A COMPREHENSIVE REVIEW ON MANAGEMENT OF TYPE 2 DIABETES THROUGH PROBIOTICS

In the recent time, people are often biased to decide an appropriate medicine to recover a chronic disease. This critical biasness is occurred due to use of some commercial drugs, which have prominent side effects. Probiotics is a promising approach for the upcoming eras. Probiotics are the live microbial food additives which give health beneficiary effects beyond basic nutrition upon consumption in adequate amount. In the recent time, consumption of probiotics based foods are increased and probiotics based foods like yoghurt is one of the best stratagies to overcome diabetes. Yoghurt is a potential source of probiotic lactobacilli. Dahi is a home made variant of yogurt. Dahi has been considered as a functional food due to its several health benefits i.e. antidiabetic, antidiarreal, anticarcinogenic, cholesterol lowering and antiatherogenic properties. In this review management of type 2 diabetes through probiotics are critically discussed.

Probiotics are the live microbial food additives which give health benefiary effects beyond basic nutrition upon consumption in adequate amount (FAO/WHO, 2001). The effect of probiotic benefits have been investigated for improving immune function, lowering blood pressure, and improving lipids. There are different strains of lactic acid bacteria (LAB), such as Lactobacillus and Bifidobacterium are considered as important probiotics regimens. Fermented dairy products such as yogurt, containing adequate probiotic LAB, are well established for several health benefits (Reid et al., 2005).
There are several reports available which suggest the antidiabetic effect of LAB (Lactic acid bacteria). Administration of Lactobacillus casei by orally has a preventive effect on promotion of plasma glucose and depletion of plasma insulin levels by preventing immune mediated destruction of pancreatic b-cells in NOD and KK-Ay mice (Matsuzaki et al., 1997a, b & c). Oral administration of dahi containing Lactobacillus acidophilus & Lactobacillus casei detained the succession of streptozotocin induced diabetes in rats (15 gm/day/rat) for 28 days .
Several research reflects that diabetic patients have altered gut microbiota compared to non-diabetic counterparts and gut microbiota are involved in the occurrence of diabetes and metabolic disorders. So therefore gut microbiota of type 2 diabetic person would be changed by using probiotics and it's a recent field of interest to the researchers. Human clinical trials of probiotic capsules or yoghurt was conducted and yielded mixed results. Some studies indicate that probiotic yogurt ingestion for 6 weeks can significantly improve blood glucose level. (Ruan et al ., 2015). From this point of view, management of type 2 diabetes through probiotics are reviewed.

Definition of probiotics:
The term probiotic is come from the Greek language defining -for life‖but the meaning of probiotics has evolved over time concurrently with the expanding interest in the use of live bacterial supplements and in relation to the progress made in understanding their mechanisms of action. Here the term was used to describe the stimulation of the growth of others microorganisms by substances produced by one microorganism and was later used to describe tissue extracts that stimulated microbial growth and animal feed supplements applying a beneficial effect on animals by contributing to their intestinal flora balance (Fuller et al .,1999). More updated definition of probiotics is -probiotics are live microbial feed supplements which beneficially affect the host animal by improving microbial balance‖ (Fuller et al .,1989). According to FAO, probiotics is defined as -live microorganisms which when administered in adequate amounts confer a health benefit on the host‖. (FAO/WHO, 2001).

Characteristics of probiotics:
Probiotics is well characterized by their capability to survive for an unspecified time period in the upper digestive tract and to colonize in the intestinal lumen and colon. It is reported that functional foods containing probiotics are safe for the consumers and already no hazardous reports have found or production of any particular toxins by these strains (Von et al .,2000&Salminen et al ., 1998. It is also reported that antimicrobial substances like bacteriocins are produced by some probiotics. Temporarily the rate of mitosis in enterocytes is increased by some probiotic strains and they can reduce intestinal transit time, improve the quality of migrating motor complexes (Husebye et al .,2001). Lactobacillus and Bifidobacterium are the most common probiotics and in general most the probiotics are gram-positive, usually catalase-negative, rods with rounded ends, and occur in pairs, short, or long chains,nonflagellated, non-motile and non-spore-forming, and are intolerant to salt, optimum growth temperature is 37°C but 278 some strains such as L. casei prefer 30 °C and optimum pH for initial growth is 6.5-7.0(Von et al .,2000).L. acidophilusis microaerophilic,anaerobic and they have capability of aerobic growth. Bifidobacteriumare also anaerobic but some species are aero-tolerant. In according to probiotics fermentation capacity, they are either obligate homofermentative (L. acidophilus, L. helvelicas), obligate heterofermentative (L. brevis, L. reuteri), or facultative heterofermentative (L. casei, L.plantarum) (Barrangou et al., 2011). Various beneficial compounds are secreted by probiotics such as antimicrobials, lactic acid, hydrogen peroxide, and a variety of bacteriocins (Holzapfel et al., 2001&Gorbach et al.,2002 and it's very necessary for healty gut environment.Interaction with the host microflora and competitor for microbial pathogens (Gorbach et al .,2002).

Selection Criteria and Requirements for Probiotic Strains:
In accordance of the WHO, FAO, and EFSA (The European Food Safety Authority), probiotic strains must be fulfill both safety and functionality criteria and these criteria should also fulfill their technological usefulness. Some selection criteria of probiotic strains is given in table 1.

Probiotic Microorganisms:
To make a consumable probiotic fermented product selected microbial species and their strains are needed and such microorganisms are Lactobacillus, Bifidobacterium, and Lactococus,Streptococcus, Enterococcus etc. Bacillus and Saccharomyces strains are more commonly used to make a good Probiotic product. (Simon et al .,2005).
Usually one or mixed microbial strains are involvrd to make a probiotic product. Lactobacillus, Bifidobacterium, and Lactococus,Streptococcus, Enterococcus are known as human probiotic microorganisms.Beside these strains bacillus and some yeast strains belonging to the genus Saccharomyces are commonly used to make a good qualityful probiotic products (Simon et al .,2005).Some probiotic microorganisms used in human nutrition is given in Table 2. 279   Bacterial micro flora resides in the small intestine enhances lactose digestion and it is possibly done possibly by increasing connection between lactose and lactase. (Shah, 2000) 02. Lowering blood glucose level in case of diabetes melitus Probiotics are effective for the diabetic patients by balancing microbial gut flora. It is reported that Low-fat (2.5%) yoghurt containing probiotics Lactobacillusacidophilus and Lactobacillus casei was tested in rats against high fructose-induced type-2 diabetes and both of these bacteria proved beneficial effect in lowering blood glucose level by decreasing insulin resistance (Yadav et al.,2006). Bifidobacteriumspp is an important probiotics and it is reported that this bacteria delivers pharmaco nutritional support in treating insulin resistance. (Cani and Delzenne, 2011).

03.
Hypocholestrolemic effects Probiotics has hypocholestrolemic effects and it is found that that lactobacillusfermented milk has hypocholestrolemic effects (Mann and Spoerry, 1974).

Management of colon cancer
Now a days management of colon cancer is a thinking issue. In case of animal studies it is proved the beneficial effects of LAB against colon cancer of rodents. In human trials it is also suggested that some types of LAB are anti-carcinogenic due to ability to lowering the activity of enzyme called β glucuronidase (which can generate cancer producing substances in the digestive system) (Brady et al., 2000).

Boosting up immune functions
Probiotics may boost up immune functions and they also inhibit the growth of harmful and bad gut bacteria. Immune cells like the IgA-producing cells, T lymphocytes and natural killer cells are boosted by some probiotics. The risk of urinary tract infections (UTIs) in women is reduced by Lactobacillus crispatus and it is reduced by 50%.

10.Against viral infections
It is reported that the efficacy of antiinfluezal and anti herpetic effect of several Thermophilus species is high in guinea-pigs(Liaskovs et al., 2007). 11. Improvement of Digestive System Probiotics are commonly found in fermented foods and they may help to balance the friendly bacteria in our digestive system. Source:(https://www.healthline.com/nutrition/) 12.Prevention of diarrhea Probiotics used as a well known biotherapeutic agent in the prevention of diarrhea or reduce its severity.It is reported that probiotics reduced antibiotic-associated diarrhea by 42% and also reduced the risk of travelers' diarrhea by 8%. In case of allergies and eczema the efficacy of probiotic strains is so high and some strains may reduce the severity of eczema in children and infants. It is reported that eczema symptoms improved for infants fed probiotic-supplemented milk, compared to infants fed milk without probiotics. Source:(https://www.healthline.com/nutrition/) 16 Several studies reported that, certain probiotics, such as Lactobacillus acidophilus, can even lead to weight gain. Another report suggested that, dieting women who took Lactobacillus rhamnosus for 3 months lost 50% more weight than women who didn't take a probiotic. Another study suggested that, intake of Lactobacillus gasseri for 12 weeks resulted in an 8.5% reduction of belly fat. Source:(https://www.healthline.com/nutrition/)

Diabetes mellitus:
Diabetes mellitus, generally people called it diabetes, is a chronic condition and it occurs when there are elevated levels of glucose in the blood because the body cannot produce any or enough of the hormone insulin or use insulin effectively ( De Fronzo et al .,2015). A common effect of uncontrolled diabetes is elevation of higher blood glucose level over time and lead to serious damage to the heart, blood vessels, eyes, kidneys and nerves. It is reported that more than 400 million people live with diabetes(WHO, 2016). The number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years) is given in Figure 1

Complications of diabetes:
All types of diabetes lead to many complications. It happens in many parts of the body and can enhances the overall risk of dying prematurely. Some major complications are heart attack, stroke, kidney failure, leg amputation, vision loss and nerve damage. In the time of pregnancy period, poorly controlled diabetes increases the risk of fetal death and other complications.(WHO, 2016).Some major complications of diabetes is given in Figure 2. Classification of Diabetes mellitus: Type 1 diabetes: Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-onset diabetes) is identified by lack of insulin production in the body. Routinely administration of insulin is crying need for type 1 diabetes patients to control the amount of glucose in their blood. It is very risk to survive a type 1 diabetes patients without the uptaking of insulin in their body externally. Causes of type 1 diabetes is not known and still it is currently not preventable. Signs of type 1 diabetes are excessive urination and thirst, constant hunger, weight loss, vision changes and fatigue.(WHO, 2016). There are lot of symptoms around type 1 diabetes patients. Some are given in Figure 3. 283 Type 2 diabetes: Type 2 diabetes (formerly called non-insulin-dependent or adult onset diabetes) is more common than type 1 diabetes and it results from the body's ineffective use of insulin. Around the world, majority of people who has diabetes are type 2(World Health Organization; 2016.). Symptoms are alike to type 1 diabetes, but are often less marked or absent. If a patient who has type 2 diabetes but still undiagnosed for several years, then he would be in massive trouble or complications. It is more common in adults but in the recent time it also found in children. There are lot of symptoms around type 1 diabetes patients .Some are given in Figure 4.

Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG):
Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are in-between state in the transition between normal blood glucose levels and diabetes (especially type 2), though the transition is not inevitable. People who has this situation ,they are at increased risk of heart attacks and strokes. d) Gestational diabetes (GDM) Gestational diabetes (GDM) is occurs in pregnancy and it's a non permanent condition and also bear a long term risk of type 2 diabetes (Bellamy et al .,2009 ).The condition is present when blood glucose values are over normal but still under those diagnostic of diabetes. During pregnancy and delivery, women with gestational diabetes are at increased risk of some complications as are their infants. By prenatal screening gestational diabetes is diagnosed, rather than reported symptoms.

Gut Microbiota:
Gut is an important organ in human body. Medical literature refers, the gut microbiota as an ‗exteriorized organ' (Zhu et al .,2010).A human body is host to 100 trillion bacteria and it is more higher than human cells in our body (Ramakrishna et al .,2007). Microbiome is a collective name and it is the total the genetic material of the intestinal microbes and it already exceeds the magnitude of the human genome(  . From stomach to small intestine,the microbial population of the gut increase in density. In the stomach, microbial population of the gut is very sparse and it is due to luminal acidity and vigorous peristalsis. From duodenum to jejunum to ileum, microbial population is also increases in density. In duodenum the population is 10 1 -10 3 organisms/ml, In jejunum 10 4 -10 6 organisms/ml) and in ileum it is 10 5 -10 7 organisms/ml (Fig 6). In the large intestine, microbial population is 10 11 -10 12 organisms/g of stool (Ramakrishna et al .,2007).

Probiotics and type 2 diabetes preventing mechanism:
Probiotics are live microorganisms and they show several health benefits.Some probiotics i.e. Lactobacillus, Bifidobacteria has effect on type 2 diabetes. These bacteria uses some mechanism collaborately and in a specialized way they lowered blood glucose level.They show satinogenic and insulionotropic effect and they also secrete gut hormone like GLP1,GLP2 etc. and these way lowered blood glucose level in type 2 diabetes patients (Fig 7). Some Potential mechanisms linking probiotics to diabetes is given Table 4.

Conclusion:-
In the recent time, a significant number of people suffer with type 2 diabetes. In developing countries a number of diabetic patients live below the poverty line. They could not meet up their daily nutritional requirement and a substantial population remains malnourished. As probiotic bacteria have potential therapeutic or prophylactic effects, so development of numerous probiotic products such as fermented milk drinks, yoghurt, cheese, icecream, sausages, probiotic juice and drinking water etc. with defined culture are badly required. These products would be able to confer health benefits and lowering blood glucose level of type 2 diabetes patients. Incoporation of probiotics live microorganisms (isolated from indigenous yoghurt) in market yoghurts can positively enhance health status of larger segment of type 2 diabetic peoples. Therefore probiotic yoghurt and other probiotic based food and feed can be used as a biotherapeutic agent for type 2 diabetes patient.