You are hereBIOLOGICAL EVALUATION OF HYPOGLYCEMIC AGENTS

BIOLOGICAL EVALUATION OF HYPOGLYCEMIC AGENTS


About Authors:
Kataria Sahil, Aggarwal Ashutosh, Middha Akanksha, Sandhu Premjeet
Seth G. L. Bihani S.D. College of Technical Education,
Institute of Pharmaceutical Sciences and Drug Research,
Sri Ganganagar, Rajasthan,
INDIA

INTRODUCTION
Diabetes is a chronic (lifelong) disease marked by high levels of sugar in the blood.
There are three major types of diabetes:
•    Type 1 diabetes is usually diagnosed in childhood. Many patients are diagnosed when they are older than age 20. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. Genetics, viruses, and autoimmune problems may play a role.

•    Type 2 diabetes is far more common than type 1. It makes up most of diabetes cases. It usually occurs in adulthood, but young people are increasingly being diagnosed with this disease. The pancreas does not make enough insulin to keep blood glucose levels normal, often because the body does not respond well to insulin. Many people with type 2 diabetes do not know they have it, although it is a serious condition. Type 2 diabetes is becoming more common due to increasing obesity and failure to exercise.

•    Gestational diabetes is high blood glucose that develops at any time during pregnancy in a woman who does not have diabetes. Women who have gestational diabetes are at high risk of type 2 diabetes and cardiovascular disease later in life.
There are many risk factors for type 2 diabetes, including:
•Age over 45 years
• A parent, brother, or sister with diabetes
•Gestational diabetes or delivering a baby weighing more than 9 pounds
•Heart disease
•High blood cholesterol level
•Obesity
•Not getting enough exercise
•Polycystic ovary disease (in women)
•Previous impaired glucose tolerance
•Some ethnic groups (particularly African Americans, Native Americans, Asians, Pacific Islanders, and Hispanic Americans)

Reference ID: PHARMATUTOR-ART-1189

Symptoms
High blood levels of glucose can cause several problems, including:
•    Blurry vision
•    Excessive thirst
•    Fatigue
•    Frequent urination
•    Hunger
•    Weight loss
However, because type 2 diabetes develops slowly, some people with high blood sugar experience no symptoms at all.
Symptoms of type 1 diabetes:
•    Fatigue
•    Increased thirst
•    Increased urination
•    Nausea
•    Vomiting
•    Weight loss in spite of increased appetite
Patients with type 1 diabetes usually develop symptoms over a short period of time. The condition is often diagnosed in an emergency setting.
Symptoms of type 2 diabetes:
•    Blurred vision
•    Fatigue
•    Increased appetite
•    Increased thirst
•    Increased urination

Signs and tests
A urine analysis may be used to look for glucose and ketones from the breakdown of fat. However, a urine test alone does not diagnose diabetes.
The following blood tests are used to diagnose diabetes:
•    Fasting blood glucose level -- diabetes is diagnosed if higher than 126 mg/dL on two occasions. Levels between 100 and 126 mg/dL are referred to as impaired fasting glucose or prediabetes. These levels are considered to be risk factors for type 2 diabetes and its complications.
•    Hemoglobin A1c test -- this test has been used in the past to help patients monitor how well they are controlling their blood glucose levels. In 2010, the American Diabetes Association recommended that the test be used as another option for diagnosing diabetes and identifying pre-diabetes. Levels indicate:
•    Normal: Less than 5.7%
•    Pre-diabetes: Between 5.7% - 6.4%
•    Diabetes: 6.5% or higher
•    Oral glucose tolerance test -- diabetes is diagnosed if glucose level is higher than 200 mg/dL after 2 hours. (This test is used more for type 2 diabetes.)
•    Random (non-fasting) blood glucose level -- diabetes is suspected if higher than 200 mg/dL and accompanied by the classic diabetes symptoms of increased thirst, urination, and fatigue. (This test must be confirmed with a fasting blood glucose test.)
Treatment
The immediate goals are to treat diabetic ketoacidosis and high blood glucose levels. Because type 1 diabetes can start suddenly and have severe symptoms, people who are newly diagnosed may need to go to the hospital.
The long-term goals of treatment are to:
•    Prolong life
•    Reduce symptoms
•    Prevent diabetes-related complications such as blindness, heart disease, kidney failure, and amputation of limbs
These goals are accomplished through:
•    Blood pressure and cholesterol control
•    Careful self testing of blood glucose levels
•    Education
•    Exercise
•    Foot care
•    Meal planning and weight control
•    Medication or insulin use
There is no cure for diabetes. Treatment involves medicines, diet, and exercise to control blood sugar and prevent symptoms8

Methods to induce experimental diabetes mellitus

Pancreatectomy in dogs
Dysfunction of the visceral tract has been considered for a long time to be the cause of diabetes mellitus. Bomskov (1910) reported severe diabetic symptoms in dogs after cannulation of the ductus lymphaticus. This observation, however, could not be confirmed in later experiments . The technique was similar to that described for ligation of the thoracic duct in dogs. Von Mehring and Minkowski (1890) noted polyuria, polydipsia, polyphagia, and severe glucosuria following removal of the pancreas in dogs. The final proof for the existence of a hormone in the pancreas was furnished by Banting and Best (1922) who reduced the elevated blood sugar levels in pancreatectomized dogs by injection of extracts of the pancreatic glands. The technique of complete pancreatectomy in the dog has been used by many scientists as a relevant animal model for diabetes mellitus in man18

PROCEDURE
Male Beagle dogs weighing 12–16 kg are used. The animal is anesthetized with an intravenous injection of 50 mg/kg pentobarbital sodium and placed on its back. After removal of the fur and disinfection of the skin a midline incision is made from the xyphoid process reaching well below the umbilicus. Bleeding vessels are ligated and the abdomen is entered through the linea alba. The falciform ligament is carefully removed and the vessels ligated. A self-retaining retractor is applied. By passing the right hand along the stomach to the pylorus, the duodenum with the head of the pancreas is brought into the operating field. First, the mesentery at the unicate process is cut and the process itself is dissected free. The glandular tissue is peeled off from the inferior pancreatico-duodenal artery and vein. The vessels themselves are carefully preserved. Along a line of cleavage which exists between the pancreas,the pancreaticoduodenal vessels and the duodenal wall, the pancreas is separated from the duodenum and from the carefully preserved pancreaticoduodenal vessels. The small vessels to the pancreas are ligated. The dissection is carried out from both sides of the duodenum. In the area of the accessory pancreatic duct the glandular tissue being attached very firmly has to be carefully removed in order to leave no residual pancreatic tissue behind.
The pancreatic duct is cleaned, doubly ligated and cut between the ligatures. The dissection proceeds until one encounters a small lobe containing the main pancreatic duct. The glandular tissue adheres here firmly to the duodenum. Blunt dissection and ligation of the vessels is followed by ligation of the pancreatic duct. By pulling on the pylorus and the stomach, the pyloric and the splenic parts of the pancreas are delivered into the wound. The duodenal part is placed back into the abdominal cavity. The mesentery of the body and tail of the pancreas is cut with scissors. The small vessels are doubly ligated and cut. The pancreatic tissue is bluntly dissected from the splenic vessels. The pancreatic branches of the splenic vessels are doubly ligated and cut. Working in direction from the spleen to the pylorus, the pyloric part of the pancreas is the last one to be dissected. Finally, all pancreatic tissue is removed. The surgical field is checked once more for pancreatic remnants. The concavity of the duodenum and its mesentery is approximated by a few silk stitches and the omentum is wrapped around the duodenum. Retroperitoneal injection of 5 ml 1% procaine solution is given to prevent intussusception of the gut. 250 000 IU penicillin G in saline solution are instilled into the peritoneal cavity. The abdominal wall and the subcutaneous layer are closed by sutures and finally the skin is sutured with continuous everting mattress stitches. After the operation, the animal receives via a jugular vein catheter for 3–4 days the following treatment:
1000 ml 10% glucose solution with 10 IU human insulin Regular, 3 ml 24% Borgal (sulfadioxin/trimethoprim) solution, 2 ml 50% metamizol and 400 IU secretin. On the third day, the animal is offered milk. After the animal has passed the first milk feces, it is given daily dry food together with a preparation of pancreatic enzymes Insulin is substituted with a single daily subcutaneous dose of 34 IU Retard-Insulin  Vitamin D3 is given every three months as a intramuscular injection of 1 ml Vigantol forte.14

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