A.Krishna Sailaja et al. / JPBMS, 2010, 3 (10)
1 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 03, Issue 03
Available online at www.jpbms.info
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES
An overall review on insulin resistance in the commencement of type 2 diabetes mellitus
* A.Krishna Sailaja1, P.Amareshwar2,P.Chakravarty3
1Research scholar, Osmania University, Hyderabad, India.
2Professor, Osmania University, Hyderabad, India.
3Research scholar, Osmania University, Hyderabad, India.
Type 2 Diabetes is a genetically heterogeneous disease consisting of several sub groups with various combinations of
susceptibility genes. Insulin resistance is considered to be highly risk factor for Type 2 Diabetes. 45% of the first-degree
relatives of patients with Type 2 Diabetes are Insulin resistant. Several studies on Asian Indians have shown that they are
characterized by higher Insulin resistanc, Early onset Type 2 Diabetes and hypertension. Several studies on various
populations reported that small size at birth coupled with subsequent obesity increases risk for Insulin resistance syndrome
in later life .Dietary modifications also play an important role in initiation of insulin resistance syndrome. So this review
article mainly focuses on the causes of Insulin resistance, Dietary and environmental factors effecting Insulin resistance and
unequivocal inherited components underlying the Insulin resistance in pathogenesis of Type 2 Diabetes.
Keywords: PPARg (Peroxisome proliferator activated receptor gama),BMI(bodymass index),TNFα(Tumor necrosis
factor),NIDDM(Non-insulin dependent Type2 diabetes), IRS(Insulin receptor substrate), BP(Blood pressure)
inappropriately low or absent response of specific target
tissues to the action of Insulin [1, 2]. As a result higher
levels of insulin are needed in order for insulin to have its
effects. The resistance is seen with both the body’s own
insulin and if insulin is given through injection. The
insulin resistance state and compensatory hyper
insulinemia are translated into wide number and type of
metabolic and non-metabolic outcomes [3, 4].The Insulin
resistance syndrome is defines by the presence of Insulin
resistance or fasting hyper insulinemia and two of the
Hyperglycemia (Fasting Plasma Glucose > 6.1 mm
Insulin resistance (IR) defines an
Causes of insulin resistance:-
(1)Abnormal B - Cell Secretary Product
(a) Abnormal Insulin Molecule
(b) Incomplete conversion of proinsulin to insulin
(2)Circulating Insulin Antagonists
hormones e.g., Growth hormone, cortisol, glucagon
(b) Anti Insulin Antibodies
(c) Anti Insulin receptor antibodies A
(3)Target Tissue defects
(a) Insulin Receptor defects
(b)Post Receptor defects
Diseases associated with Insulin Resistance : [4, 5]
Type-2 Diabetes mellitus is a condition in which insulin
resistance was already suspected often clustered with
obesity, dyslipidemia, arterial hypertension, hyper
uricemia and sedentary life style, conferring a high cardio
vascular risk on the individual.
Conditions associated with insulin resistance include:
Figure 1: Diseases associated with insulin resistance
Type 2 Diabetes
Overt diabetes may be the first sign that insulin resistance
is present. While it can be noted long before diabetes
develops, in cases where there is reluctance or inability to
see a physician regularly, insulin resistance can present as
type 2 diabetes. 
ISSN NO- 2230 - 7885
A.Krishna Sailaja et al. / JPBMS, 2010, 3 (10)
Fatty liver is strongly associated with insulin resistance.
The accumulation of fat in the liver is a manifestation of
the disordered control of lipids that occurs with insulin
resistance. Fatty liver associated with insulin resistance
may be mild or severe. Newer evidence suggests that fatty
liver may even lead to cirrhosis of the liver and, possibly,
liver cancer. 
Arteriosclerosis, also known as atherosclerosis, is a
process of progressive thickening and hardening of the
walls of medium-sized and large arteries. Arteriosclerosis
is responsible for:
Coronary artery disease(angina and heart attack )
Peripheral vascular disease.
Other risk factors for arteriosclerosis include:
High levels of "bad" (LDL) cholesterol,
High blood pressure,
Diabetes, and a
Family history of arteriosclerosis.
Skin lesions include increased skin tags and a condition
called acanthosis nigricans - a darkening and thickening of
the skin especially in fold areas such as the neckline and
axilla. This condition is directly related to the insulin
resistance, though the exact mechanism is not known.
Acanthosis nigricans: Acanthosis nigricans is a
cosmetic condition strongly associated with
insulin resistance in which there is darkening of
the skin in areas where there are creases such as
the neck and arm pits.
Skin tags: Skin tags are also seen with increased
frequency in patients with insulin resistance. A
skin tag is a common, benign condition which
consists of a bit of skin that projects from the
surrounding skin and may appear attached to the
skin. Skin tags can vary quite a bit in appearance.
They may be smooth or irregular, flesh colored or
more deeply pigmented, and either simply be
raised above the surrounding skin or have a stalk
(a peduncle) so that the skin tag hangs from the
Reproductive abnormalities in women
Reproductive abnormalities include difficulty
ovulation and conception (infertility), irregular menses, or
a cessation of menses. In contrast, there are no known
reproductive abnormalities in men with insulin resistance.
Polycystic ovary disease
Polycystic ovary disease is a hormonal problem that
affects young women. It is associated with irregular
periods or no periods at all, obesity, and increased growth
of body hair.
High male hormone levels, which are produced by the
ovaries can been seen in insulin resistance and may play a
role in PCOS described above. Why this association occurs
2 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 03, Issue 03
is not known, but it's thought that the insulin resistance
somehow causes the abnormal ovarian hormone
There may be growth affects in insulin resistance due to
the high levels of circulating insulin that may be present.
While insulin's effects on glucose metabolism may be
impaired, it's effects on other mechanisms may be intact
(or at least less impaired). Insulin is an anabolic and can
exert effects on growth, through a medicator known as
insulin- like growth factor -1. Patients may have actual
linear growth and a noticeable coarsening of features. The
increase incidence of skin tags mentioned above may be
through this mechanism as well
Who is at risk for insulin resistance?
Individuals are more likely to have or develop insulin
resistance if they:
Are overweight with a body mass index (BMI)
more than 25
Are a man with a waist more than 40 inches or a
woman with a waist more than 35 inches
Are over 40 years of age
are Latino, African American, Native American or
Have close family members with type 2 diabetes,
high blood pressure or arteriosclerosis
Have had gestational diabetes
Have high blood
components of the metabolic syndrome)
Have polycystic ovarian disease
Have acanthosis nigricans
How is insulin resistance diagnosed?[9,10]
In an effort to clinically identify patients with insulin
resistance, various organizations
diagnostic criteria. The most commonly used criteria in
the United States are those of the National Cholesterol
Education Program/Adult Treatment Panel III (NCEP/ATP
NCEP/ATP III criteria for the diagnosis of the metabolic
syndrome include the following (diagnosis is made when 3
or more are present):
Waist circumference of more than 102 cm in men
or more than 88 cm in women.
Fasting triglyceride level of 150 mg/dL or higher.
Blood pressure level of 130/85 mm Hg or higher.
High-density lipoprotein cholesterol (HDL-C)
level of less than 40 mg/dL in men or less than 50
mg/dL in women.
Fasting glucose level of 110 mg/dL or higher
(which has been changed to 100 mg/dL to reflect
revised criteria for impaired fasting glucose
The World Health Organization (WHO) criteria for the
diagnosis of the metabolic syndrome include the
Type 2 diabetes
IFG level of 101-125 mg/Dl
A.Krishna Sailaja et al. / JPBMS, 2010, 3 (10)
Impaired glucose tolerance (IGT) (glucose level of
140-199 mg/dL 2 h after administration of 75 g of
Glucose uptake level of less than the lowest
quartile for ethnic population
hyperinsulinemic, euglycemic conditions if the
fasting glucose level is normal
In addition to the aforementioned criteria, the
diagnosis must also include 2 of the following:
Use of antihypertensive medication; blood
pressure of 140 mm Hg systolic or higher, 90 mm
Hg diastolic or higher, or both.
Triglyceride level of 150 mg/dL or higher.
HDL-C level of less than 35 mg/dL in men or less
than 39 mg/dL in women.
Body mass index (BMI) of more than 30 kg/m2,
waist-to-hip ratio of more than 0.9 in men or
more than 0.85 in women, or both.
Urinary albumin excretion level of 20 mcg/min or
higher or albumin-creatinine ratio of 30 mg/g or
Insulin Resistance : A genetic Approach :
The currently available evidence from clinical family and
population based studies indicate that there are
unequivocal inherited components underlying the insulin
resistance although it greatly varies between different
ethnic groups. 45% of the first - degree relatives of
patients with type-2 diabetes are insulin resistant. Spanish
insulin resistance study group have found a strict
correlation between the amount of visceral fact estimated
by anthropometrics measurements and insulin sensitivity.
This genetic background is strongly modulated by
environmental life style related factors such as over
nutrition, poor physical activity or sedentary life style,
over consumption of saturated fat, low fiber content in the
diet, excessive alcohol intake and heavy smoking.11,12.
Figure 2: Insulin resistance: a genetic approach
3 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 03, Issue 03
How is insulin resistance managed?
Insulin resistance can be managed in two ways. First, the
need for insulin can be reduced, and second, the sensitivity
of cells to the action of insulin can be increased.
The need for insulin can be reduced by altering the diet,
particularly the carbohydrates in the diet. Carbohydrates
are absorbed into the body after they are broken up into
their component sugars. Some carbohydrates are broken
up and absorbed faster than others and are referred to as
having a high glycemic index. These carbohydrates
increase the blood glucose level more rapidly and require
the secretion of more insulin to control the level of glucose
in the blood.
Examples of carbohydrates with a high glycemic index that
rapidly raise blood glucose levels include:
Unrefined corn and potato products (for example,
bagels, mashed potatoes, doughnuts, corn chips,
and french fries).
Examples of foods with a low glycemic index include:
Foods with higher fiber content such as whole
grain breads and brown rice;
Non-starchy vegetables (for example, broccoli,
green beans, asparagus, carrots, and greens).
Since foods are rarely eaten in isolation, it can be argued
that the glycemic index of each food isn't as important as
the overall profile of the whole meal itself. Several studies
have shown that weight loss and aerobic exercise (without
weight loss) increase the rate at which glucose in the
blood is taken up by muscle cells as a result of improved
sensitivity of the cells to insulin. There are two important
studies that have looked at the prevention of type 2
diabetes. Both studies took patients who could not control
their blood glucose levels, which, for the purposes of this
discussion, can be considered the same as patients with
insulin resistance. One study done in Finland, showed that
changes in diet and exercise reduced the development of
diabetes by 58%. Another study, done in the United States
and referred to as the DPP study, showed a similar
reduction in diabetes with diet and exercise.
Metformin (Glucophage) is a medication that is used for
treating diabetes. It has two mechanisms of action that
help to control blood glucose levels. It prevents the liver
from releasing glucose into the blood, and it increases the
sensitivity of muscle and fat cells to insulin so that they
remove more glucose from the blood. Because of these
actions, metformin reduces blood insulin levels.
The DPP studied the effects of metformin in addition to
diet and exercise on the prevention of diabetes in insulin
resistance. Metformin reduced the development of
diabetes by 31%. (Note, however, that the benefit was not
as great as with diet and exercise!) Metformin is a
reasonably safe medication when used in the right
population. Although there are gastrointestinal side effects
with metformin, it usually is well-tolerated. 
Another study, the STOP NIDDM (Study to Prevent Non-
insulin Dependent Diabetes Mellitus) trial, studied
individuals with insulin resistance by treating them with a
medication called acarbose (Precose). Acarbose works in
the intestines to slow the absorption of sugars, and this
effect would reduce the need for insulin after meals. The
study found that acarbose reduced the development of
diabetes by 25%.Other medications in a class of drugs
called thiazolidinediones, for example, pioglitazone
(Actos), rosiglitazone (Avandia), also increase sensitivity
to insulin. At this time, however, these medications are not
routinely used, in part because of liver toxicity that
requires monitoring of blood liver tests.One study, the
TRIPOD (Troglitazone in Prevention of Diabetes) study,
treated patients with gestational diabetes, a precursor of
insulin resistance and diabetes, with troglitazone
(Rezulin), however, because of severe toxic liver effects;
troglitazone has been taken off the market and is no longer
available. Among the women treated with troglitazone,
diabetes was prevented in 25%.
The frequency of insulin resistance is observed to be 3% in
the general population; a several-fold increase occurs in
individuals with glucose intolerance.
Early studies indicated a more significant association
between insulin resistance and the various components of
the metabolic syndrome in white persons than in
members of other ethnic groups. However, findings have
since suggested a similar relationship in many minority
populations. However, available systematic data apply
mainly to white populations. Marked variations exist in
methodologies and diagnostic criteria. Prevalence rates of
insulin resistance syndrome
populations ranged from 3-16%; a rate of less than 2%
was reported among Japanese populations. A quarter of
the world's adults are considered to have the metabolic
syndrome. The Pima Indians living along the Gila River in
Arizona following a typical “ Westernized” life style have a
high prevalence of obesity and type -2 diabetes. By
contrast, the genetically identical pima Indians in Mexico
who retained their traditional rural life style have a low
prevalence of obesity and type-2 diabetes. Similar
1.Roger H.Under and Daniel W.Foster Diabetes Mellitus.
Williams Text book of endocrinology, Eds Wilson and
Foster.Philadelphia: W.B.Saunders Company Co. 1992, edn
8, pp 1255-1285.
resistance in non-insulin
mellitus.Non-Insulin dependent diabetes mellitus. Text
book of diabetes, Eds Wilson and Foster.Philadelphia:
W.B.Saunders company. 1997, edn 2, vol 1, PP 20.1
3.Stephen P.Wood and Rajgill. The structure and
phylogeny of insulin.Normal metabolism.Text book of
diabetes,. Eds Wilson
W.B.Saunders company. 1997, edn 2, vol 1, PP7.1
4.K.L.Manchester. General effects of insulin on nitrogen
metabolism.Insulin and protein synthesis Biochemical
action of Hormones,. Eds Geral Litwack.NewYork:
Academic press. 1970, vol 1,pp 267-268.
A.Krishna Sailaja et al. / JPBMS, 2010, 3 (10)
4 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 03, Issue 03
reported for white
observations have been reported in indigenous population
in Pacific and Indian Oceans Islands of Nauru and
Mauritius, as well as in Mexican Americans in whom the
prevalence of obesity and type-2 diabetes mellitus and
other features of MS have been examined comparatively in
rural and urban settings[15, 17]. Scientists reported that
small size at birth coupled with subsequent obesity
increases the risk for insulin resistance syndrome in later
life14. The prevalence of type-2 diabetes in low birth
children was reported to be 13-25% .In recent studies
reported from UK, low birth weight at 1 year have been
found to be associated with high prevalence of NIDDM, BP,
Serum Cholesterol in adult life, [18, 19]. Despite the
spectacular advances in the field of molecular genetics
during the past few years, we still have little
understanding of the genetic background of common
forms of type-2 DM and obesity in humans and hence of
the genes causing metabolic syndrome[20, 21]. Mutations in
the IRS-1 Protein may impair critical downstream
signaling pathways leading to impaired glucose transport
across cell membranes and impaired insulin action at
several target tissues. Polymorphisms in PPARg2 or TNFα
may impair important physiological actions such as
catecholamine-induced lipolysis, adipocyte differentiation
or insulin sensitivity at the level of adipose and other
tissues respectively. Altogether these other variant genes
may contribute to the development of type -2 DM, obesity
and Ms with different impacts according to ethnicity and
gender. Moreover environmental factors may alter the
expression of this complex genome. More research has to
be performed in order to find out the role of these
candidate genes and their contribution to type-2 DM, other
What's new in insulin resistance?
It is only in recent years that insulin resistance has been
gaining importance its own right, and as a contributor to
the metabolic syndrome. It now appears that intervention
can delay the onset of overt diabetes. Future studies will
need to be longer than the studies already done to
determine for how long treatment can prevent the
development of diabetes and its complications.
H.Barnett.Genetic factors in the pathogenesis of insulin-
dependent diabetes mellitus.Insulin dependent diabetes
mellitus, Text book of diabetes, Eds Wilson and
Foster.Philadelphia: W.B.Saunders company. 1997, edn 2,
vol 1, PP 13.1.
6.C.N.Hales . Insulin.Hormonal
diabetes.Carbohydrate Metabolism and its disorders, Eds
F.Dickens,P.J.Randle and W.J.Whelan.Newyork: Academic
press. 1968, Vol2, pp 26-28.
7.Simon L.Howell. The biosynthesis and secretion of
Insulin.Normal metabolism.Text book of diabetes,. Eds
Wilson and Foster.Philadelphia: W.B.Saunders company.
1997, edn 2, vol 1, PP 8.1.
8.Ronald T.jung. Obesity and nutritional factors in the
pathogenesis of Non- insulin dependent diabetes
mellitus.Non-insulin dependent diabetes melltus. Text
book of diabetes,. Eds Wilson and Foster.Philadelphia:
Catherine H.Mijovic and Anthony
A.Krishna Sailaja et al. / JPBMS, 2010, 3 (10) Download full-text
W.B.Saunders company. 1997, edn 2, vol 1, PP 19.1
9.Harry keen and Dannis j.Barnes. The diagnosis and
classification of diabetes mellitus and impaired glucose
tolerance.Diabetes in its historical and social context. Text
book of diabetes, Eds Wilson and Foster.Philadelphia:
W.B.Saunders company. 1997, edn 2, vol 1, PP.2.1.
10.National Diabetes Data Group. Classification and
diagnosis of diabetes mellitus and other categories of
glucose intolerance. Diabetes 1979,28, 1039-1057.
11.Hockaday TD, Yajnik CS. The thrifty phenotype
hypothesis.Diabetologia. 2003 46(2) 303-4.
12.Yajnk CS, Fall CH, Coyaji KJ, Hirve SS, Rao S, Barker DJ,
Joglekar C,Kellingray S. Neonatal anthropometry: the thin-
fat Indian baby. The pune Maternal nutrition study. Int J
Obes Relat Metab Disord 2003,27(2) 173-180.
13.Joseph Larner. Insulin and oral hypoglycemic drugs:
Glucagon. Hormones and hormone antagonists.The
pharmacological Basis of Therapeutics, Eds Goodman
Gilman, Louiss.Goodman, Alfred Gilman Newyork :
Macmillan publishing Co., INC. 1980, eds 16th, pp 1497-
14.Yajnik CS.Nutrition,growth and body size in relation to
insulin resistance and type2 diabetes. Curr Diab Rep. 2003,
15.RamachandranA,Snehalatha C, Kapur A,Vijay V,Mohan
V, Das AK, Rao PV, Yajnik CS,Prasanna kumar KM, NairJD,
diabetes epidemiology study group in India(DESI).High
prevalence of diabetes and impaired glucose tolerance in
India: National Urban Diabetes survey.Diabetologia, 2001,
5 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 03, Issue 03
16.Ravussin E,Valencia ME,Esparzaj,Bennett PH,Schulzla.
Effects oftraditional life style on obesity in Pima
Indians.Diabetes Care. 1994, 17, 1067-74.
17.Zimmet P, Taylor R, Rain P,King H. Prevalence of
diabetes and impaired glucose tolerance in biracial
population of Fiji.A rural-urban comparision.Am J
Epidemiol 1983,118, 673-88.
18.Bavdekar A,Yajnik CS, Fall CH, Bapat S,Pandit AN,
DeshpandeV, Bhave S,Kellingray
1999.Insulin resistance syndrome in 8 year old Indian
children: small at birth, big at 8 years or both?
Diabetes.1999, 48(12) 2422-9.
19.Rao S, Yajnik CS, Kanade A, Fall CH, Margetts BM,
Jackson AA, Shier R,Joshi S,Rege S,Lubree H, Desai B.Intake
of micronutrient-rich foods in rural Indian mothers is
associated with the size of their babies at birth: Pune
Maternal Nutrition Study. J Nutr 2001,131(4) 1217-24.
20.Chaoyang,Marias. Effects of low birth weight on insulin
resistance syndrome in Caucasians and African-Americans
children.Diabetes Care. 2001, 24, 2035-2042.
21.Lumey LH, Stein AD.Offspring birth weights after
maternal intrauterine under nutrition:a comparision
within sib ships. Am J Epidemiol . 1997,146, 810-819.
22.Meirhaeghe A, Fajas L, Helbecque N,etal. Agenetic
polymorphism of the peroxisome proliferator activated
receptor γ gene influences plasma leptin levels in obese
humans. Hum Mol Genet 1998, 7: 435-440.
23.Auwerx J PPAR gamma, the ultimate thrifty gene.
Diabetologia.1999, 42, 1033-1049
SD, Joglekar C