Diabetic mellitus

DIABETES MELLITUSDIABETES MELLITUS

By Sara SamiYuzuncu yil University

2015

• Diabetes mellitus derived from Greek word for fountain and the latin word from honey.

• when hyperglycemia increase it lead to polyuria, ploydipsia, ketonuria, and weigth loss. Over time can lead to hypertension, heart disease, renal failur, blindness neurophathy, stroke.

INTRODUCTION:Insulin is a peptide hormone, produced by beta cells of the pancreas, and is central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides. When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus.

Insulin resistance – reduced response to circulating insulin

Insulinresistance

Glucose output

Glucose uptake Glucose uptake

Hyperglycaemia

Liver Muscle Adiposetissue

IR

Insulin Resistance

Management of Diabetes

q Education

q Diet

q ExerciseExercise

q MedicationMedication

InsulinThe insulin plays an important role in storing the excess energy. In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles.

All the excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into fats and stored in the adipose tissue.

InsulinIn the case of proteins, insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein.

In addition, it inhibits the breakdown of the proteins that are already in the cells.

Anabolic

STRUCTURE OF INSULINv Human insulin consists of 51aa in two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification).

v T1/2~5-10 minutes, degraded by Glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links.

v Bovine insulin differs by 3aa, pork insulin differs by 1aa.

v Insulin is stored in a complex with Zn2+ions.

BIOSYNTHESIS OF INSULIN:Insulin is synthesized as proinsulin in pancreatic β-cells. It contains a signal peptide which directs the nascent polypeptide chain to the rough endoplasmic reticulum. Then it is cleaved as the polypeptide is translocated into lumen of the RER, forming proinsulin. Proinsulin is transported to the trans-Golgi network (TGN) where immature granules are formed.

Proinsulin undergoes maturation into active insulin through action of cellular endopeptidases known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. The endopeptidases cleave at 2 positions, releasing a fragment called the C-peptide, and leaving 2 peptide chains, the B- and A- chains, linked by 2 disulfide bonds. The cleavage sites are each located after a pair of basic residues and after cleavage these 2 pairs of basic residues are removed by the carboxypeptidase. The C-peptide is the central portion of proinsulin, and the primary sequence of proinsulin goes in the order "B-C-A”

The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the cell into the circulation.

EFFECT OF INSULIN ON GLUCOSE UPTAKE AND METABOLISM

Insulin binds to its

receptor

Starts many protein

activation cascades

glycogen synthesis

These include translocation of

Glut-4 transporter to the plasma

membrane and influx of glucose

glycolysis triglyceride

Insulin release qwhen Glucose get bind to

the receptor and cause.qThis lead to increase ATP

which close ATP depended K+ channel and open Ca+ valtage ligant by depolarization of the membrane.

qAs the concentration of Ca+ increase in to intracelular

Cause insulin resale from the granules

MOAInsulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very

rich.

The insulin receptor is a combination of four subunits held together by disulfide linkages:

Two alpha subunits that lie entirely outside the cell membrane

Two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm

metoblismInsulin binds with alpha

↓ beta unit autophosphorylated

↓ tyrosine kinase

↓ phosphorylation of multiple other intracellular

enzymes including a group called

insulin-receptor substrates (IRS)

MECHANISM OF ACTION of the receptor :

v The insulin receptor is a receptor tyrosine kinase (RTK) . Consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds, orienting across the cell membrane as a heterodimer

v It is oriented across the cell membrane as a heterodimer.

v The α subunits carry insulin binding sites, while the β subunits have tyrosine kinase activity.

MECHANISM OF ACTION:

qAfter insulin bend to the receptor by Alpha subunit and influence B sub unit to cause mutation and phosphorlation of tyrosin kinase to the active form which direcated to the cytoplasmic protien of (IRS) inslin receptor substrate qIRS bind to other active kinase (phosphatidylionsitol-3- kinase as reasult transation of Glucose transport (GLUT4) to the cell membran and result increase glucose up take

DEGRADATION OF INSULIN:

The internalized receptor-insulin complex is either degraded intercellularly or returned back to the surface from where the insulin is released extracellularly. The relative preponderance of these two processes differs among different tissues: maximum degradation occurs in liver, least in vascular endothelium.

FATE OF INSULIN▲ Insulin is distributed only extracellularly. It is a peptide; gets degraded in the g.i.t. if given orally.

▲ Injected insulin or that released from the pancreas is metabolized primarily in liver and to a smaller extent in kidney and muscles.

▲ Nearly half of the insulin entering portal vein from pancreas is inactivated in the first passage through liver.

▲ Thus, normally liver is exposed to a much higher concentration (4-8 fold) of insulin than other tissues.

▲ During biotransformation the disulfide bonds are reduced- A and B chains are separated. These are further broken down to the constituent amino acids

Physiologic functions of

Insulin

Diabetes• People who do not produce the necessary amount

of insulin have diabetes. There are two general types of diabetes.– The most severe type, known as Type I or

juvenile-onset diabetes, is when the body does not produce any insulin. Due to immune response,ketoacidosis more comman –Type II diabetics produce some insulin, but it is

either not enough or their cells do not respond normally to insulin. This usually occurs in obese or middle aged and older people. –Gestation diabitese :in pregnancy (metformin)–Prediabetes : (FPG 100-125) LEAD TO TYPEII

Diabetes complication

Short complication • Hyperglacymia • Hypoglacymia

Long complication • Macrovascular :-(hypertention – heart falier and

stock)• Microvascular Damagev Retinopathy v Nephropathy v Sensory and motor neuropathyv Autonomic

neuropathy(Gastroparesis)v Amputation secondary infection v Erectile dysfunction

Carbohydrate Metabolism – MuscleImmediately after a high-carbohydrate meal, the glucose that is absorbed into the blood causes rapid secretion of insulin

The normal resting muscle membrane is only slightly permeable to glucose, except when the muscle fiber is stimulated by insulin – so during much of the day, muscle tissue depends not on glucose for its energy but on fatty acids

Moderate or heavy exercise – exercising muscle fibers become more permeable to glucose even in the absence of insulin

Few hours after a meal because of insulin – Glucose stored as muscle GLYCOGEN – used during anaerobic exercise

Carbohydrate Metabolism - LiverGlucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen - Between meals – liver glycogen – glucose.

1. Insulin inactivates liver phosphorylase - enzyme that causes liver glycogen to split into glucose. This prevents breakdown of the glycogen that has been stored in the liver cells.

2. It increases the activity of the enzyme glucokinase, which is one of the enzymes that causes the initial phosphorylation of glucose after it diffuses into the liver cells - phosphorylated glucose cannot diffuse back through the cell membrane.

Carbohydrate Metabolism - Liver3. Insulin also increases the activities of the enzymes that promote glycogen synthesis, including glycogen synthase - polymerization of the monosaccharide units to form the glycogen

4. Enzyme glucose phosphatase inhibited

5. Glycolysis (oxidation of glucose) is increased in muscle & liver by activating enzyme phosphofructokinase

Carbohydrate Metabolism - LiverGlucose Is Released from the Liver Between Meals1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion.

2. Stopping further synthesis of glycogen in the liver and preventing further uptake of glucose by the liver from the blood.

3. The lack of insulin along with increase of glucagon, activates the enzyme phosphorylase, which causes the splitting of glycogen into glucose phosphate.

4. The enzyme glucose phosphatase, becomes activated by the insulin lack and causes the phosphate radical to split away from the glucose

Carbohydrate MetabolismWhen the quantity of glucose entering the liver cells is more than can be stored as glycogen, insulin promotes the conversion of all this excess glucose into fatty acids – triglycerides in VLDL - adipose tissue and deposited as fat

Insulin also inhibits gluconeogenesis & glycogenolysis. Thus inhibiting glucose production

Insulin decreases the release of amino acids from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis

Fat Metabolism - LiverInsulin increases the utilization of glucose by most of the body’s tissues – fat sparer.

Promotes fatty acid synthesis in liver from excess glucose1. Insulin increases the transport of glucose into the liver cells –

extra glucose via glycolytic pathway – pyruvate – acetyl CoA – fatty acids

2. Energy from glucose via citric acid cycle - excess of citrate and isocitrate ions - activates acetyl CoA carboxylase – acetyl CoA to form malonyl CoA

Fat Metabolism – Adipose Tissue

Fat storage in adipose tissue

1. Fatty acids (triglycerides) are then transported from the liver by way of the blood lipoproteins to the adipose cells.

2. Insulin activates lipoprotein lipase - splits the triglycerides again into fatty acids, a requirement for them to be absorbed into the adipose cells - again converted to triglycerides and stored

Fat Metabolism – Adipose Tissue

- Insulin promotes glucose transport through the cell membrane into the fat cells - large quantities of alpha glycerol phosphate - supplies the glycerol that combines with fatty acids to form the triglycerides

- Insulin inhibits the action of hormone-sensitive lipase – no hydrolysis of the triglycerides stored in the fat cells - release of fatty acids from the adipose tissue into the circulating blood is inhibited

Fat Metabolism

Insulin deficiency - free fatty acid becomes the main energy substrate used by essentially all tissues of the body besides the brain – ketoacidosis – coma, death

The excess of fatty acids in the plasma also promotes liver conversion of some of the fatty acids into phospholipids and cholesterol - atherosclerosis

Protein Metabolism and Growth1. Insulin stimulates transport of many of the amino acids into the

cells2. Insulin increases the rate of transcription of selected DNA genetic

sequences3. Insulin increases the translation of mRNA4. Insulin inhibits the catabolism of proteins5. In the liver, insulin depresses the rate of gluconeogenesis - conserves

the amino acids in the protein stores of the body

Insulin deficiency – enhanced urea excretion in the urine - protein wasting – weakness

Insulin and Growth Hormone Interact Synergistically to Promote Growth

The Summary The Summary

Effects of insulin on various tissues Adipose issue Increased glucose entry Increased fatty acid synthesis Increased glycerol phosphate synthesis Increased triglyceride deposition Activation of lipoprotein lipase Inhibition of hormone-sensitive lipase Increased K+ uptake

Muscle Increased glucose entry Increased glycogen synthesis Increased amino acid uptake Increased protein synthesis in ribosomes Decreased protein catabolism Decreased release of gluconeogenic amino acids Increased K+ uptake

Effects of insulin on various tissues

Liver Decreased ketogenesis Increased protein synthesis Increased lipid synthesis Decreased gluconeogenesis Increased glycogen synthesis General Increased cell growth

Insulin also increase in the secretion of HCL by parietal cells in the stomach via vagus nerve

Insulin test is done to check whether vagotomy is complete or not, as in case of treatment of peptic ulcer

Fasting level of blood glucose of 80 to 90 mg/100 ml, the rate of insulin secretion is minimal — 25 ng/kg of body weight per minute

Biphasic insulin response to Glucose,1st rapid phase – preformed, 2nd slow rise phase - new

DIABETES MELLITUS

Insulin is effective in all forms of diabetes mellitus and is a must for type 1 cases, as well as for post pancreatectomy diabetes and gestational diabetes. Many type 2 cases can be controlled.

Insulin therapy is generally started with regular insulin given s.c. before each major meal. The requirement is assessed by testing urine or blood glucose levels .

DIABETIC KETOACIDOSIS (DIABETIC COMA)

Regular insulin is used to rapidly correct the metabolic abnormalities.

Usually within 4-6 hours blood glucose reaches 300 mg/dl. Then the rate of infusion is reduced to 2-3 U/hr

HYPEROSMOLAR (NONKINETIC

HYPERGLYCAEMIC COMA)

This usually occurs in elderly type 2 cases. The cause is obscure.

The general principles of treatment are the same as for ketoacidotic coma, except that faster fluid replacement is to be instituted as alkali is usually not required.

CONCLU S ION :

Thank you for Washing