Diabetes mellitus (DM) is a metabolic disorder of multiple

Diabetes mellitus (DM) is a metabolic disorder of
multiple etiologies characterized by Chronic hyperglycemia with disturbances of
carbohydrate, fat and protein metabolism, resulting from defects in insulin
secretion, insulin action, or both (1).
The vast majority of cases of diabetes fall into two broad categories: type 1
and 2 diabetes. Type 2 diabetes, which accounts for ?90–95% of those with
diabetes, encompasses individuals who have insulin resistance and usually have
relative (rather than absolute) insulin deficiency (1, 2).Type1diabetes is characterized by an absolute deficiency of
insulin secretion caused by pancreatic ?- cell destruction, usually resulting
from an autoimmune attack. It accounts for approximately 10% of all cases (3).

of both type 1 and type 2 DM (T2DM) is increasing worldwide. T2DM is rising
much more rapidly, presumably because of increasing obesity, reduced activity
levels as countries become more industrialized, and the aging of the population
(4). According to International
Diabetics Federation( IDF) DM Atlas 2015 report, more than 75% of people with DM
live in low and middle income countries (5). In Africa region DM is expected to the highest increase
in the future time. It also reported
regional prevalence of 3.8% of DM and rise to 4.3% in 2030 (6).

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Risk factors for
DM  include older age, obesity, and
family history of DM, prior history of gestational DM, impaired glucose
tolerance, physical inactivity, and race/ethnicity (7).  Recently
there are also intestinal micro biotas that can be one of the risk factors for
the development of DM. The human gut micro biota is a complex ecosystem, which
is now known as a key component in gastrointestinal tract (GIT) homeostasis.
Its involvement in immune diseases has recently been demonstrated and bacterial
imbalance (dysbiosis) has been associated with pathologies such as inflammatory
bowel disease and obesity (8-10).

Evidence reveals that the gut micro
biota plays a critical role in the development of obesity, T2DM, and insulin
resistance (11-13). The total number of bacteria in the
gut is estimated at; ?1014, it has been proposed that the genome
size of this exteriorized organ largely exceeds the human genome size (14, 15).


The gut micro biota plays an
important role in the development of pre diabetes conditions, such as insulin
resistance. Studies suggested that obese people with insulin resistance were
characterized by an altered composition of gut micro biota, particularly an
elevated Firmicutes/Bacteroidetes ratio compared with healthy
people (16, 17).


T2DM patients showed an
altered intestinal micro biota which is characterized by a decrease of Bacteroidetes/Firmicutes
ratio and some functional bacteria (e.g. Bifidobacteria) with an
increase of various opportunistic pathogens and some endotoxins-producing Gram negative
bacteria (18-20) that
modify the host energy metabolism through a specific polysaccharide utilization
loci mechanism (20).
Moreover, the accumulation of gut-derived bacterial
inflammatory molecules (e.g. LPS, peptidoglycans and flagellin) in intestine is
thought to accelerate the inflammation in T2DM (21, 22).


Each human intestine harbors
not only hundreds of trillions of bacteria, but also bacteriophage particles,
viruses, fungi and archaea, which constitute a complex and dynamic ecosystem
with which we live in symbiosis throughout our lifetime (23). Host genetics is thought to contribute to the profile of the
gut micro biome, all living conditions, including dietary habits, exposure to xenobiotic
(such as drugs, toxicants and additives) or stresses (such as surgery and
infections) will modulate the gut micro biota, occasionally for a limited
period of time due to the resilience of this ecosystem (24). Therefore, T2DM, a complex disease that is often associated
with obesity, develops via the interaction between genetic and environmental
factors. So, gut micro biota represents an environmental factor of T2DM that
was neglected in the past due to the complexity of its analysis (25) and to the lack of an understanding of the mechanisms
underlying the interactions between gut microbes and host metabolism.


The gut micro biota is now considered a
separate organ that is involved in the regulation of numerous physiological
path-ways by impacting different functions of the host (26).
Among these regulatory actions, the influence of gut microbes on energy
metabolism is of particular interest, as it has been proposed to be a driving
force in the pathogenesis of metabolic diseases, especially obesity. Intestinal
microbes have developed a mutually beneficial relationship with their host, and
can influence physiological systems by modulating gut motility, intestinal
barrier homoeostasis, nutrient absorption and fat distribution (27-29). Therefore micro biotas are
important microorganisms not only monitors the body homeostasis but also for
the driving force in the pathogenesis of metabolic disease. So, studding about
gut micro biota for the contribution of T2DM is vital and current issue for the
therapeutic development of T2DM to know about the full mechanism of actions of micro
biotas for the development of T2DM.

 Gut micro biota

Microorganisms in the GIT are together
referred to as the gut micro biota. In mammalians, the gut micro biota mainly encompasses
of four main phyla: Actinobacteria, Bacteroidetes, Firmicutes and
Proteobacteria. These phyla are vital in the host metabolism and physiology
regulation (15).
During early childhood, Actinobacteria and particularly of the genus Bifidobacterium,
dominate the gut micro biota of breastfed infants. Then the micro biota
acquires a variety of new strains influenced by changes in diet and by disease
then it begins to resemble the adult composition (30).
In addition of these factors  physical
exercise is also able to modulate gut micro biota, i.e. increasing physical
activity can increase the abundance of beneficial microbial species (31).

Figure.1. Factors influencing gut micro
biota composition and its structural, protective and metabolic functions.


The gastrointestinal
system represents one of the largest interfaces between the human internal
microenvironment and the external world. This system harbors trillions of
commensal bacteria that reside in symbiosis with the host. Intestinal bacteria
play a crucial role in maintaining systemic and intestinal immune and metabolic
homeostasis because of their effect on nutrient absorption and immune
development and function. Recently, altered gut bacterial composition
(dysbiosis) was hypothesized to be involved in mechanisms through which islet
autoimmunity is triggered (32). The composition of gut microbial
communities vary along the gastrointestinal tract between individuals as the
dietary lifestyle and nutritional status of the individual varies (33).


Apart from digestion, the gut micro
biota is important in up keeping the optimal state of host health, but it is
also implicated in the pathogenesis of numerous metabolic diseases, such as
obesity (34, 35), diabetes (20, 36), chronic kidney disease (37, 38) and atherosclerosis (39-41) and intestinal diseases (42),
such as inflammatory bowel diseases (43)
and colorectal cancer (44, 45).


GIT micro biome acts as an endocrine
organ that translates nutritional cues into hormone-like signals to control
host physiology and diseases. Currently, there have been several scientific
reports that link the GIT micro biome with systemic diseases including obesity,
diabetes, hepatopathy, rheumatoid arthritis, cancer, and cardiovascular
diseases (46-49). 


Hosts and their micro biomes develop
symbiotic relationships through interactive evolutionary processes that
mutually benefit both. In a broader sense, the resident symbionts regulate host
metabolism in multiple ways, integrating physiological homeostasis,
immune-inflammatory signaling, and energy compliance. Carbohydrates are the
primary sources of energy for both the human host and their microbes (50).

Pathophysiology of micro biotas on

During the past decade there
has been increasing focus on gut micro biota as an influential factor on
inflammatory disease development in both humans and animals (51, 52). The GIT micro biome interacts with host
nutrition, the environment, and host genetics for the development of
obesity-related metabolic disorders. Various studies have reported that GIT
microbial dysbiosis enhances energy harvest and expression of obese phenotype. A
change in the Bacteroidetes/Firmicutes ratio is associated with higher
expression of microbial genes that encode enzymes related to carbohydrate
metabolism. The micro biomes of obese persons differ from those of lean
individuals and are characterized by a lower prevalence of phylum Bacteroidetes
and a higher prevalence of phylum Firmicutes (53).
Micro biome of the gut activated changes in intestine tight junction proteins
and alkaline phosphatase activity in the gut environment that may increase gut
permeability and lead to the pathogenesis of insulin resistance (28).


In addition gut bacteria induces the
inflammatory state of obesity via the activity of lipopolysaccharide (LPS), an element
of the gram-negative bacterial cell walls, which can trigger the inflammatory
process by binding to the CD14 toll-like receptor- 4 (TLR-4) complex at the surface
of innate immune cells. LPS is a ligand of the TLR-4 (54).
The importance of the TLR-4 pathways for metabolic disease was confirmed by the
finding that the deletion of TLR-4 prevented the high fat diet induced insulin
resistance (55).


Once Bacteroidetes/Firmicutes ratio portrays an
environmental factor that provides genetic material for increased capacity to
harvest energy from the diet (56).  The higher energy harvest promotes
lipogenesis and increases the number and size of lipid droplets in the extra
intestinal tissues. Most patients suffering from this metabolic syndrome have
excessive fat accumulation which suggests that the dyslipidemia is an important
etiological factor of the syndrome (57).
















Figure 2: Change in the micro biome
fermentation profile changes gut permeability and energy homeostasis which
causes endotoxemia, low-grade inflammation, and obesity. Poor energy
homeostasis leads to hyperglycemia and hyperlipidemia which may lead to obesity
and ultimately insulin resistance (58).
(NB: – SCFSs (Short Chain Fatty Acids also called Volatile Fatty Acids (VFA))


It was reported that T2DM in humans was
co-related to a lowered abundance of butyrate-producing microbes and an
increased abundance of Lactobacillus sp. (20, 36).



Figure 3: A schematic diagram describing
the role of the gastrointestinal tract micro biome in the development of the
metabolic syndrome that leads to diabetes mellitus pathogenesis. Microbial
dysbiosis impairs intestinal wall integrity and allows translocation of toxins
from the gut lumen to the systemic circulation. This endotoxemia leads to low-grade
inflammation, autoimmunity, and oxidative stress that may lead to beta cell
destruction or insulin resistance (58).

Complications of micro biotas on type 2

in the composition of the micro biota has been shown to be strongly related to
the incidence of inflammatory diseases, supporting a key role of a commensal micro
biota in host homeostasis (59). So, the disruption of the normal
physiology of micro biotas in the gut leads to different complications.

 Diabetic retinopathy

is a medical condition in which damage occurs to the retina
due to diabetes mellitus and is a leading cause of blindness
(60). Diabetic
retinopathy accounts for more than 60% incidence in T2DM (61). As expected, a higher frequency Of Gram-positive
bacteria and a higher proportion of coagulase negative staphylococci was
detected in diabetic patients, especially those with retinopathy (62, 63).
Diabetic retinopathy is caused by prolonged high blood glucose
levels that  can weaken and
damage the small blood vessels within the retina. This may cause hemorrhages,
exudates and even swelling of the retina that leads starves the retina of
oxygen, and abnormal vessels may grow (64).

Renal toxicity and kidney stones

is the leading cause of kidney disease. About 1 out of 4 adults with diabetes
has kidney disease (65). Kidney stone disease is a polygenic and multifactorial
disorder with a worldwide distribution, and its incidence and prevalence are
increasing (66). Kidney stones are the products of a pathological bio mineralization
process in the urinary system (67). High blood sugar can damage the blood vessels
in your kidneys. When the blood vessels are damaged, they don’t work as well.
Many people with diabetes also develop high blood pressure,
which can also damage the kidneys (65).


Diabetes mellitus and hypertension
are interrelated disorders, each powerfully predisposing to the development of
the other and to the future occurrence of cardiovascular disease (CVD) (68, 69). Both are considered risk factors for cardiovascular disease
and micro vascular complications and therefore treatment of both conditions is
essential. Hypertension is twice more common in diabetics than in non-diabetics
(70) and the threshold for treatment is persistent BP
values ?140/90 mmHg. As both hypertension and DM are highly
associated with obesity, it is not surprising that their co-existence is
particularly common in obese individuals (71).


Type 2 diabetes mellitus is associated
with a marked increase in the risk of atherosclerotic diseases, including
coronary heart disease, peripheral arterial disease, and cerebrovascular
disease (72).
Ongoing stress to the endothelium, through chronic inflammation, dyslipidemia,
hypertension, and other factors, ultimately results in the formation of the
early atherosclerotic lesions known as fatty streaks. Internalization of
oxidized LDL by leukocytes promotes accumulation of cholesterol esters within
the macrophages and the formation of foam cells. The continuing recruitment of
leukocytes and migration of smooth muscle cells into the intima leads to the
development of a mature fibrous atherosclerotic plaque which finally induces
death (73).  Even though we are tried to discuss the very
few types of T2DM complications there are also other complications that can be
occurred during the development of T2DM. From these complications which are not
listed from the above Cystic fibrosis,
Diabetic foot ulcers, Alzheimer’s disease are the dominant ones.

Therapeutic alternatives of gut micro
biota on diabetic patients

Metformin is the commonly used
medication for monitoring hyperglycemia in T2DM patients. The exact mode of
action of metformin is not well known, however it has been shown that the drug
improves gut microbial diversity, metalo proteins encoding gene expression in
gut bacterial species, and glycemic index (74).


Metformin enters hepatocytes via the
organic cation transporter-1 (OCT-1) transporter, to alter mitochondrial
function and AMP kinase (AMPK) activity (75)
resulting in decreased hepatic glucose production and glucose lowering, while
AMPK stimulation in skeletal muscle may increase glucose utilization (76).
In addition, metformin improves the lipid profile (77),
restores ovarian function in polycystic ovary syndrome (78),
reduces fatty infiltration of the liver (79)
and lowers micro vascular and macro vascular complications associated with T2DM.
Recently, metformin has been
proposed as an adjuvant treatment for cancer (80), as a treatment for gestational diabetes and for
the prevention of T2DM in pre-diabetic individuals (81).


Bariatric surgery significantly changes
the composition and diversity of the gut micro biota in humans, rats and mice (82-84). Adjustment of microbial dysbiosis
by supplementation with prebiotics, improved bifidobacterium abundance which is
significantly and positively correlated with improved glucose tolerance and
inflammation in prebiotic treated mice (85).


Therefore rehabilitation of
our intestinal micro biota by the mean of pre- or pro-biotic is the one way
treatment alternative for T2DM patients. With regard to prebiotic there is now
much interest in manipulation of the microbiota composition in order to improve
the potentially beneficial aspects. The prebiotic approach dictates that
non-viable food components are specifically fermented in the colon by
indigenous bacteria thought to be of positive value, e.g., bifidobacteria,
lactobacilli (86, 87).


There are researches and reviews based
on the contribution of gut microbiotas for T2DM and their complications.  A review conducted on this issue describes genetics;
ethnic origin, obesity, age, and lifestyle are considered as few of many
contributory factors for the disease pathogenesis. And now a day’s disease
progression is particularly linked with functional and taxonomic alterations in
the GIT microbiome (58).
These findings are supported by
other researches by explaining it’s becoming increasingly evident that
gut micro biota is contributing to many human diseases including diabetes both
type 1 and type 2 (88).


In other
literature review performed discuses on dysbiosis
is associated with endotoxemia and chronic inflammation, with disruption of the
intestinal barrier and depletion of beneficial bacteria producing SCFAs (89). Other literatures describes the gut
micobiota for the treatment purpose through the administration of prebiotics or
probiotics may assist in weight loss and reduce plasma glucose and serum lipid
levels, decreasing the incidence of cardiovascular diseases and type 2 diabetes
mellitus (90).


Researches and literature reviews are
agree with this idea for the rehabilitation of gut micro biotas by describing
in the way that specific probiotics, prebiotics and
related metabolites might exert beneficial effects on lipid and glucose
metabolism and the inflammatory tone related to obesity and associated
metabolic disorders (91).


Bariatric surgery was initially designed
to achieve weight loss, and subsequently was noted to induce improvements or
remission of type 2 diabetes. Currently, these bariatric operations, such as
Roux-en-Y gastric bypass and sleeve gastrostomy, are the most effective
procedures for the treatment of obesity and type 2 diabetes mellitus worldwide (92).