This document discusses various types of diabetes and animal models used to study diabetes. It describes the main types of diabetes as type 1, type 2, and gestational diabetes. It then provides details on several methods for inducing diabetes in animal models, including chemically induced models using alloxan and streptozotocin, genetically induced models using various diabetic rat and mouse strains, and other models such as viral infection, hormone manipulation, and antibody induction. Specific protocols are outlined for commonly used chemical diabetes induction methods and some genetically induced rodent strains.
2. INTRODUCTION
Diabetes
Diabetes is a disease that occurs when your blood glucose, also called
blood sugar, is too high.
Blood glucose is your main source of energy and comes from the food
you eat.
Insulin which are responsible for the lower the blood glucose level.
diabetes mellitus, describes a group of metabolic diseases in which the
person has high blood glucose (blood sugar), either because insulin
production is inadequate, or because the body's cells do not respond
properly to insulin, or both.
3. Types of diabetes
• The most common types of diabetes are type 1, type 2, and
gestational diabetes.
• Type 1 diabetes
• type 1 diabetes, the body’s immune system, which normally fights
infection, attacks and destroys the cells in the pancreas that make
insulin.
• As a result, your pancreas stops making insulin.
• Without insulin, glucose can’t get into your cells and your blood
glucose rises above normal.
• People with type 1 diabetes need to take insulin every day to stay
alive.
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• Type 1 diabetes typically occurs in children and young adults,
although it can appear at any age.
• symptoms of type 1 diabetes
• increased thirst and urination
• increased hunger
• blurred vision
• fatigue
• unexplained weight loss
5. Type 2 Diabetes
• In type 2 diabetes, which is characterized by insulin resistance, can
be treated using a variety of therapeutic approaches.
• Too much glucose then stays in your blood, and not enough reaches
your cells.
• type 2 diabetes occurs most often in middle-aged and older people.
• Causes type 2 diabetes:
• overweight and obesity
• not being physically active
• insulin resistance
• genes
6. Gestational diabetes
• Gestational diabetes develops in some women when they are
pregnant.
• Most of the time, this type of diabetes goes away after the baby is
born.
• The secretion of placental hormones causes insulin resistance,
leading to hyperglycemia.
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• Type 2 diabetes mellitus has major problems of insulin
resistance and impaired insulin secretion.
• Insulin could not bind with the special receptors so insulin becomes
less effective at stimulating glucose uptake and at regulating the
glucose release.
• There must be increased amounts of insulin to maintain glucose level
at a normal or slightly elevated level.
• However, there is enough insulin to prevent the breakdown of fats
and production of ketones.
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13. Screening model of anti-diabetes
1) Chemically induced diabetes:
• Alloxan induced diabetes
• Streptozotocin induced diabetes
(A) Neonatal Streptozotocin induced diabetes rat model (n-STZ)
(B) Nicotinamide-Streptozotocin (NAD-STZ) induced diabetic model
(C) Sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S)
(D) Low dose STZ with high fat diet-fed rat model
• Goldthioglucose obese diabetic mouse model
• Atypical antipsychotic-induced diabetic model
16. Alloxan induced diabetes
• Hyperglycaemia and glucosuria after administration of alloxan has
been described in several species, such as in dog, in rabbits, in rats
and in other species. Guinea pigs have been found to be resistant.
• In most species a triphasic time course is observed: an initial rise of
glucose is followed by a decrease, probably due to depletion of islets
from insulin, again followed by a sustained increase of blood glucose
PROCEDURE:
• Rabbits weighing 2.0 to 3.5 kg are infused via the ear vein with 150
mg/kg alloxan monohydrate (5.0 g/100 ml, pH 4.5) for 10 min
resulting in 70% of the animals to become hyperglycaemic and
uricosuric.
• The rest of the animals either die or are only temporarily
hyperglycemic
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• Rats of Wistar or Sprague-Dawley strain weighing 150–200 g are
injected subcutaneously with 100–175 mg/kg alloxan.
• Male Beagle dogs weighing 15–20 kg are injected intravenously with
60 mg/kg alloxan. Subsequently, the animals receive daily 1000 ml 5%
glucose solution with 10 IU Regular insulin for one week and canned
food and libitum. Thereafter, a single daily dose of 28 IU insulin is
administered subcutaneously.
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19. Streptozotocin induced diabetes
• the diabetogenic activity of the antibiotic streptozotocin. The
compound turned out to be specifically cytotoxic to beta-cells of the
pancreas.
PROCEDURE:
• Male Wistar rats weighing 150–220 g fed with a standard diet are
injected with 60 mg/kg streptozotocin intravenously.
• It causes swelling of pancreas followed by degeneration of
Langerhans islet beta cells and induces experimental diabetes
mellitus in the 2-4 days.
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(A) Neonatal Streptozotocin induced diabetes rat model (n-STZ):
• one of the suitable animal models of Type-2 diabetes mellitus.
• Single dose of STZ 100 mg/kg i.p. to the one day old pup and 120
mg/kg i.p. to the two, three, or five day old pups induces diabetes.
(B) Nicotinamide-Streptozotocin (NAD-STZ) induced diabetic model:
• Non insulin dependent diabetes mellitus (NIDDM) was induced by a
single intraperitoneal injection of STZ (60mg/kg) and NAD
(120mg/kg) to rats.
• NAD is an antioxidant which exerts protective effect on the cytotoxic
action of STZ by scavenging free radicals and causes only minor
damage to pancreatic beta cell mass producing type-2 diabetes.
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(C) Sucrose-challenged streptozotocin-induced diabetic rat model
(STZ-S):
• This model screened in vivo anti diabetic activity in sucrose loaded
model (SLM) male albino rats.
• Foster/Wistar strain rats of average body weight 160 ± 20 g weight
were used.
• STZ dissolved in 100 mM citrate buffer, pH 4.5 and calculated amount
of the fresh solution was injected intraperitoneally to overnight
fasted rats (60 mg/kg).
• Blood glucose levels were checked 48 h later by glucostrips and
animals with blood glucose values between 144 and 270 mg/dl (8–15
mM) were considered as diabetic.
• A sucrose load of 2.5 g/kg body weight was given 30 min later.
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• Thirty minutes post sucrose load, blood glucose levels were again
checked by glucostrips at 30, 60, 90,120, 180, 240, 300 min and at 24
h, respectively.
• Animals not found diabetic after 24 h post treatment of the test
sample were termed as non-responders.
• The animals, which did not show any fall in blood glucose profile in a
group
• while the others in that group, showed fall in blood glucose profile
have also considered as non- responders.
(D) Low dose STZ with high fat diet-fed rat model:
• The rats are administered high-energy diet of 20% sucrose with single
injection of STZ (30mg/kg body weight).
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• After 4 weeks changes in body weight are recorded and levels of
glucose, TG, TC, LDL in serum are analysed by standard methods.
• The results suggested that a combination of low dose STZ and high-
energy diet intake can effectively induce type-2 diabetes by altering
the related gene expressions in major metabolic tissues.
3) Goldthioglucose obese diabetic mouse model:
• Type-2 diabetes with obesity can be induced in mice by
intraperitonial injection of goldthioglucose (GTG) in a dose of 150-
350 or 200 mg/kg.
• The animal gradually develops obesity, hyperinsulinaemia,
hyperglycemia, insulin resistance over a period of 16- 20 weeks after
GTG injection.
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• The GTG is transported in particular to the cells of ventromedial
hypothalamus and causes necrotic lesions, which subsequently are
responsible for the development of hyperphagia and obesity.
• It also increases body lipid, hepatic lipogenesis and triglyceride
secretion, increased adipose tissue lipogenesis and decreases glucose
metabolism in muscle, abnormalities that are qualitatively similar to
genetically obese mice.
4) Atypical antipsychotic-induced diabetic model:
• Healthy animals have treated acutely with clozapine (10 mg/kg),
olanzapine (3.0 mg/kg), risperidone (1 mg/kg), ziprasidone (3
mg/kg) or haloperidol (0.25 mg/kg) and tested using the
hyperinsulinemic-euglycemic and hyperglycemic clamp procedures.
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• Clozapine and olanzapine had a rapid and potent effect on insulin
sensitivity by lowering the glucose infusion rate and increasing
hepatic glucose production.
• Both clozapine and olanzapine, as well as risperidone, decreased
peripheral glucose
• In the hyperglycemic clamp, clozapine and olanzapine impaired beta
cell function as reflected by a decrease in insulin secretion utilization.
26. Genetically induced diabetic animal model:
• type-2 diabetes may be obtained from the animals with one or
several genetic mutations transmitted from generation to generation
(e.g. db/db mice) or by selected from non-diabetic out bred animals
by repeated breeding over several generation.
• These animals generally inherit diabetes either as single or multigene
defects as seen in KK mouse, db/db mouse, or Zucker fatty rat.
