Carbohydrate metabolism

 In carbohydrate metabolism we will study, the types of carbohydrate, how they are digested and absorbed, then we will the cycles of carbohydrate oxidation which generate the energy required for life…. these cycles are:

1. Glycolysis  = Glucose oxidation (i.e. break down of glucose to get energy).
2. Frucose metabolism.
3. Galactose metabolism.
4. Gluconeogensis = formation of Glucose form non-carbohydrate sources.
5. Kerbs cycle.
6. Glycogen Metabolism including breaking and formation of glycogen.
7. Pentose phosphate pathway = which generate NADH

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A) Types of carbohydrates:

1. Monosaccharides

-   They are those carbohydrates that cannot be hydrolyzed into simpler carbohydrates.

-   They may be classified as trioses (3-carbon sugar), tetroses (4-carbon sugar), pentoses (5-carbon sugar), hexoses (6-carbon sugar), or heptoses (7-carbon sugar).

2. Disaccharides:are condensation products of two monosaccharide units. Examples are maltose and sucrose.

3. Oligosaccharidesare condensation products of 2 to 10 monosaccharides; Example: maltotriose

4. Polysaccharidesare condensation products of more than ten monosaccharide units; examples are the starches and dextrins, which may be linear or branched polymers.

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B)   Carbohydrate digestion:

After eating, digestion begins as follow:

1) In the mouth, salivary amylase, hydrolyze starch partially into a mixture of dextrins and maltose.

2) In the stomach, salivary amylase continues hydrolysis of starch only for few minutes then stop because the pH becomes acidic due to the presence of the HCl in stomach and this is unfavourable condition for the amylase to work.

3) In the intestine, pancreatic amylase, completes the digestion of starch into maltose with little isomaltose and maltotriose which are then hydrolyzed in the intestine into glucose. Fructose and Galactose.

Starch + H₂O   ===== Amylase ====>  Dixterns + Maltose

Dixterns + H₂O  ===== Amylase ====> Maltose + Isomaltose + Maltotriose

Maltotriose + H₂O ===== Maltase====>Maltose + Glucose

 Maltose + H₂O  ======== Maltase====> Glucose + Glucose

Isomaltose + H₂O===== Isomaltase====> Glucose + Glucose

Sucrose + H₂O========== Sucrase=====>Glucose + Fructose 

Lactose + H₂O ========Lactose=======>Glucose + Galactose

4. Sucrose and the enzymes that complete hydrolysis into Monosaccharides presents in the mucus layer of the intestine

5. The net result of carbohydrate hydrolyses is glucose, fructose and Galactose

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C) Absorption:

- The polysaccharides and oligosaccharides are not absorbable so, they must be converted to Monosaccharides.

- Monosaccharides are principally absorbed from the duodenum then pass into the blood through the hepatic portal vein to the liver where:

• Part of these monosaccharides  is stored as glycogen and part is oxidised through glycolysis to obtain energy
• Part is oxidised through the pentose phosphate pathway to regenerate NADPH which, together with glucose itself, is used in synthesis of such molecules as amino acids, nucleotides, fats and cholesterol
• Part is oxidised to produce energy (ATP) which is used in the anabolism processes.

Before we know the mechanism by which the glucose is absorbed into the cells we must know the composition of the cell membrane through which the glucose pass.

this part will help any any one who don’t study biology or cell before to be able to understand biochemistry

Composition of the cell membrane:

==>  As from the previous picture, the cell membrane is composed of 2 layers each of them consists of a layer of phospholipids.

==>  Each phospholipid molecule consists of a polar hydrophilic head and a non-polar hydrophobic tail.

==> How the bilayer membrane is formed: And as we know, the extracellular and intercellular fluid are polar, therefore the polar heads are arranged towards the polar fluids and the non-polar tails arranged toward themselves  inward the membrane where there are a hydrophobic interaction between them and thus forming a phospholipids bilayer membrane

==> And across the membrane there are transport proteins and receptor proteins

==> Function of the cell membrane:-

• Protection of cells.

• On the other hand, it represents a barrier which prevents entry of some molecules into cells such as polar molecules but it uses other mechanism by which the molecules enter the cells such as Na-K pump through which ions are transported into the cell.

In case of glucose:

Any polar molecules can’t pass through the inner non-polar layer of cell membrane so, how glucose enter the cell through the cell membrane while it is polar?

===> The answer is that glucose has 2 mechanism to enter the cells:

1) The passive diffusion or transport:

===> DEF: it transport of biochemical and other atomic or molecular substance across the cell membrane into the cell from higher concentration region to a lower concentration region without any need for energy. (i.e. the substance enter the cell only if its concentration outside the cell is more than its concentration inside the cell.)

===> It depends on the concentration gradient.

===> It doesn’t need energy.

===> Depends on the permeability of the cell membrane.

===> Types:

• Simple diffusion:in which the substance are transported from higher concentration to lower concentration region through the phospholipids bilayer without any need for energy and without using the transmembrane proteins (carriers/transporters/channels/pores).

• Facilitated diffusion or passive-mediated-transport:in which the substance are transported from higher concentration to lower concentration region through the phospholipids bilayer using the transport proteins  and without any need for energy.

-          Fructose and pentose use this mechanism.

-          Glucose is transported by this mechanism into brain, kidney and liver.

2) Active diffusion or transport

===> DEF: it means transport of a substance from region of lower concentration to a region of higher concentration (i.e. against the concentration gradient) utilizing energy from ATP molecules and carrier proteins.

===> It doesn’t depend on the concentration gradient.

===> It needs energy.

===> This mechanism applied by the cell to accumulate high concentration of molecules that the cell needs such as ions, glucose and amino acids.

===>Doesn’t depend on the permeability of the cell membrane because this mechanism transports the substance through the transport proteins and carrier proteins.

===> It has 2 types:

• Primary active transport: in which the cell uses chemical energy such as ATP.
• Secondary active transport: in which the uses electrochemical gradient such as sodium and potassium dependent ATP bump

===> It is the mechanism by which glucose is transported from intestinal tract

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Glucose transportation into the cell by insulin action:

===> When the blood glucose level is high, the nervous system sends signals to the beta-cells of the pancreas to secrete insulin.

===> Then insulin binds to its receptors on the outside surface of the cell membrane causing conformational changes to the receptors (where the receptors are soft protein) leading to conformational changes to the cell membrane and opening of protein gates which called glucose transporter (GLUT) leading to entrance of glucose inside the cell.

===> Opening of these gates lead to activation or deactivation of some enzymes that responsible to glucose oxidation.

===> Insulin binding to the receptor is a reversible process because it will leave the receptor after delivering the message.

===> This process is regulated by the central nervous system.

===> Then after the glucose level returns normal; the insulin leave the receptor and no glucose will enter the cell

===> But in some cases the B-cells is highly activated secreting more insulin which make the glucose to enter the cell and  its level is lowered causinghypoglycaemia

===>The receptors of the insulin are specific for insulin and are distributed in all tissue with different concentration where the receptor concentration increases in the tissue:

• Which utilize glucose as the main source of energy such as brain and cells of the nervous system, red blood cells, muscles,…..etc

• At which the blood supply is low such as the peripheral tissues.

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Some Important Questions:

What is the difference between the receptors and enzymes?

P.O.C	Receptor	Enzyme
Composition	Protein	Protein
Active site	Present	Present
Function	Just delivering messages sent by the nervous system into the cell (just letter box) Doesn’t catalyse any reaction	Catalyse reactions and doesn’t deliver any messages.

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Why glucose is stored in the liver and muscles as glycogen and not as it is (i.e. glucose)?

Because glycogen is solid polymer that is compacted and occupy a small size inside the cell which prevents cell membrane rupture by the pressure on the cell membrane.

While if the glucose is stored as glucose, it will take large size which then cause pressure on the cell membrane and then rupture of the cell membrane.

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What is the factor that determines the amount of glucose that enters the cell?

The amount of glucose after meal where the glucose must be maintained at the normal level and the excess must enter the cells

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Is the metabolism of fats can be used in formation of glycogen?

The answer is yes because the result of oxidation of fat is formation of glycerol which can enter the gluconeogensis process in which glucose is formed.

So, if glucose can be formed from fats thus glycogen can be form fats

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D)  Structure of glucose:

===> Glucose is aldose sugar and has 2 isomers: (D-glucose and L-Glucose)

It has 2 chiral carbon atoms (i.e. the carbon atom that carry 4 different groups); the carbons number 2 and 3

The (L)-glucose is the isomer that is utilized by the cells. WHY?

Because the amino acid molecules which forms the enzyme present in the L- form which make the enzymes in the L- form, therefore the L-glucose is the more suitable substrate which is the more matching with the binding groups in the active site than the D-glucose

Proteins molecules also have L- and D- forms because all has a chiral carbon except glycine which doesn’t carry 4 different groups.

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How the scientists classified the isomers into L- and D- forms?

They use the glyceraldehyde as a standard as follow:

-          Each isomer has a chiral carbon (i.e. the carbons atom which carries 4 different groups)

-          The isomer that has L- and D- forms are called enantiomers

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Differentiate between the following terms:

1.      Enantiomers:

Are 2 stereoisomers that are mirror images of each other that are “non-superposable” (not identical), much as one’s left and right hands are “the same” but opposite

2.     Epimers:

Epimers are diastereomers that differ in configuration of only one carbon atom and they are non-superposable, and non-mirror images of one another

The glucose molecules are non-mirror image to each other but aren’t identical because they differ in one carbon atom.

3.    Anomers:

In carbohydrate chemistry, an anomer is a special type of epimer because it is a stereoisomer of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon, also called the anomeric carbon

The cyclic structure of glucose has 2 anomers because the hydroxyl groups orientation differes on the hemiketal carbon atom.

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بالصور خطوبة دنيا سمير غانم | اخبار الفن | نادي الفن

بالصور خطوبة دنيا سمير غانم | اخبار الفن | نادي الفن

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الهام شاهين رئيس مصر رجعلى حقى واعاد للفن كرامته | اخبار الفن | نادي الفن

الهام شاهين رئيس مصر رجعلى حقى واعاد للفن كرامته | اخبار الفن | نادي الفن

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ضوابط صرف بدل الجامعة

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كادر العاملين في الصحة -الصيادلة-التمريض-العلاج الطبيعي-الاسنان-الطب

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Insulin Biosynthesis, Secretion, and Action

Biosynthesis

Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent Proteolytic processing removes the amino terminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds (Figure-1)The mature insulin molecule and C peptide are stored together and co secreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia.

Figure-1-showing the synthesis of Insulin

Secretion

Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin synthesis, primarily by enhancing protein translation and processing. Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via Glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K⁺ channel. This channel consists of two separate proteins: one is the binding site for certain oral hypoglycemic (e.g., sulfonylureas, meglitinides); the other is an inwardly rectifying K⁺ channel protein Inhibition of this K⁺ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. (See figure-2)

Figure-2- showing mechanism of secretion of insulin

Insulin secretory profiles reveal a pulsatile pattern of hormone release, with small secretory bursts occurring about every 10 min, superimposed upon greater amplitude oscillations of about 80–150 min. Incretins are released from neuroendocrine cells of the gastrointestinal tract following food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion (Figure-3). Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and that stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion.

Figure-3- showing Insulin release. The release is more marked after oral glucose load due to the release of Incretins from GIT.

Action

Once insulin is secreted into the portal venous system, ~50% is degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites.

Figure-4 -showing the structure of Insulin receptor.The receptor is composed of two extracellular α-subunits that are each linked to a ß-subunit and to each other by disulfide bonds.

Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity (See figure -5) leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). IRS and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3'-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to the cell surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells.

Figure-5- showing the mechanism of action of Insulin

Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium, but neural input, metabolic signals, and other hormones (e.g., glucagon) result in integrated control of glucose supply and utilization.

In the fasting state, low insulin levels increase glucose production by promoting hepatic Gluconeogenesis and glycogenolysis and reduce glucose uptake in insulin-sensitive tissues (skeletal muscle and fat), thereby promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla.

Figure-6- showing glucose homeostasis mediated by Insulin

Postprandially, the glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes( Figure-6). Insulin, an anabolic hormone, promotes the storage of carbohydrate and fat and protein synthesis. The major portion of postprandial glucose is utilized by skeletal muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most notably the brain, utilize glucose in an insulin-independent fashion.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:

Fatty acid synthesis-Insulin promotes synthesis of fatty acids in the liver. insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.

When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

Fatty acid oxidation-Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Synthesis of Glycerol-Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.

Figure-7 -showing the effect of Insulin of fatty acid synthesis and oxidation. Insulin inhibits hormone sensitive lipase and hence inhibits adipolysis.

Other Notable Effects of Insulin

Amino acid metabolism-In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation.

Electrolyte balance-Insulin also increases the permeability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.

Insulin Deficiency and Excess Diseases

Diabetes mellitus, the most important metabolic disease ,is an insulin deficiency state. Two principal forms of this disease are recognized:

Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.

Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents.

Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock).

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