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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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كرم الزوج و علاقته بالساعادة الزوجية

كرم الزوج و علاقته بالساعادة الزوجية

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Providence, RI Traffic Cop Dancing

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Animation: carbohydrate digestion - myDr.com.au

Animation: carbohydrate digestion - myDr.com.au

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edewcate - The Skull Video

edewcate - The Skull Video

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مقدمة عن الميتابولزم (الايض الحيوى)

http://clinical-med.com/

A) Metabolism:

Metabolism is the set of chemical reactions that happen in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments.

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فالكورس ده احنا بندرس الmetabolism بتاع الكروبوهيدرات والبروتين والدهون والmetabolism عبارة عن عمليات حيوية داخل الجسم محكومة بانزيمات معينة للحصول على الطاقة اللازمة للنمو والتكاثر وبالتالى الحفاظ على الحياة واحنا اليهمنا من العمليات الحيوية دى هو اكسدة الglucose الناتج عن تكسير الكربوهيدرات المعقدة والfatty acids الناتج عن تكسير الدهون والamino acids الناتج من تكسير البروتينات ودول بيدونا الطاقة القولنا عليها والهنستخدمها فى بناء مركبات اخرى يحتاجها الجسم.

 ——————————————————————-

B) Types of Metabolic processes:

   -  Metabolism starts by the digestion of nutrients obtained from the diet where:-

• The complex molecules of carbohydrates, proteins and lipids obtained from the diet are converted into simple molecules (glucose, amino acid and fatty acids respectively) then absorbed in the intestine from which the simple molecules move through the hepatic portal vein to the liver which is the factory responsible for more than 90% of the metabolic processes.

فالهضم الجزيئات المعقدة من الكربوهيدرات والبروتينات والدهون بتتكسر الى glucose وamino acid وfatty acids وبعد كدة تمتص فالامعاء وبعد كدة تمشى فالوريد البابى الكبدى (hepatic portal vein) ومنه للكبد البيحصل فيه 90% من العمليات الحيوية

والعمليات الحيوية دى تشمل حاجتين الاولى تكسير المواد المعقدة الى مواد بسيطة يسهل اكسدتها للحصول عالطاقة والعمليه دى تسمى الهدم (catabolism) والحاجة التانيه هى بناء مواد معقدة تانية مفيدة للجسم باستخدام الطاقة الناتجة من التكسير وتسمى هذه العملية بالبناء (anabolism)

   -  The metabolism is classified into two process:

1) Catabolism:

It is the breakdown of the complex molecules into small molecules to produce the energy which stored in ATP molecule (Adenosine Tri-Phosphate called the bank of energy) and required for life and cell reproduction.

2) Anabolism:

It is the process of building up complex molecules – required for normal life and health – form the simple molecules using the stored energy resulting from the catabolism process.

-  For Example: The regeneration of dead cells is a dynamic process (i.e. involve movement) which means that it requires energy thus the nutrients is the fuel of the human body.

تجديد الخلايا الميتة او المفقودة دى عمليه ديناميكية يعنى فيها حركة وطبعا عشان فيها حركة يبقى محتاجة طاقة وبالتالى الغذاء هو الوقود بتاع جسم الانسان

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C) Properties of metabolism:

1) Integrated:

Where the carbohydrates, proteins and lipids participates in the energy production (Complementary in ) whatever the place of the metabolic process in the cell where

•  They are converted into simple molecules where:

Fats → fatty acids

Proteins → amino acids

Carbohydrate → glucose + (galactose + fructose)

 ↓             ↓

glucose     glucose

and then all the simple molecules enter the same cycle which known as kerb’s cycle.

• Some of these metabolic processes occur in cytoplasm and others occur in mitochondria according to the enzymes used by the metabolic process.

FOR EXAMPLE:

Glycolysis, which is the oxidation of glucose, occurs in cytoplasm because the enzymes used in it are present in cytoplasm.

In other words, the metabolism is integrated process because the net result of the breakdown of the carbohydrate, protein and lipid is the production of energy.

بالعربى هو يقصد ان تكسير الكربوهيدات والدهون والبروتين مكملين لبعض فى انتاج الطاقة اذاى: -

-      الجلوكوز خلال الglycolysis بيتحول الى pyruvate ده بيتحول الى acetyl coA وoxaloacetate ودول البتبدا بيهم الkerbs cycle –

-     البروتين بتدينا amino acids ودى بعد كدة بتتحول الى intermediate فى الglycolysis يعنى فالنهاية هيدينا pyruvate اللى فى النهاية هيدينا acetyl coA وoxaloacetate ويدخلو فالkerbs

-    الدهون بتدينا fatty acids بتدينا acetyl coA الهيدخل برضو فالkerbs

وبالتالى يكون الكربوهيدرات والبروتين والدهون مكملين لبعض فانتاج الطاقة بس

2) Regulated:

Where the cell has the enzymes which represent the controlling mechanisms which organize the metabolic processes in order to use the optimum benefits from the energy where if the metabolic processes aren’t controlled the energy will be dispersed without any benefits.

بالعربى يقصد ان الخلية عندها اليات تتحكم وتنظم العمليات الحيوية عشان لو مكانش عندها الاليات دى هتستهلك طاقة بدون فايدة لذلك هى عندها انزيمات تنظم هذه العمليات الحيوية عشان ميحصلش تشتيت للطاقة بدون فايدة وذى ما ضرب الدكتور مثال فالمحاضرة وقال ذى بالظبط لما اجى املى ماء فكباية من الحنفية هملى لحد ما الكباية تتملى وبعد كدة هقفل

Remember Mechanisms of controlling Enzymes:

The feedback mechanism:

Which is the control of the activity of the enzymes by inhibition of activation of them according to the need for the enzyme

دى ميكانيزم بيتحكم فى نشاط الانزيمات عن طريق منع تنشيطهم من البداية او تنشيطهم على حسب الحاجة وهنفهمها فيما بعد

The allosteric control:

1. In which certain molecules bind to certain chemical groups at a certain area on the surface of the enzyme, called the “allosteric site”, resulting in conformational changes that lead to changes in the arrangement of the chemical groups at the catalytic site.
2. It is a type of feedback inhibition

وده ميكانزم تانى بنتحكم بيه فى نشاط الانزيمات عن طريق ان فى مركبات او مجموعات كيميائية معينة ذى الOH مثلا تمسك فحتة على سطح الانزيم بنسميه ال  “allosteric site” ولما ده يحصل بيتغير شكل الانزيم وبالتالى يتغير ترتيب المجموعا الكيميائية فى الActive site اللى على سطح الانزيم واللى بيحصل عنده تحيز التفاعل  اللى بيسرعه الانزيم وده يعتبر طريقة من الfeed back mechanism

http://clinical-med.com/

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Biochemistry | Medicine, Science and More

Biochemistry | Medicine, Science and More

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Best Marriage Proposal: Hidden Sign revealed on Behind the Scenes Tour a...

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A marriage proposal with a difference at Plymouth National Marine Aquari...

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