Acta Physiologica Hungarica, Volume 101 (4), pp.

408–420 (2014)
DOI: 10.1556/APhysiol.101.2014.4.2

Streptozotocin-nicotinamide-induced rat model

of type 2 diabetes
(Review)
A Ghasemi1,2, S Khalifi3, S Jedi1,2
1
Endocrine Physiology Research Center, Research Institute for Endocrine Sciences,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Endocrine Research Center, Research Institute for Endocrine Sciences,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
3
Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences,
Shahid Beheshti University of Medical Sciences, Tehran, Iran

Diabetes is one of the five leading causes of death in the world, with type 2 diabetes occurring more frequently than
type 1. Management of diabetes without side effects is still a challenge and therefore new strategies need to be
examined. Because of difficulties in human research, animal models of diabetes are useful research tools for this
purpose and rodent models of type 2 diabetes are the first choice. The aim of this study is an overview on one of the
most frequently used models of type 2 diabetes in rat, induced by streptozotocin and nicotinamide, considering its
advantages and disadvantages for diabetes research in humans.
Keywords: animal model, nicotinamide, rat, streptozotocin, type 2 diabetes

Diabetes mellitus, as an international public health concern, affects 5% of people worldwide

(19, 52, 75, 77) and accounts for about 10% of total health care expenditure in many countries
(57). In human history, the 21st century has the most diabetogenic environment (4). It has
been estimated that 439 million people worldwide will have diabetes by 2030 (21) and more
than 100% increase in its incidence is expected between 2000 and 2030 (56). Diabetes is one
of the five leading causes of death in the world and about six deaths per minute are attributable
to diabetes complications (39). In adults, type 2 diabetes is more frequent than type 1 (19, 31,
74, 31, 77) and is mostly characterized by peripheral insulin resistance (19, 20, 31, 41) and
inadequate functional mass of β-cells (13, 20, 41).
Medications currently available for treating hyperglycemia in type 2 diabetes include:
(1) biguanides (metformin), (2) sulfonylureas (glibenclamide, known as glyburide in the
U.S. and Canada, gliclazide, glimepride, and glipizide), (3) thiazolidinediones or glitazones
(pioglitazone), (4) glucagon-like peptide-1 (GLP-1) agonists (exenatide and liraglutide), (5)
amylin agonists (pramlintide), (6) dipeptidyl peptidase four (DPP-4) inhibitors (sitagliptin,
vildagliptin, saxagliptin, alogliptin, and linagliptin), (7) alpha-glucosidase inhibitors
(acarbose, miglitol, and voglibose), (8) glinides or meglitinides (repaglinide and nateglinide),
(9) sodium-glucose cotransporter-2 inhibitors (canagliflozin and dapagliflozin), and (10)
insulin (30, 35, 45). Although, currently insulin and oral antidiabetic agents are used for

Corresponding author: Dr. Asghar Ghasemi, PhD

Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of
Medical Sciences
24 Parvaneh street, Velenjak, Tehran, Iran
PO box: 19395-4763
Fax: +98 21 22416264; E-mail: Ghasemi@endocrine.ac.ir
0231–424X/$ 20.00 © 2014 Akadémiai Kiadó, Budapest
 Streptozotocin-nicotinamide rat model of type 2 diabetes 409

treatment of diabetes, most of them are expensive, and have inadequate efficacy and adverse
effects, such as liver toxicity, lactic acidosis, and diarrhea; management of diabetes without
side effects is therefore still a challenge (2, 51, 59, 73, 80, 81).
Because of difficulties in human research, animal models of diabetes are useful and
essential research tools for understanding the molecular basis, pathogenesis of complications,
and the utility of therapeutic agents in diabetes (19, 20, 31, 73). In an animal model, a
phenomenon in one or more aspects resembles the same phenomenon in human (19). Rodent
models of type 2 diabetes are the first choice and are most widely used, as they share many
similarities with diabetes in human including dependence on genetic background, sex, and
age of the animal (19, 31). There are two major categories of rodent models: genetic
(spontaneously) and experimentally-induced (non-spontaneously) (31), the latter being much
simpler, cheaper, and more widely available (23, 31, 76). Experimentally-induced models of
diabetes could be created by chemicals, dietary manipulation, or surgery (23, 31). Different
approaches have been used for induction of non-spontaneously models of type 2 diabetes in
rodents; the most important ones are summarized in Table I (3, 20, 23, 31, 41, 43, 46, 47, 73,
38, 66). In experimental animals, the most prominent diabetogenic chemical in diabetes
research is streptozotocin (STZ) (6, 19, 23, 38, 69, 76) among other substances that also have
diabetic effects (alloxan, vactor, dithizone, and 8-hydroxyquinolone) (67). Alloxan destroys
pancreatic beta cells by oxidative stress and compared to STZ, is less used for induction of
diabetes because of its lower efficacy and side effects, which include liver and kidney damage
(28, 31). The aim of this study is an overview of one of the most frequently-used model of
type 2 diabetes in rat, induced by STZ and nicotinamide (NA), STZ-NA model, considering
its advantages and disadvantages for diabetes research in humans.

Beta cell turnover in rat pancreas

Rat beta cells have a life-span of approximately 58 days (12, 14), a cell cycle of 14.9 h (14),
a very slow turnover involving 0.5% of the cell population (41), and their frequency of
apoptosis is 0.5% (in 3-month-old rat), (12–14). Adult rat pancreas contains about 100 μg of
insulin compared to 8 mg (or about 200 units) in adult human (14). The average rat islet is
150 μm (range between 40 to 400 μm) in diameter and contains about 45 ng of insulin (14).
In rodents, neogenesis (differentiation of ductal precursor cells to islet cells) and
replication are main ways of increasing number of beta cells (14). Neogenesis is predominant
during early to late gestation and replication is predominant during late gestation and the
neonatal periods (12, 14). In rodents, new islets are formed during the first days after birth
and a second wave of neogenesis occurs around the time of weaning; after 30 to 40 days of
age, limited change in replication rates occurs (12, 14) but both neogenesis and replication
continue throughout adult life (12, 14). A transient wave of apoptosis has also been reported
between 1 and 3 weeks of age (41). Beta cell mass is dynamic (11, 14) and is determined by
rate of replication, neogenesis, apoptosis, and cell size (14); beta cell mass increases 12–15-
fold from birth to adulthood (14) and is linearly correlated with age (11, 13) and body weight
in adult rats (14). Compensatory changes in function and mass of beta cells occur to maintain
euglycemia (14) in case of increased demand in situations like obesity or pregnancy; however,
only 15–20% (13) or one-third (41) of human subjects with obesity become diabetic. In the
male Lewis rat, β cell mass increases by an increase in cell numbers until 15 months and
thereafter by increase in cell size (hypertrophy) (12).

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410 Ghasemi A et al.

Table I. Main experimentally-induced rat models of type 2 diabetes

Model Associated Associated Advantages Disadvantages

insulin obesity
resistance*
Neonatal STZ or No (41) No (41, 43, Suitable for assessing regeneration of Glucose
alloxan injection 73) β-cells (73) and study the pathogenesis insensitivity
of diabetic complications (31, 41); (3, 43); long
diabetic condition can be maintained induction period
for a long time (52 weeks) in particular (at least 12 weeks)
with alloxan (31); live without needs (31); damage to
for insulin treatment (41, 73); cheap and other organs in
easy induction (73) particular liver
and kidney
(23, 28, 38, 73)
Partial No (41) No (73) Helpful for understanding adaptive Regeneration
pancreatectomy mechanisms of residual pancreatic of the remnant
β-cells (31, 41) and assessing the pancreas (31);
effectiveness of the potential therapeutics advanced surgical
acting through increase β-cell growth skill required;
and/or survival (41); no toxic effects digestive problem
on other organs (31, 73); intact residual due to damage to
β-cells (41) exocrine pancreas
(31, 41, 73)

High-fat diet-fed Yes (31) Yes (31) No toxicity of chemicals (73) Long induction
period (> 10
weeks) (31, 73)
Fructose-fed Yes (31) Yes (31) No toxicity of chemicals (73) Long induction
period (31)
Fat-fed STZ Yes (31, No (66) Replicate the natural pathogenesis of Long induction
66) type 2 diabetes which resembles to period (31)
human disease (20, 31); response to anti-
diabetic drugs (31, 66)
suitable for pharmacological screening of
anti-diabetic drugs (20, 31)
Injection of Yes (31, Yes (31) Presents insulin resistance (31, 41) Developing
monosodium 41) hepatic
glutamate tumors; long
induction period
(31)
Intrauterine growth Yes (31) Yes (31) Follow natural pattern of developing type Long induction
retardation 2 diabetes, i.e. developing early insulin period (31)
resistance, followed by hyperglycemia
and subsequent pancreatic β-cell
dysfunction (31); Suitable for studies
on late metabolic effects of altered
intrauterine environment (41)
Combination of No No (46, 47)
nicotinamide and
STZ injection†

* Having insulin resistance is considered as an advantage

† See Table II for features of this model
STZ, streptozotocin

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 Streptozotocin-nicotinamide rat model of type 2 diabetes 411

Streptozotocin
Streptozotocin, [2-deoxy-2-(3-methyl-3-nitrosurea) 1-D-glucopyranose], is an antibiotic
produced by Streptomyces achromogenes and a nitrosourea analogue in which N-methyl-N-
nitrosourea is linked to the carbon-2 of a hexose (38, 67, 73). STZ has selective toxic effects
on β-cells (3, 33, 73, 77) because of high affinity for β-cell membrane (6), low capacity of
β-cells to scavenge free radicals (50, 52, 54), and low NAD+/DNA ratio in islets (6). Because,
STZ accumulates in pancreatic β-cells by Glut2 (38, 76, 77), other organs like kidney, liver,
and intestine are also damaged by STZ (9, 23, 38).

Mechanism of STZ action

In β-cells, STZ impairs glucose oxidation (7, 76), decreases insulin synthesis and secretion
(76), and disrupts glucose transport and glucokinase activity (31, 67). The sugar moiety,
2-deoxy-D-glucose, of STZ may direct the preferred alkylation of pancreatic β-cell through
Glut2 (9, 50) because of its ability to methylate DNA in kidney, liver, and intestine and
inability to methylate DNA in brain cells (9). Nitrosoamide moiety of STZ (methylnitrosurea)
is responsible for the toxicity (77) through generation of highly reactive methyl carbonium
ions (CH3+) which causes DNA methylation and breaks (6, 9, 50, 54) and activation of poly-
ADP-ribose polymerase-1 (PARP-1) within 10 min, which substantially decreases NAD+ in
beta cells within 20 min and leads to energy deprivation and death of beta cells (3, 51, 73).
PARP-1 is a nuclear enzyme that catalyzes the synthesis of poly(ADP-ribose) from NAD+(77).
PARP activity in pancreas causes ATP and NAD+ depletion, decrease in protein synthesis,
and necrotic β-cell death (3, 6, 51, 54, 73). In addition through DNA alkylation (10, 38, 54,
68), STZ causes β-cell death through oxidative stress (10, 39, 44, 54, 56, 68, 76) and nitric
oxide (NO) production (7, 10, 27, 28, 52, 54, 68, 76). STZ increases NO levels both through
induction of NO synthase enzymes (7) and when is metabolized inside cells, which does not
require NO synthases (50, 76); NO combines with superoxide anion to form peroxynitrite
which decomposes to genotoxic hydroxyl radicals (7). STZ also causes decreases in oxygen
consumption by mitochondria and therefore it limits ATP production and this effect is
mediated at least in part by NO (76) (Fig. 1).
Following STZ injection, an acute triphasic response has been observed in rats: (a) early
hyperglycemia at 2–4 hours which may be due to mobilization of liver glycogen (32, 62)
without parallel increase (32) or even with concomitant drop (76) in serum insulin,
(b) hypoglycemia observed 6–10 h after injection due to increased serum insulin levels
(32, 62, 76), and (c) permanent hyperglycemia from 24 h onwards, characterized by polyuria,
glycosuria, hyperglycemia, and decreased pancreatic insulin content (32, 62). Many of the
metabolic changes occur within the first 2–8 weeks, following STZ injection (6).

STZ preparation and administration

There is no standard protocol for the preparation, dose, or administration of STZ (23).
Maximum stability of STZ is at pH 4 (6). However, despite a general belief that STZ should
be dissolved immediately before use (24, 26, 32, 43, 46, 61, 62, 64), it is unstable at neutral
pH (32), and low pH solution is required to maintain its stability (23); it has been reported
that STZ solutions with a pH of 7.2 are as stable as those with a pH of 4.5 (23) and STZ
solution is relatively stable at pH of 7.4 and 37º C, for at least up to one hour (38) and pH
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412 Ghasemi A et al.

Streptozotocin

Methylation Xanthine oxidase NO production

Free radical generation

+
↑ CH3 H 2O 2
DNA alkylation

O 2- NO

OH -
O2-

β-cell DNA
damage Peroxynitrite

Nicotinamide

NAD+

PARP-1 ↓ Intracellular NAD+

3-aminobenzamide
and taurine
Cessation of NAD+- ↓ Insulin synthesis and
ADP ribose units
dependent energy secretion
metabolism (↓ ATP)

β-cell death
(necrosis & apoptosis)

PARP, poly ADP-ribose polymerase; NO, nitric oxide; H2O2, hydrogen peroxide; O2–, Superoxide anion.
Inhibitory; Excitatory
Fig. 1. Mechanism of streptozotocin toxicity on diabetes induction and partial protection exerted by nicotinamide
against β-cytotoxic effect of streptozotocin [mostly based on references (6, 7, 10, 54, 55, 76)]

6.7–7.8 on ice for 30 min (23). These observations have questioned the need for low pH, low
temperature, and immediate use of STZ solutions (23). STZ is dissolved in saline (43, 79),
acidified 0.9% saline at pH 4.5 (7, 32, 58), and ice-cold 0.05–0.1 M citrate buffer adjusted
to pH 4.5 (1, 2, 5, 18, 24–26, 37, 39, 46, 48, 50, 51, 55–57, 59, 60, 61, 64, 65, 70, 71, 81).
A stable solution of STZ in citrate buffer (pH 4.5) is most suitable for injection (38). STZ
could cause neoplastic growth, and precautions should be applied during its preparation (9).
Animal age, weight, sex, and the dose and time of the drug injection affect sensitivity to
STZ and severity of the diabetes (16, 23, 32). Compared to males, female rats are less
sensitive to STZ and this may be due to anti-apoptotic activity of estradiol (23). Following
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 Streptozotocin-nicotinamide rat model of type 2 diabetes 413

STZ injection, the highest incidence of diabetes induction has been seen at 16:00 and the
lowest incidence at 08:00, indicating a circadian rhythm (16). STZ dosages > 65 mg/kg BW
are considered a high dose, 40–55 mg/kg BW intermediate, and < 35 mg/kg BW as low
dosages (31). A single dose of 25 mg/kg (32) or < 35 mg/kg (31) in rats produces no major
effect; at a dose of 35 mg/kg, spontaneous recovery from diabetic state has been reported in
25% of rats (32), and stable diabetes has been observed at doses of 55–65 mg/kg (32). LD50
of STZ is about 130 mg/kg (6). STZ rapidly undergoes metabolic degradation in rat liver (33)
and has a half-life of 6.9 min (6) or 15 min (73).
The route of STZ administration is usually through intraperitoneal (23, 31) or intravenous
(23) injections, however, other routes of administration including subcutaneous (6, 23),
intramuscular (6, 23), or even intracardiac (6, 23) have also been reported. It has been
reported that more stable and reproducible diabetic models could be created using intravenous
injection of STZ (79), however, this is difficult and needs experience (23).

Nicotinamide
Nicotinamide, pyridine-3-carboxamide, is a vitamin B3 (niacin) derivate with antioxidant
capacity which reduces cytotoxic actions of STZ (76, 77). NA protects β-cell against STZ by
several mechanisms (Fig. 1); NA is a scavenger of oxygen-free radicals (7, 8, 29, 63) and NO
(7), inhibits both PARP (7, 8, 29, 51, 54, 63, 77) with IC50 value of 210 ± 2.9 μM (54),
cytokine-induced MHC class II expression (29, 34), and provides NAD+ (29, 39, 54, 63, 77).
NA also enhances β-cell regeneration and islet cell growth and inhibits apoptosis (54). In
addition, NA may act as a methyl group acceptor, which reduces DNA methylation (9). NA
is a cytoprotective agent that inhibits apoptosis through prevention of both externalization of
phosphatidylserine and DNA degradation (40); however, it has been reported that the
administration of NA before STZ administration had no effect on DNA methylation in other
organs except in pancreatic β-cells, which reduced DNA methylation (9); the mechanism of
this selective protection remains to be determined. NA has a half-life of 9 h (63) and is mainly
secreted in the urine (63). NA is dissolved in normal saline (1, 5, 24, 26, 32, 37, 39, 46, 49,
57, 58, 59, 60, 61, 65, 70, 71, 80, 81) and is usually administrated intraperitoneally (32).

STZ-NA type 2 diabetic rat model

The STZ-NA rat model of type 2 diabetes is based on protective effects of NA against
β-cytotoxic effects of STZ (41). This model was first introduced by Masiello et al. using
10-week-old male Wistar rats (31, 43). The STZ-NA model of type 2 diabetes has the
following features (Table II): (1) stable moderate (non-fasting) hyperglycemia which does
not require exogenous insulin to survive (26, 31, 43, 77); (2) reduction of β-cells (–40%) (17,
26, 41, 47) and reduced pancreatic insulin stores by 60% (31, 43); (3) glucose intolerance
(43, 77) mainly due to impaired insulin secretion (77); (4) presence (although impaired)
glucose-stimulated insulin secretion (26, 37, 43, 77); (5) responsiveness to sulfonylureas (i.e.
tolbutamide and glibenclamide) (26, 37, 43, 77); and (6) polyphagia and polydipsia (5).
Insulin responsiveness to glucose and sulfonylureas distinguished this model from others
(26, 41, 43, 47). This model, as a model for non-obese type 2 diabetes, is reported to be more
suitable for both biochemical and pharmacological researches testing potential antidiabetic
effects of pharmacological and natural compounds on the course of diabetes (15, 26, 31, 41,
43, 47, 77, 81).
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414 Ghasemi A et al.

Table II. Advantages and disadvantages of streptozotocin-nicotinamide rat model of type 2 diabetes

Advantages Disadvantages Other features

Stable hyperglycemia, 150–180 mg/ Lack of insulin resistance (41, 75) Increased plasma triglyceride
dL (41) and glucose intolerance and no effect on plasma insulina levels (40%), no effect on plasma
(36, 75) (15, 46, 47) cholesterol, and slight trend to
increases in plasma free fatty
acids (47)
Insulin responsiveness to glucose Blunted first phase of glucose-induced Hyper-responsiveness to arginine
and sulfonylureas (47) insulin secretion and absence (47)
of second phaseb (47)
Cheap and easy induction (41, 73) Hyperglycemia only in non-fasting Normal weight gain (46, 47)
statec (41) or no weight loss (36)
Suitable for assessing effectiveness Residual β-cells potentially damaged Reduction of β-cells (–40%)
of new potential anti-diabetic agents by STZ (41) (17, 26, 41, 47) with no change
(15, 26, 31, 41, 43, 47, 77) and of α-cell mass (41)
a good model in studies of diabetic
complications (77)
Live without needs for insulin Toxic actions of STZ on other body Polyphagia and polydipsia (5)
treatment (73) organs (73)
a
Decreases in plasma insulin levels was also reported (26, 75, 78).
b
In human type 2 diabetes the first phase of insulin secretion is more impaired than the second phase (47).
c
It has been stated that type 2 diabetes results in hyperglycemic state under both fasted and fed conditions (36).

The STZ-NA model of type 2 diabetes has also been reported to be a good model for
studies of diabetic complications and has been used in studies focused on diabetes
complications (77) including diabetic nephropathy (53) and neuropathy (69, 70), and
cardiovascular complications of diabetes (17, 18, 37). It has however, been reported that STZ
exerts direct renal toxicity and it is difficult to distinguish that renal dysfunction is a
complication of diabetes or drug-related non-specific cytotoxicity (23, 28, 38); however the
kidney recovers from STZ-induced renal toxicity after three weeks (28). In addition, single
doses of STZ could produce renal tumors, which make STZ-treated models of diabetes not
suitable for long-term effects of diabetes on kidney (9). NA could prevent renal dysfunction
(40), which further questions using this model for studying diabetic nephropathy. Although
single doses of STZ could not produce liver tumors, such tumors are seen with prolonged
exposure (9). High extent of DNA methylation by STZ in liver and kidney may also influence
metabolism in these organs (9). In addition, NA inhibits P450 and hepatic metabolism (40).
Using STZ-NA as a model of type 2 diabetes, one should consider the other effects of STZ
and NA in addition to the effects on β-cell function.

Induction of diabetes
Masiello et al. examined the effects of 100–350 mg/kg NA injected intraperitoneally 15 min
before intravenous administration of 65 mg/kg STZ and suggested NA dosage of 230 mg/kg
to be the most appropriate (43). Following injection of 200–230 mg/kg NA 15 min before
STZ administration (60 mg/kg i.v.), 75–80% of rats became diabetic with stable non-fasting
hyperglycemia (150–180 mg/dL), 20–25% of treated animals became either severely diabetic
within 2–3 weeks or remained normoglycemic (41). Two to 3 weeks after diabetes induction
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 Streptozotocin-nicotinamide rat model of type 2 diabetes 415

abnormalities in glucose tolerance and insulin responsiveness were seen (41). Doses of STZ
and NA, the age of animals, and relative time of the administration of the two compounds
affect the results (32, 42, 54, 77). Younger animals are less sensitive to STZ and are better
protected by NA (42, 77). In subsequent studies, intraperitoneal or intravenous injections of
STZ at dosage between 45–65 mg/kg and intraperitoneal NA injection at dosage between
60–290 mg/kg have been used for diabetes induction (Table III). In most experiments NA is
given to rats 15 min before STZ (77), however, NA injection has also to be done 20 min (5)
or 30 min (17, 18) before STZ injection. It has been reported that NA prevents the onset of
diabetes when is administrated 15 min before or up to 2 hours after STZ injection (33); with
time lapse after the STZ administration protective effect of NA on β-cells decreases (77). In
addition, it has been reported that NA exerts the best protection against STZ toxicity when
administrated shortly after STZ (76). Because of fatal hypoglycemia due to massive insulin
release after STZ injection, in some studies, rats were provided with 10% glucose solution
after 6 h of STZ injection for the next 24 h to prevent hypoglycemia (51, 52) or 20% glucose
solution for 24 h (55).
The best index of diabetogenic activity of STZ is the pancreatic insulin content 24 h
after i.v. administration of the drug (32). However, as shown in Table III, in most studies,
serum/plasma glucose is measured at different times after STZ injection as an index of
diabetogenicity (1, 2, 5, 58, 60, 64), whereas time for blood glucose measurement varies from
72 h to 8 weeks. Although it has been stated that in STZ-NA model of type 2 diabetes in rats,
hyperglycemia is only seen in non-fasting state (41), fasted and non-fasted blood glucose at
different levels have been used for defining diabetic state (Table III).

Table III. Different protocols used in the selected studies for induction STZ-NA type 2 diabetes in rat

Straina Weight (g)/ age Fasting NA dose STZ Time Time of Glucose Refer-
at time state (mg/kg) dose between blood levels ence
of diabetes before (mg/kg) NA and glucose (mg/dL)
induction diabetes STZ test after to be
induction injection diabetes considered
(min) induction/ diabetics
fasted or
non-fasted
Wistar 200–220/NR Overnight 110 i.p. 45 (i.p) 15 72 h/NR > 250 (60)
Wistar 180–200/9 weeks Overnight 110 i.p. 45 i.p. 15 72 h/NR > 250 (1)
Wistar 180 ± 10/8 weeks NR 230 i.p. 65 i.p. 15 2 days/NR 180 ± 8 (64)
Wistar 200–220/NR Overnight 110 i.p. 65 i.p. 15 72 h/NR > 250 (58)
Wistar 150–180/NR 12 h 110 i.p. 50 i.p. 15 72 h/NR > 250 (2)
Sprague 180–220/NR Overnight 100 i.p. 55 i.p. 20 15 days/NR > 200 (5)
Dawley
Wistar 200–300/NR NR 95 i.p. 60 NR 15 1 week/ ≥ 126 (61)
fasted
Wistar 250–280/ Overnight 120 i.p. 60 i.p. 15 72 h and > 126 (71)
2–3 months 7 days/
fasted
Wistar 160–180/NR 12 h 110 i.p. 50 i.p. 15 1 week/NR 250 (51)
Wistar 200–250/NR Overnight 230 i.p. 65 i.p. 15 72 h/NR > 150 (48)
Wistar 180–220/NR Overnight 110 i.p. 45 i.p. 15 72h/fasted > 250 (56)

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416 Ghasemi A et al.

Straina Weight (g)/ age Fasting NA dose STZ Time Time of Glucose Refer-
at time state (mg/kg) dose between blood levels ence
of diabetes before (mg/kg) NA and glucose (mg/dL)
induction diabetes STZ test after to be
induction injection diabetes considered
(min) induction/ diabetics
fasted or
non-fasted
Wistar 200–220/NR Overnight 110 i.p. 45 i.p. 15 30 days/ 262 ± 16 (57)
fasted (mean ± SD)
Wistar NR/2–3 months NR 210 i.p 60 i.v. 15 2 weeks/NR 149 ± 3.6 (37)
Wistar 250-300/NR NR 200 i.p. 60 i.v. 15 NR > 180 (22)
Sprague- NR/8–10 weeks Overnight 120 i.p. 60 i.v. 15 3 and 238 ± 14.4 (74)
Dawley 7 days/NR
Wistar 180–200 g/8weeks Overnight 110 i.p. 65 i.p. 15 72 h and > 200 (44)
7 days/NR
Wistar NR/2 months NR 180 i.p. 50 i.v. 30 8 weeks/NR 159.6 ± 23.8 (18)
(mean ± SD)
Wistar NR/2–3 months NR 270 i.p. 60 i.v. 15 5–8 weeks/ 151 ± 7.5 (47)
non-fasted
Wistar 220–240/10 weeks NR 260 i.p. 65 i.v. 15 15 days/NR 140–200 (36)
Wistar 220–230/ NR 270 i.p. 60 i.v. 15 2 weeks/NR 137 ± 3 (26)
2.5 months (mean ±
SEM)
Wistar NR/2–3 months NR 290 i.p. 60 i.v. 15 3–5 weeks/ 150-180 (46)
non-fasted
Wistar 220–230/10 weeks NR 230 i.p. 65 i.v. 15 3 weeks/NR 163 ± 4 (15)
(mean ±
SEM)
Wistar 180–220/NR Overnight 110 i.p. 45 i.p. 15 3 days/ > 250 (59)
fasted
Wistar 160–180/6 weeks 12 h 110 i.p. 50 i.p. 15 1 week/NR ≥ 252 (52)
Wistar 180–200/6 weeks NR 110 i.p. 45 i.p. 15 72 h/NR > 250 (55)
Wistar 200–220/NR Overnight 110 i.p. 45 i.p. 15 72 h/NR > 250 (65)
Wistar 150–200/NR Overnight 60 i.p. 65 i.p. 15 2 weeks/ ≥ 200 (39)
fasted
Wistar 220–240/NR Overnight 110 i.p. 65 i.v. 15 7 days/ ≥ 126 (81)
fasted
Wistar 200–220/NR Overnight 120 NR 60 i.m. 5b 3 days/ >250 (70)
fasted
Wistar 200–250/NR Overnight 110 i.p. 65 i.p. 15 7 days/NR > 150 (80)
Wistar 160–180/8 weeks 12 h 110 i.p. 50 i.p. 15 1 week/NR ≥ 250 (50)
Wistar 160–180/NR Overnight 90 i.p. 60 i.p. 15 1 week 216–270c (75)
Wistar 180–220/NR Overnight 230 i.p. 65 i.v. 15 15 days/ 228–280 (72)
fasted
Sprague- 200–225/NR 15 h 210 i.p. 55 NR 15 96 h 198–252 (78)
Dawley

a
All studies have been carried out on male rats.
b
Unlike other studies, NA has been injected after STZ injection.
c
30 min after gavaging 2 g glucose to overnight fasted animals
i.p., intraperitoneal injection; i.v., intravenous injection; NR, not-reported.
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 Streptozotocin-nicotinamide rat model of type 2 diabetes 417

In conclusion, although none of the animal models of type 2 diabetes represents

complexity of the human disease, it seems that STZ-NA model, which appears to be closer to
human type 2 diabetes is an advantageous model for testing potential antidiabetic effects of
pharmacological and natural compounds on the course of diabetes. In addition, there are
great variations between dose of both STZ and NA for inducing diabetes that may explain
some differences observed in different studies.

Acknowledgement
The authors wish to thank Ms N. Shiva for critical editing for English grammar and syntax of the manuscript.

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