Nsulin Dependent Diabetes Mellitus

Published Date: 02 Nov 2017

Introduction

Old classififcation system was based on insulin was not upto the mark and was mis leading; under the past system patients were either classified as either

Insulin Dependent Diabetes Mellitus (IDDM) or

Noninsulin Dependent Diabetes Mellitus (NIDDM)

In 1998, a new classification system based upon the etiological (etiology the science dealing with causes of disease) factors at work in diabetes were proposed by the WHO

A. Type 1 diabetes arising from an unknown cause forms of B cell dysfunction, which cause to complete insulin deficiency. T1DM or juvenile diabetes or insulin-dependent diabetes, is a chronic condition where pancreas produces little or no insulin, Biomarkers of the immunity destruction of the β-cell include islet’s cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β.

B. Type 2 diabetes: Disease of adult onslaught, which initiate either from insulin resistance or relative insulin deficiency/from a secretory defect.It is a disease, which appears to have a very strong genetic predisposition and is caused by a combination of inadequate insulin secretion and an insensitivity of the body tissues to insulin so leaving patients with this condition relatively deficient in insulin(WHO).

C. Type 3diabetes: Insuling has direct effect on brain. In Type 3 diabetes Brains cease to produce enough insulin for brain.In absense of insulin brain got affected in same way as Type 1 or 2 diabetes.Type 3 diabetes only found in those who already have T1DM or T2DM.Type 3 diabetes is resposible for Alzheimer's disease which results from resistance to insulin in the brain various genetic defects in insulin action, and diseases of the exocrine pancreas (WHO).

D.Type 4 diabetes: Gestational diabetes is high blood sugar (diabetes) that starts or is first diagnosed during pregnancy gestational diabetes(WHO).Pregnancy hormone blocks insulin function cause diabetes.

Type 1 diabetes

Type 2 diabetes

Onset

Acute –symptomatic

Slow often symptomatic

Clinical View

Weight loss

Obese

Polyuria

Strong family history type 2 diabetes

Polydipsia

Ethnicity –high-prevalence populations

Acanthuses’ nigricans

PCOS

Ketosis

Almost always present

Usually absent

C-reactive protein

Low/absent

Normal /elevated

Antibodies

ICA Positive

ICA Negative

Anti-GAD Protein

Anti-GAD protein

Ica 512 Protein

ICA 512 Protein

Therapy

Insulin variably

Lifestyle, OHA, Insulin

Associated auto-

Yes

No

immune disease

Table no.- 1 Difference between Type 2 and Type 2 Diabetes Melitus

(latent autoimmune diabetes in adults (LADA); glutamic acid decarboxylase (anti-GAD); impaired fasting glycaemia IFG; PCOS –polycystic ovarian syndrome; ICA –islet cell antibodies; Anti-GAD –glutamic acid decarboxylase antibodies; OHA –oral hypoglycaemic agents.

EPIDEMIOLOGY OF DIABETES

T2DM is responsible for 90% of the diabetes case (Malecki et al., 2005). In the western world, T2DM has virtually become epidemic due to the typical western life style of not working or inactive(lazy) behavior and high calorie diet.Rates of diabetes are increasing in non-Western countries too; for example, the greatest percentage increase in diabetes incidence is expected to occur in Africa over the next 20 years (WolfsMGM et al., 2009). According to statistics from the World Health Organization (WHO), in 2006, 170 million people have been suffered from T2DM and the annual death rate was 2.8 million by that time. Is is obviously expected that numbers to double over the next 25 years (Wolfs MGM, et al., 2009). T2DM varies with different ethnic groups,this is very surprising fact in study of T2DM (Selvin E et al., 2011),which show that genetic diversity play a crucial role in evaluation of T2DM.

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Figure no.. Prevalence of Diabetes byRace/Ethnicity in the United States. Type 2 diabetes mellitus is more prevalent among Hispanics, NativeAmericans, African Americans, and Asians/Pacific Islanders than in non-Hispanic whites (Selvin Eet al., 2011).

Plasma Venous Glucose mmol/L(mg/dl)

Diabetes mellitus:

Fasting and /or

2 hour post glucose load/casual

>126

>200

Impaired glucose tolerance(IGT):

Fasting and /or

2 hour post glucose load/casual

<126

140-190

Impaired fasting glycaemia(IFG):

Fasting and /or

2 hour post glucose load/casual

100-125

<140

Table no.2- Values for diagnosis of diabetes mellitus and other categories of hyperglycaemia

Perniciousness

Aprox 30% of people suffers from diabetes also has to face kidney failure . After this condition a long term renal dialysis treament is necessary to overcome this situtaion. 40% of population suffering from diabetes has to have a most of problems including from foot ulceration, sexual difficulties, cardiac arrhythmias and sudden death.

Mortality Rate

Aprox. 22000 peple die because of diabetes. Main cause of death due to diabetes is the macro vascular complications of diabetes such as myocardial infarcts and cerebrovascular accidents.The death count of people suffering from Type 2 diabetes is just double then peole dying without type 2 diabetes

Etiology

Type 2 Diabetes mellitus provides the clue about it its relation to history of weight loss,suprising thirst and polyuria (passing lots of urine).Patients are often thin, when there is not any famioly history about T2DM then it is thought to be triggered by a viral infection. It is not known why the disease develops but it may be related to over-eating.

Genetic studies of Dibetes Mellitus

Through genome wide association studies identified 19 loci in human which are related to T2DM,In studies it has been verified that insluin helps in DNA replication and protein synthesis also.Glucagon like peptide GLP 1 gene helps in insulin controlled release.

CARBOHYDRATE METABOLISM

Diabetes Mellitus is characterized by defective insulin secretion in body, which help to raise glucose concentration.

Capturedtttt

Figure no : Simplified scheme of pathophysiology of T2DM. As a combination of impaired insulin secretion and resistance, the effects are often associated to elevated levels of free fatty acids in plasma, decreased glucose transport into muscle cells, increased hepatic glucose production and increased breakdown of fats. All the defects as a whole result in increased blood glucose level in the end (Boden et al., 1996).

Type 2 diabetes mellitus is ciertified by defect in insulin secretion by pancreatic β-cell and peripheral insulin resistance, which can be attached to obesity (Bodenet al., 1996). Insulin resistance is caused bysignling pathway which is responsible for insulin secretion and its binding to its receptor (Wolfs MGMet al., 2009).

β-cell regeneration,

β-cell survival, or

β-cell development (Wolfs MGMet al., 2009).

Figure no-Diabetes carbohydrate metabosim on organs

Many case of diabetes are obese(Pimenta W, 1995).So diabetes main cause is obesity.Insulin resistance and low insulin production is the cuase of T2DM.Hyperglycemia is the main cause for these microvascular desease whereas macrovascular risks are related with insulin resistance. ‘Ticking clock’ hypothesis given by (Stern et al., 1996)inthis we take T2DM as , it starts ticking at onslought of hyperglycemia cause microvascular deasease, where else in macrovscular desease clock start ticking in when insulin resistence occur.

T2DM genetics/family history and pre- and post-natal environmental factors (Jin etal., 2009). Suboptimal intrauterine environment, low birth weight (LBW), obesity, inactivity, gestational diabetes and advancing age (Jin etal., 2009).T2DM becomes much compact by the secondary effects of ‘glucolipotoxicity’ (hyperglycemia and hyperlipidaemia) (Freeman H,et al., 2006).

Capture

Figure : Classical genetic risk (family history) and environmental risk factors for T2DM.Adipose tissue is highly associated to T2DM. The capacity of adipocyte to replicate,differentiate and store lipids goes down with age, which makes T2DM and obesity age-related diseases. (Jin, 2009) (Lazar, 2005) (Manson, 1991)

DIAGNOSIS AND TREATMENT OF DIABETES MELLITUS

The diagnosis of T2DM done by identifying polyuria, polydipsia, fatigue and weight loss,hyperglycemia include blurred vision, extremity paresthesia or yeast infection (particularly balanitis in men) (Freeman H,et al., 2006). T2DM can be proceed by hypertension, dyslipidemia and polyphagia.

There are following test applied to diagnose T2DM:-Disease,diagnostic,biochemical.

Biochemical tests:- Fasting plasma Glucose (FPG) and Oral Glucose Tolerance Test comes in category of Biochemical test

Diagnosis and diagnostic tests:-The body usually maintain the glucose concentrations stable. The normal fasting blood sugar is usually between 3.5-6.7mmol/l. After a meal it rarely exceed 8mmol/l.Dip-sticking urine for the presence of glucose is often used as a screening test for diabetes mellitus. The diagnosis of diabetes mellitus is done by a fasting blood glucose of over 6.7mmol/l or a random glucose of >10mmol/l. If a patient presents symptoms of diabetes and is validated to have a single very high glucose measurement eg >15mmol/l then this can be diagnostic.

The oral glucose tolerance test measures how the body responds to glucose presence. Patient had to go for fast overnight and patient’s blood glucose level took & then given a drink, which contains 70 -75gm of glucose. After 2 hours blood sample took again.By analyzing the results we can obtain the full performa about disease onset.

Currently, there are 7 major products are available to treat T2DM: sulfonylureas (e.g. glibenclamide), meglitinides (e.g. nateglinide), biguanides (e.g. metformin), thiazolidinediones (e.g. pioglitazone), α-glucosidase inhibitors (e.g. acarbose), DPP-IV inhibitors (e.g. sitagliptin) and GLP-1 agonists (e.g exenatide) (Glamoclija Una, 2010). Sulfonylurea derivatives are insulin secretagogues and function by closing the ATP-sensitive potassium channel (KATP) of ß-cells leading to more (or prolonged) insulin secretion (Evans JL,et al., 2010). Meglitinides non-sulfonylurea insulin secretagogues it stimulates first-phase insulin release(Evans JL,et al., 2010).Biguanides decreases endogenous glucose production aapproximately 25-35%.Thiazolidinediones act as agonists for the peroxisome proliferator-activated receptor.

DNA diagnostics and pharmacogenetic

Genetic information provided from HGP has given a sight to clinically manage Diabetes.In some patients A MODY mutation in TCF1 has 5-6 % higher response to gliclazide then the metformin and it has veen proved by HGP( Human Genome Project). One more example is about heterozygous mutations in the ATP-sensitive K+ channel’s (Kir6.2 gene) in many patients with neonatal diabetes.This gene has a crucial role in glucose-stimulated insulin secretion.BARI 2D The Bypass Angioplasty Revascularization Investigation 2 Diabetes solve the problem related to CAD Diabetes.

Findings of Potential regulatory regions of candidate genes

SNPs in the coding region of HNF4A, which become mutated in case of MODY Mutation, had yielded no association with T2D. After that it has been identified that one more so called second promotor found on 40 kb upstrem on gene & some SNP’s also found in that part & noncoding sequence of HNF4A were associated with T2D in Ashkenazi Jews & Finland.

COMPLICATIONS OF DIABETES:

The complications of diabetes can be classified as:

1. ACUTE PROBLEMS: (Otherwise termed the diabetic medical emergencies) Diabetic ketoacidosis, Hypoglycemia.

2. THE CHRONIC COMPLICATIONS OF DIABETES: Micro vascular complications. Macro vascular complications

1. THE ACUTE COMPLICATIONS OF DIABETES:-Two most important acute emergencies, diabetic ketoacidosis and hypoglycemia. The acute diabetic emergencies can be found in supplement.

2. THE CHRONIC COMPLICATIONS OF DIABETES:-These are the complications that occur because of long term exposure of the body’s tissues to hyperglycemia, hypoinsulinanemia or their associated metabolic disturbances.

The chronic complications of diabetes are classified as follows:

1.MICROVASCULAR:- (microangiopathic) Diabetic Retinopathy’s, Diabetic Neuropathy, Diabetic Nephropathy, Diabetic skin problems (the "Diabetic foot")

2.MACROVASCULAR:-Accelerated propensity to atherosclerosis/atheroma, Peripheral vascular disease/ coronary heart disease, Myocardial infarction. Arteriosclerosis, Hypertension and cerebrovascular disease.

3. OTHER METABOLIC ABNORMALITIES:-Hypercholesterolemia

4. INCREASED SUSCEPTIBILITY TO INFECTION:-Bacterial,viral and many other infection becomes so prone for diabetic pateint.

1. MICROVASCULAR (Microangiopathic) disease:- Principle clinical manifestations are;

1. Diabetic retinopathy.

2. Diabetic neuropathy.

3. Diabetic nephropathy.

4.Diabetic foot ulcers.

The Diabetes chronic complications trial (DCCT) and the UK Prospective Diabetes study (UKPDS).that complicatn associated with diabetes can be contrled by tight glycemic control only.

1. DIABETIC RETINOPATHY:-

Retinopathy is a micro vascular disease. After 20 years of age mostly people sometime face the prblem of retinopathy,

A. Muscular edema:-Increased vascular permeability is a feature of micro vascular disease. Some people develops capillary leakage at the mascular and this leads to tissue edema, structural disruption of the photoreceptors and ultimately to visual disturbance.

B. Retinal ischemia: Retinal ischemia can impact on vision in one of two ways

I. The retina’s response to ischemia is to generate angiogenic factors, which stimulate new vessel formation with the intention of reperfusion the ischemic areas. Unfortunately these new vessels doesnot forms and therefore they start to bleed. Visual loss due to preretinal or vitreous hemorrhage is the ely symptoms Pan-retinal photocoagulation (PRP).

II. Retinal ischemia at the central macula leads to loss of neural elements at the fovea. This manifests clinically as the loss of central vision; ischemic diabetic maculopathy. Unlike macular edema, ischemic maculopathy is untreatable.

2. DIABETIC NEUROPATHY:-

Diabetes may affect both the somatosensory system causing a variable sensory and motor deficits and the autonomic nervous system. About 30% of diabetic patients have evidence of neuropathyThe principle menifestation are:-

Focal

Diffuse

3. DIABETIC NEPHROPATHY:

Diabetic nephropathy is a specific micro vascular disease affecting the renal glomerulus.It is almost always associated with retinopathy. The kidneys are the bodies purifying system and our entire blood volume passes through them many times a day. Kidney main role is to filter the body fluid and excrete the waste products in form of urine,Principle structure where it has to be performed is renal glomerulus & this comprised of the glomerular basement membrane and mesangial cells.This micro vascular disruption of the kidneys renal glomeruli is known as diabetic nephropathy, End stage diabetic nephropathy can have a profound effect on vision.

4. SKIN AND THE DIABETIC FOOT: Peripheral neuropathy means patients are often unaware of skin trauma making foot ulceration more common. Their loss of pain sensation may be compounded by poor eye sight, if the patients can’t see the ulcers it goes unnoticed and untreated. As people with diabetes have an increased propensity to bacterial infection, any untreated skin wound can rapidly get infected and because of poor circulation once infection has set in it often spreads very rapidly and responds slowly if at all to treatment.

2. MACROVASCULAR DISEASE.

Although micro vascular disease is only seen in people with diabetes, they are also predisposed to developing atherosclerosis and arteriosclerosis, diseases of the large blood vessels that affect the general population.

ATHEROSCLEROSIS:- Atherosclerosis is the deposition of plaques of a mixture of lipid, and fibro vascular tissue (atheroma) on the inside of the vessel wall of the large blood vessels. Once established these plaques usually slowly increase in size with two important clinical Consequences:

I. Chronic ischemia. (Coronary heart disease and peripheral vascular disease) as the athermanous plaques get bigger the lumen of the blood vessel gets narrower. Over time the total blood flow along the affected vessel is gradually reduced leading to ischemia of the tissue it supplies

II. Acute vessel ischemia (Myocardial infarction): Athermanous plaques may rupture. Plaque rupture activates the body’s intrinsic clotting system, which forms a blood clot over the rupture site. This clot may completely block the affected vessel leading to acute ischemia and cell death of all the tissues supplied by that vessel.

ARTERIOSCLEROSIS: Arteriosclerosis is a histological term meaning the loss of elastic tissue from the walls of the medium and large arteries (arterial-), which consequently become rigid (-sclerosis).

3.METABOLIC DISTURBANCES ASSOCIATED WITH DIABETES: Although the most profound metabolic disturbance in diabetes is hyperglycemia, other metabolic disturbances also occur. The most important of these is hyperlipidemia or hypercholesterolemia. Diabetes is main cause to 20% kidney failure all over the word.

Figure . Kidney and other organ structure involved in T2DM complications

Genetic studies of T2DM

Animal Model developement

"An animal model for the biomedical research is one in which prescriptive biology or behavior can be studies, or in which a induced pathological process can be assessed,and in which the Hypothetical phenomena in one or more respects reflects the phenomenal species of animals". Defination given by American National Research Council Committee((ANRCC).There are many kind of animal models for T2DM some of them are following

Spontaneous models:- Disease induced spontaneously

Experimental model:- In which disease is induced

Genetically modified models:- Those models in which disease induced by genetic methods

Negative models:- Negative animals are those involve resistent for particular condition or disease and

Orphan models:- Orphan models are those which includes animal models with disease Unknown to human counterparts

Type II Diabetes (TIIDM) Models:-

a. Obese Models:-The Zucker (fa/fa) fatty (obese) rat has been found with same physiological traits like db/db mouse. Sexual union or mating of fa/fa rat for hyperglycemia gave birth to offspring ZDF(Zucker diabetic fatty rat strain ), that cause diabetes (only in males) in 8 weeks,because of high rate of apoptosis of β-cells, which can not compete the insulin resistance, same in fa/fa rat, it develops diabetes in 14 weeks.The KK mouse, the NZO mouse, the OLETF rat and the NSY mouse are related with obesity-induced diabetes models having polygenic background.The KK (Kuo Kondo) KK Japanese KK mouse, strain with large body.Hyperplasia, hyperinsulinaemia and insulin resistanceare main advantage of this KK mouse, kk/AY mouse have yellow obese gene (Ay).KK and KK/Ay mouse are knwon as model for obesity-induced T2DM, The New Zealand obese (NZO) known as good model for polygenic obesity, that gains the weight in 2 month,[e.g. the No obese No diabetic mouse (NON/Lt).The OLETF rat & NSY can also used as model for developing obesity-induced diabetes,The Otsuka Long Evans Tokushima Fatty (OLETF ) rat originated long-Evans rats and males which can develop diabetes at about the age of 18-25 weeks.The NSY mouse is also an important polygenic model, which produce diabetes in a sex-dependent manner & the severity is related to age.NSY mouse originated from the Jc1: ICR mouse,NOD mouse (Model of T1DM).

b) Non-obese rodent models of T2DM:- The GK (Goto-Kakizaki) rat is a polygenic non-obese model which has been developed through selective inbreeding glucose intolerant Wistar rats over many generations.Main advantage of this models are insulin resistance, normolipidaemia and impaired insulin secretion,Neonatal GK rats main charecteristics are reduced islets mass.GK rat is used to study. Akita(C57BL/6) akita, mouse comes from the C57BL/6 colony in japan,Main charecteristics of this model is polydipsia, polyuria, progressive hypo-insulinaemia and finally hyperglycemia at an age of 3-4 weeks.

c) Non-rodent models of spontaneous T2DM:- Feline, swine models has also been used as perfect sponteneous model of T2DM. Feline and domestic rats are similer to human in most condition so they are very good model also.Swine models works for both T1DM and T2DM,(e.g. Female Yucatan mini pigs,The Gottingen mini pigs).T2DM can be sponteneously induced in many primate models like bonnet, Macaques,cynomolgus,rhesus,baboons and others.

Model category

Classification of type 2 diabetes in animals

Type 2 diabetic models (Obese)

(Non obese)

I. Spontaneous or genetically derived

diabetic animals

ob/ob mouse

db/db mouse

KK mouse

KK/A y mouse

NZO mouse

NONcNZO10 mouse

TSOD mouse

M16 mouse

Zucker fatty rat

ZDF rat

SHR/N-cp rat

JCR/LA-cp rat

OLETF rat

Obese rhesus monkey

Cohen diabetic rat

GK rat

Torri rat Non obese C57BL/6

(Akita) mutant mouse

ALS/Lt mouse

II. Diet/nutrition induced

diabetic animals

III. Chemically induced

diabetic animals

Sand rat

C57/BL 6J mouse

Spiny mouse

GTG treated obese mice

Low dose ALX or STZ adult

rats, mice, etc.

Neonatal STZ rat

IV. Surgical diabetic

animals

VMH lesioned dietary obese

diabetic rat

Partial pancreatectomized animals

e.g. dog, primate, pig & rats

V.Transgenic/

knock-out

diabetic animals

b 3 receptor knockout mouse

Uncoupling protein (UCP1)

knock-out mouse

Transgenic or knock out mice involving

genes of insulin and insulin receptor

and its components of downstream

insulin signaling e.g. IRS-1, IRS-2,

GLUT-4, PTP-1B and others

PPAR-g tissue specific knockout

mouse

Glucokinase or GLUT 2 gene knockout

mice

Human islet amyloid polypeptide

overexpressed rat (HIP rat)

Table no.- Classification of type 2 diabetes in animals

Table II. Advantages and disadvantages of different categories of type 2 diabetic animal models

Model Category

Advantages

Disadvantage

I. Spontaneous

diabetic animals

Development of type 2 diabetes is of

spontaneous origin involving genetic

factors and the animals develop

characteristic features resembling

human type 2 diabetes

Mostly of inbred animal models in

which the genetic background is

homogeneous and environmental

factors can be controlled, allow

genetic dissection of this multifactorial

disease easy

Variability of results perhaps minimum and

require small sample size

Highly inbred, homogenous and mostly

monogenic inheritance and development of

diabetes is highly genetically determined

unlike heterogeneity seen in humans

Limited availability and expensive for the

diabetes study

Mortality due to ketosis problem is high

in case of animals with brittle pancreas

(db/db, ZDF rat P. obesus, etc.) and require

insulin treatment in later stage for survival

Require sophisticated maintenance

II. Diet/Nutrition

induced diabetic

animals

Develop diabetes associated with obesity

as a result of overnutrition as in diabesity

syndrome of human population

Toxicity of chemicals on other body

vital organs can be avoided

Mostly require long period of dietary

treatment

No frank hyperglycaemia develops upon

simple dietary treatment in genetically

normal animals and hence become not

suitable for screening antidiabetic agents

on circulating glucose parameter

III. Chemical induced

diabetic animals

IV. Surgical diabetic

Animals

Selective loss of pancreatic beta cells

(alloxan/STZ) leaving other pancreatic

alpha and delta cells intact

Residual insulin secretion makes the

animals live long without insulin

treatment

Ketosis and resulting mortality is

relatively less

Comparatively cheaper, easier to

develop and maintain

Avoids cytotoxic effects of chemical

diabetogens on other body organs

Resembles human type 2 diabetes due

to reduced islet beta cell mass

Hyperglycaemia develops primarily by

direct cytotoxic action on the beta cells

and insulin deficiency rather than

consequence of insulin resistance

Diabetes induced by chemicals is mostly

less stable and at times reversible because

of the spontaneous regeneration of beta

cells. Hence, care must be taken to assess

the pancreatic beta cell function during

long-term experiments

Chemical produce toxic actions on other body

organs as well besides its cytotoxic action on

beta cells

Variability of results on development of

hyperglycaemia is perhaps high

Involvement of cumbersome technical and

post operative procedures

Occurrence of some other digestive

problems (as a result of part of excision of exocrine

portion (deficiency of amylase enzyme)

Dissection of alpha islets (glucagon

secreting cells) too along with beta cells

leading to problems in counter regulatory

response to hypoglycaemia

Mortality is comparatively higher

V. Transgenic/knock

out diabetic animals

Effect of single gene or mutation on

diabetes can be investigated in vivo.Dissection of complex genetics of

type 2 diabetes become easier

Highly sophisticated and costly procedure

for the production and maintenance

Expensive for regular screening

Experiment.

Table no- Advantages and disadvantages of different categories of type 2 diabetic animal models

Enzymatic assay:-

Aspartate transaminase (EC 2.6.1.1), Alanine transaminase (EC 2.6.1.2), Alkaline phosphatase (EC 3.1.3.1), Acid phosphatase (EC 3.1.3.2) Leucine arylamidase (EC 3.4.1.1), Aldolase (EC 4.1.2), Lactate dehydrogenase (EC 1.1.1.27), Malate dehydrogenase (EC 1.1.1.38) and Cholinesterase (EC 3.1.1.7) were measured in serum of male rabbits and albino Wistar rats.Activity of specific enzymes in a sample of blood serum is used to identify disease diagnosis:-

(1)Transaminases (GOT and GPT) GOT level is used to identify mycardial infection,

Severe angina of the heart, liver damage and arrhythmias in range of 10-46 hours.Glutamic-Pyruvic Transaminase (GPT).Liver damage give rise to GPT Got level high.

(2). Lipase,a fat digesting enzyme

(3) Alkaline phosphatase, increased enzyme concentration in serum cause Paget’s disease(inflammation of the bone) and osteomalacia (softening of the bone),

(4) Acid phosphatase,not present in usual condition in prostate gland; it is released into the circulation in metastatic cancer of the prostate;

(5) Peptidases, produced in condition such as shock, fever, and traumatic injury,anemia resulting from fragility or increased destruction of the RBC

(6) Transaminases, increased enzyme concentration in serum cause hepatitis, and the heart, such as myocardial infarction.

(7) Gamma-glutamyl Transpeptidase (GGT),GGT it effect celluler signling in pancreatic tissue

(8) Creatine phospho kinase (CPK),Found in acute mycardial disease

(9) Amylase, a starch-digesting enzyme increased enzyme concentration in serum cause acute inflammation of the pancreas, in obstruction of the pancreatic duct, and in mumps;