increase their glycogen level.
Other Effects of Insulin
- Blood Flow • Insulin affects vascular endothelium and increases
muscle and adipose tissue blood flow by increasing
vasodilation and bulk flow to the tissues, and by
increasing capillary recruitment.
• Insulin-mediated increases in blood flow and insulin’s
effects on tissue glucose uptake and metabolism are
tightly coupled processes and therefore important
determinants of tissue sensitivity to insulin.
• Exposure of endothelial cells to increased NEFA impair
endothelial function and insulin mediated NO production.
→ reduction in tissue blood flow
=> Dysregulation of fatty acid metabolism may lead to
impairment of vascular reactivity and endothelial function
and finally to insulin resistance.
Other effects
• Insulin elevates PAI-1 and inhibits plate
aggregation (antiatherogenic effect)
• Insulin increases the reabsorption rate of sodium,
potassium, and uric acid in the kidney. (vs.
vasodilating effects of insulin)
• Stimulate the activity of the sympathetic nervous
system: HR, SBP, noradrenalin levels ↑
(due to direct effects of insulin on the
hypothalamus)
Concluding remarks
• Insulin increases the rate of transport of glucose
into the muscle cell (1950)
• Insulin decreases the rate of adipose tissue
lipolysis
→ decrease in blood NEFA
→ increase the glucose utilization in muscle
→ decrease endogenous glucose production
• In the postprandial state, insulin incorporates the
fatty acids of the meal into the adipose tissue
TAG.
• In the postabsorptive state, decrease in insulin
increases NEFA → gluconeogenesis ↑