Diabetes has been considered as the most dreaded non-communicable disease consuming the mankind rapidly. WHO has predicted the number of diabetics to be approximately 366 millions by 2030. The disease is characterized by hyperglycemia and the basic symptoms are polyphagia, polydipsia and polyuria. The autoimmune type 1 diabetes represent almost 1% of the total diabetic population, the rest being that of type 2 diabetes (T2D). Type 2 diabetes has been linked to a variety of factors such as heredity, environmental factors, unhealthy eating habits, sedentary lifestyle, stress etc. The uncontrolled hyperglycemia has profound deleterious effects on almost all the organs and results in various cardiovascular disorders, retinopathy, neuropathy, and nephropathy. Recent studies have revealed an array of pulmonary dysfunctions related with T2D ranging from respiratory defects to tuberculosis. Diabetes also predisposes the person to hepatic dysfunctions like NAFLD and HCC and a range of infections at various sites which are difficult to manage. Post-surgical infections are of special interest for subjects with uncontrolled hyperglycemia prior to surgery. Scientists all over the world are revealing different pathways and associated therapies for type 2 diabetes in order to control the pathological effects covering almost whole body physiology.

1. Type 2 D
Diabetes M
mplications M
Com
ellitus: T
s and Tar
The Conc
rget Organ
cerned
ns

2. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 6 1 e1 6 6
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/apme
Review Article
Type 2 Diabetes Mellitus: The Concerned
Complications and Target Organs
Ashwini Kumar a, Sudhanshu Kumar Bharti b, Awanish Kumar c,*
a Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India
b Department of Biochemistry, Patna University, Patna 800005, Bihar, India
c Assistant Professor, Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh,
India
a r t i c l e i n f o
Article history:
Received 7 January 2014
Accepted 31 January 2014
Available online 22 February 2014
Keywords:
Diabetes
Pathology
Cardiovascular
Retinopathy
Nephropathy
a b s t r a c t
Diabetes has been considered as the most dreaded non-communicable disease consuming
the mankind rapidly. WHO has predicted the number of diabetics to be approximately 366
millions by 2030. The disease is characterized by hyperglycemia and the basic symptoms are
polyphagia, polydipsia and polyuria. The autoimmune type 1 diabetes represent almost1%of
the total diabetic population, the rest being that of type 2 diabetes (T2D). Type 2 diabetes has
been linked to a variety of factors such as heredity, environmental factors, unhealthy eating
habits, sedentary lifestyle, stress etc. The uncontrolled hyperglycemia has profound dele-terious
effects on almost all the organs and results in various cardiovascular disorders,
retinopathy, neuropathy, and nephropathy. Recent studies have revealed an array of pul-monary
dysfunctions related with T2D ranging from respiratory defects to tuberculosis.
Diabetes also predisposes the person to hepatic dysfunctions like NAFLD and HCC and a
range of infections at various sites which are difficult to manage. Post-surgical infections are
of special interest for subjects with uncontrolled hyperglycemia prior to surgery. Scientists
all over the world are revealing different pathways and associated therapies for type 2
diabetes in order to control the pathological effects covering almost whole body physiology.
Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Type 2 diabetes mellitus (T2DM) has been one of the most
widely diagnosed non-communicable diseases in adults
worldwide. The reason expands from genetic predisposition,
environmental factors, obesity, sedentary lifestyle, polycystic
ovary syndrome (PCOS), unhealthy eating habits etc. The
number of diabetic patients, as predicted by WHO would
approximately be 366 millions by the year 2030.1 The type 2
diabetes patients experience unusual polyuria (frequent
urination mainly nocturia), polydipsia (thirst) and polyphagia
(excess hunger) and weight loss as most general symptoms
apart from the hyperglycemia.2,3 The uncontrolled high blood
glucose leads to serious health complications and may even
be fatal. Diabetes has been a major risk factor for cardiovas-cular
disease and stroke and the diabetic adults have 2e4
times increased chance of such pathologies.4 Other major ef-fects
include retinopathy, nephropathy and neuropathy. The
current most effective parameter for predicting diabetes is the
measurement of glycated hemoglobin (HbA1c).4
* Corresponding author.
E-mail addresses: drawanishkr@gmail.com, awanik.bt@nitrr.ac.in (A. Kumar).
0976-0016/$ e see front matter Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2014.01.009

3. 162 a p o l l o me d i c i n e 1 1 ( 2 0 1 4 ) 1 6 1 e1 6 6
2. Pathophysiology of type 2 diabetes
mellitus
The glucose obtained from food is either immediately uti-lized
by the body or is converted to liver and muscle
glycogen (storage polysaccharide) and adipose triglyceride
(energy reservoir) by the action of insulin. Diabetes mellitus
is the condition when the body is incapable of utilizing the
glucose present in the blood for various cellular activities.
According to the Williams Textbook of Endocrinology (10th
edition), the pathophysiology of type 2 diabetes primarily
demonstrates the following three abnormalities: (i) non-responsiveness
of insulin receptors even though the body
exhibits the physiological insulin level; (ii) the body is not
manufacturing enough insulin; (iii) increased hepatic
glucose production.
A decreased insulin secretion results from impairment in
glucose response by insulin secreting b-cell of pancreas. A
mutation in glucokinase gene, which plays an important role
in glucose sensing mechanism of pancreatic beta cells, is also
an important factor of impaired glucose tolerance in pancreas.
Insulin resistance, on the other hand, is the condition when
the insulin receptors become less responsive towards insulin
even when the hormone is present in physiological amount.
This condition is attributed to many factors major being the
obesity which exerts its effect via free fatty acids and in-flammatory
cytokines (like TNF-a) which downregulate the
insulin receptor and insulin receptor substrate (IRS) protein5,6
(Fig. 1).
The diagnosis of diabetes depends on the conventional
criteria of fasting plasma glucose (FPG) and 2 h post-prandial
plasma glucose (2h-PG) where FPG 126 mg/dL (7.0 mmol/L)
and 2h-PG 200 mg/dL (11.1 mmol/L). The latest addition to
the diabetes diagnosis has been the calculation of glycated
hemoglobin (HbA1c) which has been treated as better criterion
than the former two as it estimates an average hyperglycemia
over several months with International Diabetes Federation
(IDF) declared this in 2009 and American Diabetes Association
(ADA) adopted in 2010. The cut-off for HbA1c has been 6.5%.7
3. Diabetes related complications
According to the American Diabetes Association, a diabetes
patient, as compared with the normal non-diabetic one, has
approximately 7 year shorter life span resulting from various
diabetic related complications.7 Some of the major compli-cations
include coronary artery disease, stroke, peripheral
vascular disorders, nephropathy, neuropathy and diabetic
retinopathy. People having diabetes have greater risk of
acquiring cancer, cardiovascular complications and renal
failure because of their susceptibility towards the diseases7
(Fig. 2).
3.1. Cardiovascular disorders
Uncontrolled hyperglycemia results in non-enzymatic
glucose (aldose sugar) attachment (glycation) on the physio-logical
proteins and lipids which disrupts their normal func-tion
and increases the related pathology. These altered
products are known as advanced glycated end-products
(AGEs) and the reaction involving the formation is known as
Maillard reaction. The AGE receptors, known as RAGE
belonging to immunoglobulin superfamily, have been shown
to influence the cellular signaling on binding with AGEs.
Cross-linking of AGEs with type I collagen and elastin in vessel
wall leads to vasculature stiffness. Studies suggest that lipid
AGEs like glycated LDL reduces the nitric oxide (NO) produc-tion
which is a vasodilator and suppresses LDL receptor
mediated LDL uptake by endothelial cells. The suppression of
NO production from endothelial cells due to action of AGEs in
diabetic patients can be an important factor promoting the
atherosclerosis since NO show a range of anti-atherogenic
actions like inhibition of platelet adhesion and aggregation,
leukocyte adhesion to vessel walls etc.8,9
The vascular conditions arising from AGEs namely arterial
stiffness and platelets adhesion aggregation can lead to
stroke, myocardial infarction, cardiac failure and overall
Fig. 1 e Physiological action of insulin on liver, muscles
and adipocytes.
Fig. 2 e Major pathological conditions associated with
diabetes type 2.

4. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 6 1 e1 6 6 163
mortality. Myocardial stiffness due to extracellular matrix
collagen e AGEs cross-linking in myocardium may lead to left
ventricular hypertrophy (LVH) and pressure overload. The
suppression of LDL receptor mediated LDL uptake can pose a
significant risk of atherosclerosis leading to hindered blood
flow in major coronary arteries. The pathological results
begin with hypertension, ischemia, infarction and cardiac
attack. Untreated diabetes, thus, pose a critical risk towards
cardiovascular disorders.10e12 Studies done in India by Madras
Diabetic Research Foundation and Indian Diabetic Research
Foundation independently found that Indians, especially
south Indians, are at high risk of developing insulin resis-tance,
diabetes and related cardiovascular conditions. The
major risk factors observed in study involving children and
adolescent subjects were low high density lipoprotein (low
HDL) and high triglyceride level and increased risk of meta-bolic
syndrome.13e15 Diabetic cardiomyopathy is defined as
myocardial dysfunction seen in subjects with diabetes in
absence of CAD, hypertension and valve defects. The devel-opment
of diabetic cardiomyopathy has been attributed to
various factors namely metabolic disturbances, insulin resis-tance,
hyperlipidemia, cardiac autonomic dysfunction etc.
Hyperglycemia, hyperinsulinemia and elevated FFA are the
major factors leading to cardiac steatosis. Brain natriuretic
peptide (BNP) is a biomolecule released from ventricles and
found elevated in patients with heart failure. The gene
expression of BNP was found to be increased in animal models
of insulin resistance and hyperinsulinemia along with other
markers such as left ventricular hypertrophy (LVH).16
3.2. Diabetic retinopathy
Diabetic retinopathy (DR) is the microvascular damage to the
retina because of prolonged hyperglycemia. This kind of
retinal damage is irreversible and has been a major cause of
blindness in young working population. The disease is char-acterized
by alteration in retinal vasculature and damage to
ocular nerves. Study on mice model has revealed a difference
in proteome of diabetic, non-diabetic and metformin treated
mice and found that many of these proteins were involved in
synaptic transmission. The excitatory neurotransmitter
glutamate is loaded in synaptic vesicles by the major trans-porter
VGLUT1 and is expressed in photoreceptors. The study
has shown a decreased expression of VGLUT1 in diabetic mice
retina and was not normalized even after metformin treat-ment.
17 Recent finding has shown that phospholipase A2
(PLA2) is upregulated early in glucose induced alteration of
retinal layer. PLA2, VEGF and COX-2 expression level were
found to be significantly increased in retinal microvessels of
diabetic rat model.18 A study conducted by Diabetic Research
Centre India on one thousand patients in 1996 revealed that
retinopathy increased linearly with progressing diabetes.19 In
a study done by Madras Diabetic Research Foundation India,
the diabetic retinopathy was found to be associated with
increased thickness of intima-media and arterial stiffness in
ocular vessels and that DR begin to develop years before the
diagnosis if the hyperglycemia remains untreated for as long
as 3e4 years.20 In another study, it was found that retinal hard
exudates and macular edema were seen in case of DR and it
was positively correlated with dyslipidemia (higher
cholesterol and LDL) in patients, but it was not the only risk
factor for DR.21
3.3. Diabetic nephropathy
Renal disorder and eventual renal failure is the major organ
targeted by hyperglycemia after cardiovascular system. Glo-merulosclerosis
induced renal pathology in uncontrolled
diabetes include increased thickness of basement membrane,
diffuse mesangial sclerosis with nodule formation, micro-aneurysm,
hyaline arteriosclerosis which result in micro-albuminuria,
followed by macroalbuminuria proceeding to
loss of glomerular filtration rate (GFR) and probable end stage
renal failure. A study conducted on diabetic patients in USA
demonstrated that the patients had increased urine albumin
secretion and high systolic pressure as compared to non-diabetic
subjects. Currently, almost half of the individuals
with renal disease attempting to go for renal replacement
therapy in USA are type 2 diabetic.22 An Indian study from
2009 to 2011 demonstrated that microalbuminuria was
elevated in population with uncontrolled hyperglycemia and
even led to increased serum creatinine level indicating a renal
damage with high significance (p 0.0001).23 Persistent pro-teinuria
and albuminuria also lead to renal tubule dysfunction
due to epithelial damage by continuous passage of plasma
protein. This condition results in tubulointerstitial fibrosis
followed by irreversible kidney damage. Serum cystatin C, a
protease inhibitor, is completely filtered through glomerulus
and almost completely catabolized by the tubular epithelium.
A study on 70 diabetic and 20 control subjects in 2013
demonstrated that serum cystatin C level was significantly
elevated in diabetic patients as compared to control popula-tion
and was positively correlated with urine albumin and
creatinine secretion.24 Diabetic nephropathy is also charac-terized,
at molecular level, by the excessive deposition of the
proteins of extracellular matrix (ECM) in basement membrane
and mesangium of the basement membrane and renal tubu-lointerstitium
due to increased production of reactive oxygen
species (ROS) and increased expression of TGF-b while a
decreased expression of matrix metalloproteinases (MMP).
This is followed by an increase in thickness of glomerular
basement membrane. Physiological changes include glomer-ulosclerosis
and tubulointerstitial fibrosis too. Biochemical
changes thus follows are decreased creatinine clearance and
microalbuminuria.25
3.4. Pulmonary defects
Despite the fact that pulmonary functions are neglected in
diabetic patients, they have been found to encounter various
respiratory problems. The most common problem associated
has been the deposition of non-enzymatically glycosylated
collagen in the lung parenchyma and chest walls increasing
the stiffness of lungs thus reducing its expansion. The lung
muscle strength also decreases based on neuropathic changes
affecting respiratory muscles. Obesity has been related to
increased leptin level and T2D (insulin resistance) and high
leptin in obese-diabetic subjects has been significantly asso-ciated
with ailments such as obstructive sleep apnea, asthma,
chronic obstructive pulmonary disorder (COPD) and lung

5. 164 a p o l l o me d i c i n e 1 1 ( 2 0 1 4 ) 1 6 1 e1 6 6
Table 1 e Type 2 diabetes related complications, markers and related pathology.
Diabetes related complications Diagnostic markers Related pathology References
Cardiovascular disorders Hypertriglyceridemia,
cancer.26 It has been reported that diabetic subjects with poor
glycemic control have lower forced expiratory volume in 1 s
(FEV1) and forced vital capacity as compared to the normal
subjects.26 The histo-pathological examination of lungs of
diabetic subjects has evidence of thickened alveolar, epithelial
and capillary basal lamina. Pulmonary vascular damage has
been related to diabetic microangiopathy.26 Indian scientists
have also found a negative correlation between lung function
and glycemia with reduction of FEV1 and forced vital capacity
(FVC) in a study involving forty diabetic patients.27,28 Another
Indian study involving sixty type 2 diabetic and sixty control
individuals exhibited the reduction in all pulmonary param-eters
in diabetic individuals as compared to the control ones29
(Table 1).
3.5. Diabetic neuropathy
Diabetic peripheral neuropathy (DPN) is one of the major ef-fects
of uncontrolled hyperglycemia affecting almost 50% of
diabetic patients not receiving proper diagnosis and treat-ments.
It can be seen as distal, symmetric and sensorimotor
neuropathy. Around 30% of the patients exhibit painful neu-ropathy
while the rest experience numbness and loss of
sensation. The disease is clinically determined by poor gait
and balance (with large sensory fibers) and abnormal heat and
cold sensation (with small sensory fibers). Patients also
complain of chronic pain and very often perceived symptoms
are tingling, itching and “pin needle poking sensation”,
walking on hot coal, bee stinging etc. The chronic pain expe-rienced
can be described as hyperesthesias (increased sensi-tivity
to touch), allodynia (pain from normal stimuli) and
hyperalgesia (increased sensitivity to painful stimuli). The
advanced stage affects the limbs and commonly leads to
diabetic foot (foot ulceration). International Association for
the Study of Pain has defined the diabetic neuropathic pain as
“a pain arising as a direct consequence of abnormalities in
peripheral somatosensory system in people with dia-betes”.
30,31 A recent study conducted on DPN patients and
control subjects has shown a positive correlation between
serum TNF-a and DPN.32
Diabetic foot infection (DFI) is the most common result of
peripheral neuropathy, starting with a neuropathic ulcera-tion.
Vascular insufficiency and diminished neutrophil func-tion
augment the DPN resulting in infection. Most DFIs are
associated with aerobic gram-positive cocci especially staph-ylococci
and aerobic gram negative bacilli as common co-pathogens.
37 The most common organisms colonizing the
infected area are Staphylococcus aureus and beta-hemolyzing
streptococci. Apart from the above stated, Escherichia coli,
Klebsiella and Methicillin Resistant Staphylococcus aureus
(MRSA) are common inhabitant.33
3.6. Hepatic dysfunction
Type 2 diabetes has begun to be recognized as an important
factor for the development of non-alcohol fatty liver disease
(NAFLD) and chronic liver diseases. Nonalcoholic steatohe-patitis
(NASH), the most severe form of NAFLD, is a chronic
necro-inflammatory condition resulting in fibrosis, cirrhosis
and finally to hepatocellular carcinoma (HCC). In a large
cohort study it was found that T2DM doubled the risk of
NAFLD and HCC.34 Insulin resistance increases peripheral
lipolysis leading to accumulation of free fatty acids in liver
resulting in NAFLD.34 In another human cohort study con-ducted
between 1994 and 2006, it was concluded that subjects
with diabetes had higher risk of developing serious hepatic
disorder compared to control subjects. Diabetes was found to
pose a greater risk than hypertension, dyslipidemia and
obesity.35,38 A vast medline literature study has revealed an
elevation of liver enzyme alanine aminotransferase (ALT) very
commonly in T2DM patients while uncommon in normal
subjects. The survey shows a high incidence of development
of liver diseases in patients with type 2 diabetes.36
3.7. Other complications
3.7.1. Post-surgical infection
Type 2 diabetes mellitus is also considered a major risk factor
for surgical site infections (SSI). In a review case study of 195
selected patients who underwent spinal arthrodesis, 30 were
hypercholesterolemia,
circulating rAGE.
Arterial stiffness, atherosclerosis,
LVH, hypertension etc.
8,9,11,12
Diabetic retinopathy Increased PLA2, VEGF,
COX-2, macular edema,
retinal exudate.
Ocular arterial stiffness,
permanent blindness.
17,18,21
Diabetic nephropathy High glycated albumin, increased
serum cystatin C, high serum
creatinine, low GFR.
Glomerulosclerosis, end
stage renal disease.
22e25
Pulmonary defects Reduction in PFTs, elasticity,
parenchymal aberrations etc.
COPD, obstructive sleep
apnea, lung cancer.
26e29
Diabetic neuropathy Reduction in serum TNF-a. Pain, numbness,
hyperesthesia, allodynia,
hyperalgesia, severe lower
limb infections.
30e33
Hepatic dysfunction Lipid accumulation in hepatocytes,
elevated liver enzymes.
NAFLD, cirrhosis, HCC. 34e36

6. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 6 1 e1 6 6 165
diabetic and the rest non-diabetic. The review of the case re-cord
found that 30% of diabetic subjects developed SSI while it
was only 11% for non-diabetic subjects with the similar
arthrodesis, thus providing evidence that T2DM elevates the
risk of SSI with spinal surgeries.39 A recent published study
also supports the finding that uncontrolled blood glucose
before surgery increased the risk of SSI.40
3.7.2. Genito-urinary infections
Diabetes mellitus type 2 has been a well-known risk factor for
vulvovaginitis in females and balanitis in males, the most
common urinary tract infections (UTI) reported. Hyperglyce-mia
and glycosuria, the two most common symptoms of T2D
represent the favorable factors for the growth of Candida
albicans at vaginal epithelium, since hyperglycemia may
interfere with normal host-defence mechanism and also
helps the growth of the pathogenic candida.41,42 In one of the
study conducted in UK using the General Practice Research
Database (GPRD), it was concluded that T2D increases the risk
of UTI by 60% as compared to the non-diabetic subjects. It was
also concluded from one of the database survey that T2D
increased the risk of vulvovaginitis by 2 folds and balanitis by
3 folds.43,44 Type 2 diabetes mellitus also predisposes females
with a rare fungal infection of mucormycosis in pouch of
douglas, as reported recently for a patient in Kolkata, India.45
3.7.3. Tuberculosis
In a recent large population based cohort study, it was found
that type 2 diabetes significantly increased risk of develop-ment
of tuberculosis (TB). Diabetes also increased the risk of
relapse of the disease after successful completion of treat-ments
for TB and also high bacillary load in sputum. The study
was significant for the young diabetics.46 Diabetes patients are
shown to have lower circulating neutrophils and activated
macrophages and there was a negative correlation found be-tween
the increased HbA1c and phagocytic activity and that
the controlled glucose level improved the phagocytic activ-ity.
47 In another meta-analysis based review covering
research articles based on association of T2DM and TB, it was
observed that diabetes led to a 3-fold increase in the risk of
developing active TB.48 This study too emphasized on the
higher risk in young subjects. The study also pointed to the
observations that diabetic mice infected with Mycobacterium
Tuberculosis had higher bacterial load than the control pop-ulations.
The diabetic mice had low levels of IFN-g and IL-12
and Th1 responsiveness towards TB which play a crucial
role in controlling TB. In humans too, hyperinsulinemia
resulted in a decrease in Th1 cell and reduction in essential
protective cytokines too. It also pointed that level of HbA1c
and IFN-g had a negative correlation.48
4. Summary
Diabetes is one of the very few diseases adversely affecting
almost all the organs. This review has focused on various
complications arising from type 2 diabetes primarily empha-sizing
on cardiovascular diseases, neuropathy, retinopathy,
pulmonary defects. Diabetes can be said to be a syndrome
which exhibits various different organ-related dysfunctions.
Organ dysfunction significantly affects the quality of life and
has been the major cause of diabetic morbidity. Diabetic
subjects are also susceptible to various serious and different
infections which respond poorly to the available antibiotic
treatments. Post-surgical infections have been amajor feature
of uncontrolled blood glucose prior to surgical procedure. The
number of diabetes patients projected by WHO and CDC
should be considered a serious event. Lifestyle modifications
can result in a significant reduction in the incidence of
diabetes.
Conflicts of interest
All authors have none to declare.
Acknowledgments
Authors are thankful to Department of Biotechnology, Na-tional
Institute of Technology (NIT), Raipur (CG), India and
Department of Biochemistry, Patna University, Patna, Bihar,
India for providing facility, space and resources for this work.
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