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Small intestine, sperm

Fructose transport

?

Active glucose transporters SGLT1 664 Intestine, kidney Intestinal absorption, renal reabsorption

Active glucose transporters SGLT1 664 Intestine, kidney Intestinal absorption, renal reabsorption

" Indicates the extent of stimulation of insulin secretion: +, modest; + + +, vigorous; -, no effect; ?, effect not known. h Modified with permission from Stephens, J. M., and Pilch, P. F. (1995). The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endoc. Rev. 16, 529-546.

Table 7-9). The transmembrane positioning of the GLUT4 sequence is based upon the predicted topography of GLUT1; the 12 membrane-spanning helices are numbered and boxed. Those amino acids that are conserved among GLUT 1^4 are indicated by a boldface single-letter code. Sites of glycosylation are indicated by CHO. [Modified with permission from Stephens J. M. and Pilch, P. F. (1995). The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endocr. Rev. 16, 529-546.]

Table 7-9). The transmembrane positioning of the GLUT4 sequence is based upon the predicted topography of GLUT1; the 12 membrane-spanning helices are numbered and boxed. Those amino acids that are conserved among GLUT 1^4 are indicated by a boldface single-letter code. Sites of glycosylation are indicated by CHO. [Modified with permission from Stephens J. M. and Pilch, P. F. (1995). The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endocr. Rev. 16, 529-546.]

fected by the presence or absence of glucagon or insulin. Activation of the glycogenolytic system involves the phosphorylation of key enzymes, while inactiva-tion necessitates dephosphorylation. On the one hand glycogen is phosphorylyzed (broken down) by the cascade of cAMP-governed reactions that convert the rela tively inactive phosphorylase b into the more active phosphorylase a. On the other hand, under conditions where it is appropriate to convert glucose into glycogen, there is activation of a phosphatase that converts the phosphorylated D or dependent form of glycogen synthetase into the dephosphorylated I or independent

TABLE 7-10 Summary of Actions of Insulin on Several Tissues

Tissue

Insulin-sufficient state

Insulin-deficient state

Liver No effect on glucose uptake

Stimulates biosynthesis of hexokinase IV and activates glycogen synthetase I Promotes glycolysis and formation of ATP

Muscle Stimulation of glucose uptake

Stimulates biosynthesis of hexokinase II and pyruvate kinase Stimulates glycolysis and formation of ATP Increases muscle glycogen levels and creatine phosphate Adipose Stimulation of glucose uptake

Enchances glycolysis, which makes available glycerol phosphate, which, in turn, enhances triglyceride synthesis Inhibits lipase activity Brain No direct actions of insulin; brain dependent upon blood glucose

Uptake of free fatty acids and conversion to ketones

Impaired blood glucose

Decreases triglyceride synthesis due to a lack of glycerol phosphate Stimulation of lipolysis and release of FFA into the bloodstream

None

TABLE 7-11 Summary of Actions of Glucagon on Several Tissues in the Glucagon-Sufficient State

Tissue Effect

Liver Inactivates glycogen synthetase and activates phosphorylase a, which leads to an activation of glycogenolysis Increases the activity of glucose 6-phosphatase Enhances synthesis of glucose from pyruvate and lactate as well as amino acids, especially arginine and alanine (i.e., activates gluconeogenesis)

Muscle Muscle does not contain receptors for glucagon, and accordingly it has no effect Major effects on muscle metabolism are mediated by epinephrine (see Chapter 11)

Adipose In large doses can stimulate lipolysis, but under normal circumstances it has little or no effect

Pancreas Stimulates insulin secretion, particularly after intestinal absorption of amino acids

Brain None form. It will be noted that a key feature of this system is the unique role played by the protein phosphorylase b kinase-kinase, which has two distinct catalytic activities. When it is phosphorylated (as a consequence of the presence of glucagon), it initiates the cascade that ultimately leads to the conversion of phosphorylase b into phosphorylase a and the production of glucose-1-P. Alternatively, when the phosphorylase b kinase-kinase is not phosphorylated, it acquires the activity of glycogen-I-synthetase-kinase. Thus, the presence of glucagon favors the generation of an active phosphorylase b kinase-kinase, while the presence of insulin activates a phosphatase that leads to glycogen formation.

In addition to the glucagon-insulin modulation of glycogen storage and mobilization in the liver, these two peptide hormones also modulate the balance between gluconeogenesis and lipogenesis. Under circumstances of glucose demand, gluconeogenesis will predominate to convert into glucose those carbon skeletons derived from amino acids or glycolytic intermediates produced prior to pyruvate. Under conditions of glucose excess, glycolytic intermediates and free fatty acids can be directed either to storage as triglycerides, to oxidation by the TCA cycle, or to production of ketone bodies. It is not yet clear which detailed cellular or hormonal signals determine whether a given free fatty acid is dedicated to storage as triglyceride or to conversion to C02 and / or ketones. These relationships are diagrammed in Figure 7-34. Reversal of the glycolytic pathway requires access to NADH, whereas lipo genesis is dependent upon access to NADPH for fatty acid biosynthesis.

In summary, glucagon has been shown to stimulate the conversion of pyruvate, lactate, alanine, and glycerol into glucose. This is accomplished largely by modulating key enzymes of the gluconeogenic pathway. There appear to be no effects of glucagon on stimulating substrate supply or in increasing amino acid uptake by the liver. Insulin appears to exert its inhibitory effects on liver gluconeogenesis by (i) inhibiting or slowing the enzymes of gluconeogenesis and (ii) diminishing the flow of amino acids from peripheral tissues, principally muscle, to the liver (discussed later).

Phosphorylated glycolytic intermediates are not capable of traversing the outer cell membrane of the liver. However, the liver contains an active glucose-6-phosphatase. The activity of this enzyme is increased in the absence of insulin or the presence of Cortisol; this ensures the ready conversion of glucose 6-phosphate to free glucose, which may then be exported from the liver cell. By contrast, muscle cells do not have measurable glucose-6-phosphatase activity, and thus the muscle glycogen stores cannot be mobilized for the maintenance of blood glucose levels.

3. Muscle

In the absence of insulin there is a stimulation of net protein catabolism in muscle. The resulting free amino acids are released into the bloodstream and delivered to the liver where they are oxidatively deami-nated. The resulting carbon fragments are then committed to gluconeogenesis or catabolism to yield ketone bodies and/or C02. The resulting increase in nitrogen is converted to urea and excreted in the urine.

Muscle tissue is known to contain insulin but not glucagon receptors. Insulin occupancy of these receptors leads to an increased uptake of both glucose and amino aids; there is also an associated stimulation of protein synthesis. The biochemical bases for these effects are not yet clearly understood, in that they cannot be explained by changes in cellular cAMP levels. Also, actinomycin D does not block insulin-mediated stimulation of protein synthesis. It has been proposed that the 40 S large subunit of ribosomes obtained from the muscle of diabetic animals is defective.

After an overnight fast and in the absence of physical activity, muscle tissue is largely dependent upon the oxidation of free fatty acids to meet its energy demands. Under these conditions there would be a significant pool of muscle glycogen. With the initiation of mild-to-moderate exercise, the muscle tissue successively oxidizes its own glycogen, then blood glucose,

7. Pancreatic Hormones liver

Glucose

Amino Acids muscle

Glucose :

Amino Acids ;

Protein

ZGlucose -

"Amino Acids:

Protein

Glucose

Amino Acids

' Triglycerides

Pyruvate f Fatty Acids ^

| Acetoacetyl CoA ;

Protein

■ Phosphogluconate Pentose Pathway

' Triglycerides

Pyruvate f Fatty Acids ^

| Acetoacetyl CoA ;

Glycogen

; Pyruvate

TCA Cycle COi+ H2O

Ketone Bodies-

; Acetyl CoA 1

: Fatty Acids

-Ketone Bodies

Fotty Acids Ketone Bodies adipocyte

Glucoset

Glycogen

Pyruvate

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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