Glucose

In every mammal, Glucose is acts as an important energy source metabolic substrate. It is obtained directly from the diet, principally following the hydrolysis of ingested disaccharides and polysaccharides, and by synthesis from other substrates in organs such as the liver. In the breakdown of each gram of carbohydrates, four calories of energy are consumed. Once ingested into the body, special enzymes in the digestive system break down the carbohydrates into simple sugars called glucose. This breaking down process allows the body to access the calories of energy contained in the carbohydrate. Glucose derived from the diet is transferred from the lumen of the small intestine, and both dietary glucose and glucose synthesized within the body have to be transported from the circulation into target cells.

Normally a healthy individuals completed their daily works by the help of energy which is actually derived from the breakdown of simple sugars. Glucose – C6H12O6 – a simple sugar that is influential in providing energy for cells in our body. In fact, it’s the main power supply for most cells, and is the only energy supply for certain cells like brain cells and red blood cells because, under normal conditions, glucose is the sole substrate for these tissues. In our body glucose is mostly utilized by the brain, neurons and developing red blood cells for achieving energy. In all these tissues, after the glucose metabolism the main outcome is to yield energy in the form of adenosine triphosphate (ATP).

There are two methods by which glucose is produced endogenously to maintain plasma glucose levels: glycogenolysis and gluconeogenesis

Gluconeogenesis (GNG) is a metabolic pathway that results in the synthesis of glucose from non-carbohydrate precursors, such as pyruvate, lactate, glycerol, and glucogenic amino acids.

According to the David, Nelson and Michael, plants, animals, fungi, bacteria, and other microorganisms plays a pivotal roles for spontaneous generation of glucose by gluconeogenesis(1). However, some precursors for biosynthetic reactions, such as the formation of some amino acids, nucleotides and other intermediary metabolites has been produced after the metabolism of glucose. If unfortunately our carbohydrate level will goes down from the normal levels, then our normal body homeostasis make it balanced by depletion of glycogen stores to give the brain fuel. Once the stores fail, the body begins to break down muscle tissue to make glucose.

In 1977, Young told that Gluconeogenesis took place mainly in the liver for vertebrates, and, to a lesser extent, in the cortex of the kidneys (2). During periods of fasting, starvation, low-carbohydrate diets, or intense exercise this process occurs rapidly in many other animals (3).Usually the liver and the kidneys are the two major sites for gluconeogenesis, but the 90% of the gluconeogenesis is happened in the liver & the rest of the glucose production is carried out by the kidney in healthy individuals. But very small amount of glucose production is happened by other tissues. For maintain the metabolic demand of glucose on the brain, muscle & red blood cells, the liver and kidneys plays a vital roles.

(4) In the 1st step of Gluconeogenesis, the breakdown of glycogen is happened to produce glucose-6-phosphate and its consequent hydrolysis of glucose-6-phosphatase to glucose. In contrast, for the events of gluconeogenesis, glucose-6-phosphate is generated from a variety of precursors such as lactate, glycerol, and amino acids. Only the liver and kidney provides sufficient gluconeogenic enzyme activity and glucose-6-phosphatase activity to contribute significant amounts of glucose via endogenous production. The liver (primarily) and kidney (secondarily & during starvation) uses this reaction to maintain blood glucose concentrations. Small intestine uses this enzyme as a digestive enzyme. Scientist Kevin & Siebenlist in 2014 discloses that Glucose-6-phosphatase is part of a multimeric intrinsic protein embedded in the membrane of the smooth endoplasmic reticulum (ER) of these tissues. Finally the prepared glucoses are moved into the cytoplasm by the Microsomal glucose transport protein (GLUT7). As the cytoplasmic concentration of glucose increases above that in plasma the GLUT2 transport protein moves the glucose from the cell to the blood.

Figures 1: Pathway of Gluconeogenesis. Copy right from Kevin R. Siebenlist, 2014.

THE ROLE OF KIDNEYS IN GLUCOSE HOMEOSTASIS

Rossenwasser and Sultan explain on 2013 that Plasma glucose concentrations is maintained within a normal range of 3.9–8.9 mmol/L by the healthy individuals, despite their diet, due to a closely regulated homeostatic system balancing glucose production, reabsorption, and utilization.6 Many organs are involved in glucose homeostasis and the kidneys are now recognized as a major contributor to both gluconeogenesis and glucose reabsorption (5,6,7).

Figure 2: kidney’s role in glucose reabsorption. Copy right from 2013.Rebecca F, RossenWasser, Sultan S, Sutton D, Choksi R. SGLT-2 inhibitors and their potential in the treatment of diabetes

Sultan and Choski also expressed that the glucose homeostasis is mainly contributed by Kidney by filtering and reabsorbing glucose back into the circulatory system. In the fasted state, about 20–25% of glucose released into the circulation is derived from the kidney, and this proportion increases with a longer duration of fasting. In healthy individuals, renal glomeruli filter ~180 gm. of glucose each day; so there is enormous loss of glucose through urine, if it is not recovered. So our own body physiological condition maintain this level by undertaking regain or reabsorb the filtered glucose as much as possible in the proximal convoluted tubule (8,9,10 & 11) (Figure 2).

This reabsorption is specially carried out by the sodium glucose co transporters (SGLTs) and facilitative glucose transporter member 2(GLUT2). Membrane-associated carrier proteins are necessary for reabsorption or transportation of glucose across the cell from the lumen into the blood circulation due to its polar in nature (12,13,14,15).

In animals, SGLT2 and GLUT2 are located in the early portion of the proximal convoluted tubule of the renal nephron and are responsible for the majority (90%) of glucose reabsorption. Other glucose transporters such as SGLT1andGLUT1are present in the distal portion of the proximal tubule in animals and it may account for additional (10%) glucose reabsorption.

Figure 3: Distribution of SGLTs

The kidneys continue to reabsorb glucose even in the presence of abnormally high plasma glucose concentrations seen in type 2 diabetes and can contribute to the hyperglycemia characteristic of this disease.

But there is also available the maximum level of reabsorption capacity (Tm), which is also called maximum reabsorptive capacity which is ∼350 mg glucose/minute. When around a blood glucose concentration of approximately 10.0–11.1 mmol/L in healthy individuals occurs then this level is reached & ultimately glucose is excreted through the urine. This capacity for glucose reabsorption increases in diabetics due to the up regulation of SGLT2 and GLUT2 in the proximal tubule, resulting in hyperglycemia and reduced glycosuria(16,17,18).

Under normal conditions, almost all of the filtered glucose is reabsorbed and returned to the circulation in the proximal tubule of the nephron. Glucose is reabsorbed by Sodium-Glucose Cotransporters (SGLTs) in concert with facilitative glucose transporters (GLUTs).

• Ability of the proximal tubule to reabsorb the filtered glucose increase when

1. The filtered load increased by either elevation in plasma glucose.

2. Increase in glomerular filtration rate

When the reabsorption capacity reaches the threshold (TM ) that represent maximum absorptive capacity of the proximal tubule and increased the filtered load above this point result glycosuria(glucose in urine).

Tubular reabsorption increases linearly with filtered load as a part of glomerulotubular balance. When reabsorption reaches the tubular capacity (TM glucose), glucose starts appearing in the urine.

Sodium-dependent glucose transporters:

Stuart Wood and Paul Trayhurn reveals in his journals named Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins in 2003 that sodium glucose co transporters is structurally divided on 2 types, 1) Sodium glucose co transporters member 1(SGLT1); 2) Sodium glucose co transporters member 2 (SGLT2);

But unfortunately this protein is not available on Protein Data Bank (PDB). So this transporter protein was genetically engineered by cloning with the high-affinity transporter from rabbit intestine, SGLT1 (Hediger et al. 1987). For the development of prepared human analogue soon homology cloning technique will be utilized (Hediger et al. 1987).Dr. Wells & Kanai reveals on 1994 that SGLT2 has taken a pivotal role for controlling the glucose homeostasis on kidney due to low affinity but high capacity for glucose absorption on the apical membrane of the renal convoluted proximal tubules at S1 and S2 segments (Wells et al. 1992; Kanai et al. 1994). So it is well accepted that 90% of the glomerular filtrate glucose is again reabsorbed and transported back to the blood circulation by SGLT2 protein on account of controlling the blood glucose level & remaining 10% glucose is reabsorbed by the SGLT1 on S3 segment of proximal tubule (high affinity, low capacity) thus preventing glucose loss in the urine. (Hediger et al. 1995; Wright, 2001).

The reabsorption mechanism:

Amanda Mather and Carol Pollock describes this transportation mechanism on their paper named Glucose handling by the kidney that this reabsorption of filtered glucose and galactose is principally carried out by the active transportation of SGLTs and then facilitative diffusion by GLUT2.

The main carbohydrates, such as glucose and galactose are actively transported with different affinities by an active process of Na dependant glucose transporter which is present on the apical membranes.

These active transportations of glucose are carried out by the Na+-electrochemical gradient across the cell membranes, which is created and maintained by Na+–K+ ATPase pumps to transport glucose into cells against its concentration gradient. This form of glucose transport is the main transport system for glucose in any mammals which takes place across the lumenal membrane of cells lining the small intestine and the proximal tubules of the kidneys (19).

A low-affinity glucose co-transporter has been developed from the pig renal amino acid co-transporter (SAAT1) (Mackenzie et al. 1994) and finally renamed pSGLT3. However, current studies with the human analogue of SGLT3 (EMBL accession number, AJ133127) suggest that its function may require a re-evaluation (EM Wright, personal communication).

Signals have been detected for SGLT3 in the small intestine of pigs by northern blot analysis (Kong et al. 1993) and in human subjects by reverse transcription polymerase chain reaction (IS Wood, unpublished data). These findings conflict with the collective data indicating that SGLT1 is the only Na+–glucose co-transporter expressed in the small intestine. The potentially fatal neonatal condition of glucose, galactose malabsorption is happened by Mutations of human SGLT1 (Turk et al. 1991). The severe diarrhoea associated with glucose-galactose malabsorption is corrected by replacing dietary glucose with fructose.

CLASS I FACILITATIVE TRANSPORTERS

The class I facilitative transporters contain GLUT1 – 4, and these have been comprehensively characterised in terms of structure, function and tissue distribution.

Glucose transporter 1 (or GLUT1), also known as, as facilitated glucose transporter member 1. It is a uniporter protein that means glucose is transported in a one-directional way. In human, GLUT1 is expressed particularly from SLC2A1 gene. GLUT1 is expressed particularly in the brain (including the blood brain barrier) and erthyrocytes, but in adipose tissue, muscle and the liver, moderate levels of its expression are also followed.

GLUT1 contains 12 membrane-spanning alpha helices, each containing 20 amino acid residuesThe spanning alpha helices are amphipathic, with one side being polar and the other side hydrophobic.GLUT1 is also a major receptor for uptake of Vitamin C as well as glucose, GLUT1 is also responsible for reabsorbtion of filtered glucose at S3 segment of proximal tubule and returned into the blood stream.

GLUT2 is expressed primarily in pancreatic β-cells, the liver and the kidneys. The glucose-sensing mechanism is maintained by GLUT2 in the β-cells, while in the liver it is expressed on the sinusoidal membrane of hepatocytes and allows for the bidirectional transport of glucose under hormonal control. On the basolateral surface of proximal renal tubules and enterocytes, GLUT2 is mainly found where it forms part of the trans-cellular pathway for glucose and fructose transport. In humans, this protein is encoded by the SLC2A2 gene. Unlike GLUT4, it does not rely on insulin. So no chance of insulin resistance. It is the principal transporter for transfer of glucose between liver and blood, and has a role in renal glucose reabsorption.

GLUT3 has a high affinity for glucose and this is consistently goes high as the high presence of glucose in tissues which is acts as a fuel for individual cells, especially brain cells.

On the paper of Rayner et al. at 1994, the reduction in the postprandial rise in plasma glucose levels is responsibly maintained by the insulin-responsive glucose transporter, GLUT4 which is expressed on the heart, skeletal muscle and adipose tissue ;(Rayneret al.1994). Insulin acts by stimulating the trans-location of specific GLUT4-containing vesicles from intra-cellular stores to the plasma membrane resulting in an immediate 10 – 20-fold increase in glucose transport (Shep-herd & Kahn, 1999; Bryantet al.2002). Various animal and human models of ‘diabetis’ (Astrup & Finer, 2000) exhibit reduced expression levels of GLUT4 in adipose tissue, but not muscle, suggesting that this decline is not the causative factor of insulin resistance (Shepherd & Kahn, 1999).

Mechanism of action of SGLTs and GLUTs:

Renal glucose reabsorption is the principal means by which the kidney regulates glucose homeostasis. Usually about 180g of glucose is filtered by the kidneys every day; however, almost all of this is reabsorbed into the circulation by means of sodium glucose co-transporters (SGLTs). SGLTs transport sodium and glucose into cells using the sodium gradient produced by sodium/potassium ATPase pumps at the basolateral cell membranes. This is in contrast to the glucose transporters (GLUTs) which allow passive transport of glucose along its concentration gradient.

Figure 5: Transportation pathway of glucose on intestine and proximal tubule. Copyright from Mammalian Sugar Transporters.2014. Robert Augustin and Eric Mayoux

The transfer of glucose from the tubular lumen to the interstitial space is executed by the active process of Na+ dependent glucose transport on the apical membrane to take glucose from the lumen to the cell, and facilitated diffusion glucose transport on the basolateral membrane to release glucose into the interstitium (Figure 5).

The first step, in which glucose is transported across the apical brush border of kidney epithelial cells, requires the presence of a Na gradient across the cell membrane. A low intracellular Na concentration is created and maintained by Na-K-adenosine-triphosphatase pump located on the basolateral region, which forces out 3molecules of intracellular Na across the basolateral membrane. The electrochemical gradient thus created provides the driving force for ongoing transport of Na into the cell across the apical membrane, allowing for glucose to be concurrently cotransported by specific Na+ dependent glucose transporters (SGLTs).

Facilitated diffusion glucose transport by the Glucose Transporter 2(GLUT2) located on the basolateral membrane is happened to release glucose from interstitial space to the blood.

So it is cleared that, in the healthy individuals, sodium glucose co transporters and glucose transporters plays a vital role for glucose reabsorption for preventing the enormous loss of glucose from body circulation. But in diabetic condition that means when the blood glucose levels is already high, this filtered glucose reabsorption into the circulation resulting a high mortality. So the target of diabetes therapy is the prevention of reabsorption of filtered glucose in proximal tubule & allowed to excrete them through urine. This methodology is applicable by inhibiting the SGLTs and GLUTs.

SGLT2 inhibitors under clinical development

Due to the novel mechanism of SGLT2 inhibitors, numerous compounds are entangled in a race to market with the ultimate goal of emerging first to market or arriving with a distinct in-class advantage. However, US Food and Drug Administration (FDA) has given recent approval for canagliflozin. Others inhibitors mainly available in the development are dapagliflozin, canagliflozin, and empagliflozin, ertugliflozin, which is listed according to the possible submission of New Drug Application [NDA] to the FDA. Figures 2 clearly exhibit the drugs present on the clinical-trials.Supplementary data also discloses the clinical efficacy and safety for dapagliflozin,canagliflozin, and empagliflozin, others can be found online (www.eastcoastresearch.net/#/sglt2inhibitor/)

Figure 6: SGLT2 inhibitors on development. Copy rights from Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2013

The natural Citrus flavonoids also shows maximum anti-diabetic and anticancer activities.

Citrus bioflavonoids:

Kingdom: Plantae

Order: Sapindales

Family: Rutaceae

Subfamily: Aurantioideae

Tribe: Citreae

Genus: Citrus

Citrus is a common term and genus (Citrus) of flowering plants in the rue family. The most recent research indicates an origin in Australia, New California and New Guinea. Citrus fruit has been cultivated in an ever-widening area since ancient times; the best-known examples are the oranges, lemons, grapefruit, and limes (20).

Two flavonoids called naringenin, neohesperidin found in citrus fruits helps the body burn extra fat to check weight gain. It also has insulin-like properties to check Type-2 diabetes, says a study by the University of Western Ontario (21).

Citrus constituents may be helpful for reduce blood sugar for those with or at risk for type 2 diabetes and suffer from poor glucose control and/or heightened glucose tolerance.

The high content of vitamin C, which prevents scurvy is spontaneously found on oranges. Scurvy is caused by vitamin C deficiency, and can be prevented by having 10 milligrams of vitamin C a day.

Pectin is a structural hetero-polysaccharide contained in the primary cell walls of plants. Limes and lemons as well as oranges and grapefruits are among the highest in this level.

Citrus fruit intake is associated with a reduced risk of stomach cancer. Also, citrus fruit juices, such as orange, lime and lemon, may be useful for lowering the risk of specific types of kidney stones. Citrus fruit is another fruit juice that can be used to lower blood pressure because it interferes with the metabolism of calcium channel blockers. Lemons have the highest concentration of citrate of any citrus fruit, and daily consumption of lemonade has been shown to decrease the rate of kidney stone formation.

Cancer Treatment:

Clinical studies investigating the relationship between flavonoid consumption and cancer prevention/development are conflicting for most types of cancer, probably because most studies are retrospective in design and use a small sample size (22). Two apparent exceptions are gastric carcinoma and smoking-related cancers. Dietary flavonoid intake is associated with reduced gastric carcinoma risk in women (23).

On Inflammation

Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such as cancer, diabetes mellitus, and celiac disease. Preliminary studies indicate that flavonoids may affect anti-inflammatory mechanisms via their ability to inhibit reactive oxygen or nitrogen compounds. Flavonoids have also been proposed to inhibit the pro-inflammatory activity of enzymes involved in free radical production, such as cyclooxygenase, lipoxygenase or inducible nitric oxide synthase, and to modify intracellular signaling pathways in immune cells.

As Antibacterial

Flavonoids have been shown to have (a) direct antibacterial activity, (b) synergistic activity with antibiotics, and (c) the ability to suppress bacterial virulence factors in numerous in vitro and a limited number of in-vivo studies. Noteworthy among the in vivo studies is the finding that oral quercetin protects guinea pigs against the group 1 carcinogen Helicobacter pylori. Additional in-vivo and clinical research is needed to determine if flavonoids could be used as pharmaceutical drugs for the treatment of bacterial infection, or whether dietary flavonoid intake offers any protection against infection.

 Structural features of Citrus bioflavonoids:

 A flavonoid skeleton is composed of two aromatic rings (designated as A and B).

 Both rings are connected through a pyrone ring (C) in the case of flavones, or a dihydropyrone ring in the case of flavanones (Figure 7).

 Occurrence:

 Flavonoids are mainly present in Citrus fruits as their glycosyl derivatives.

 Aglycones (these contain less sugar moieties) occur less frequently in juices, owing to their lipophilic nature and hence their low solubility in water.

 The relatively large numbers of flavonoids are present in Citrus juices in various structural combinations.

 Structural Characteristics of Flavanone Aglycone:

Figure 8: Flavanone Aglycone

 All these aglycones have a common skeleton in which two hydroxyls are present at the C-5 and C-7 positions.

 Identified and quantified in only citrus juices.

 In hesperetin (1) and isosakuranetin (4) methoxylation is occurred at C-4´ position.

 The flavanonetaxifolin (3) contains a hydroxyl (OH) group in the C-3 position, and can thus also be classified as a flavanol.

Table 1: Flavanone aglycones

S.No Compound Name R1 R2 R3

1. Hesperetin H OH OMe

2. Naringenin H H OH

3. Taxifolin OH OH OH

4. Isosakuranetin H H OMe

5. Eriodictyol H OH OH

Figure 9: Flavanoneglycones

Table 2: Flavanoneglycones

Sl.NO Compound

Name R1 R2 R3 R4

6. Acacetin H H H OMe

7. Isoscutellarein H OH H OH

8. Luteolin H H OH OH

9. Kaempferol OH H H OH

10. Quercetin OH H OH OH

11. Apigenin H H H OH

12. Diosmetin H H OH OMe

13. Chrysoeriol H H OMe OH

 Acacetin (6) and diosmetin (12) contain a methoxy moiety at C-4´ position.

 Chrysoeriol(13) contain the methoxyl group at C-3´ position.

 The hydroxyl groups are present on 3position of kaempferol (9) and quercetin (10) and are often referred to as flavonols.

 Structural Characteristics of Polymethoxyflavones:

 These are group of compounds classified as polymethoxyflavones (PMFs). These are usually found as components of the essential oil fraction of Citrus peels.

Figure 10: Polymethoxyflavones

Table 3: Polymethoxyflavones.

Sl.No Compound Name R1 R2 R3

14. Quercetogetin OMe H OMe

15. 3,3’,4’,5,6,7,8-Heptamethoxyflavone OMe OMe OMe

16. Natsudaidain OH OMe OMe

17. Nobiletin H OMe OMe

18. Sinensetin H H OMe

19. Tangeretin H OMe H

20. Tetramethylscutellarein H H H

Figure 11: Rutinose and neohesperidose

 Structural Characteristics of Flavanone-O-Glycosides:

 The flavanone O-glycosides found so far present in juices are listed in Table 4.

 These derivatives have a glycosyl substitution exclusively on the C-7 position (on ring A). Furthermore, only two disaccharides have so far been identified.

I. L-rhamnosyl-D-glucosyl derivatives: rutinose, which presents a α-1,6 interglycosidic linkage

II. neohesperidose, in which the two sugars are linked via a α-1,2 interglycosidic bond (Figure 12).

Figure 12: Flavanone-O-Glycosides

Table 4: Flavanone-O-glycosides.

Sl.No Compound Name R1 R2 R3

21. Isosakuranetin 7-O-rutinoside

(Didymin, Neoponcirin) O-Rua H OMe

22. Eriodictyol 7-O-rutinoside

(Eriocitrin) O-Rua OH OH

23. Hesperetin 7-O-rutinoside

(Hesperidin) O-Rua OH OMe

24. Naringenin 7-O-neohesperidoside

(Naringin) O-Nhb H OH

25. Naringenin 7-O-rutinoside

(Narirutin) O-Rua H OH

26. Hesperetin 7-O-neohesperidoside

(Neohesperidin) O-Nhb OH OMe

27. Eriodictyol 7-O-neohesperidoside

(Neoeriocitrin) O-Nhb OH OH

28. Isosakuranetin 7-O-neohesperidoside

(Poncirin) O-Nhb H OMe

aO-Rutinose; bO-Neohesperidose.

 Structural Features of Flavone O-Glycosides:

Figure 13: Flavone O-Glycosides

 Flavone O-glycosides found in Citrus juices, which are generally 7-O-rutinosides or 7-O-neo hesperidosides (Table 5),

 A 3-O-rutinoside namely rutin (39) has also been found in citrus fruits.

 Citrus juices also contain a large number of di-C-glycosides, along with smaller amounts of mono-C-glycosides.

 For di-C-glycosides compounds, substitution is generally on either the C-6 or the C-8, or on both positions.

Table 5: Flavone-C-glucosides

S.No Compound name R1 R2 R3 R4 R5 R6

29. Luteolin 6,8-di-C-glucoside

(Lucenin-2) H Glu OH Glu OH OH

30. Apigenin 6,8-di-C-glucoside

(Vicenin-2) H Glu OH Glu H OH

31. Chrysoeriol 6,8-di-C-glucoside

(Stellarin-2) H Glu OH Glu OMe OH

32. Diosmetin 6,8-di-C-glucoside

(Lucenin-2 4´-methyl ether) H Glu OH Glu OH OMe

33. Apigenin 7-O-neohesperidoside-4´-glucoside

(Rhoifolin 4´-glucoside) H

H

O-Nhb

H OH O-Glu

34. Chrysoeriol 7-O-neohesperidoside-

4´-glucoside H

H

O-Nhb

H OMe OH

35. Apigenin 6-C-glucoside

(Isovitexin) H Glu OH H H OH

36. Luteolin 7-O-rutinoside

H H O-Rua H OH OH

37. Chrysoeriol 8-C-glucoside

(Scoparin) H H OH Glu OMe OH

38. Diosmetin 8-C-glucoside

(Orientin 4´-methyl ether) H H OH Glu OH OMe

39. Quercetin 3-O-rutinoside

(Rutin) O-Rua H OH H OH OH

40. Apigenin 7-O-neohesperidoside

(Rhoifolin) H

H

O-Nhb

H OH OH

41. Apigenin 7-O-rutinoside

(Isorhoifolin) H

H

O-Rua H OH OH

42. Chrysoeriol 7-O-neohesperidoside H H O-Nhb H OMe OH

43. Diosmetin 7-O-rutinoside

(Diosmin) H

H

O-Rua H OH OMe

44. Diosmetin 7-O-neohesperidoside

(Neodiosmin) H H

O-Nhb

H OH OMe

aO-Rutinose; bO-Neohesperidose

Conclusion

Inspite of the worldwide use of herbs and medicinal plants, the effective treatment of diabetes with phytochemicals has not been validated with scientific criteria which may support their substitution for the current therapy. None of the known single species is exactly equivalent to human diabetes, but too some extent the citrus species show the potential for the treatment of diabetes due to its high content of flavonoids, especially naringenin, narirutin,rutin,vicenin-2 etc. Not only that, the other standard inhibitors of SGLT2 had similar kind of skeletal structures with the citrus backbones. Each model act as essential tool for investigating treatment during the evolution of Type 2 diabetes in humans. The selection of particular animal model is particularly depending on the investigator’s choice,availability of particular strain, aim of scientific strategy, type of drug being sought, institutional financial and facility resources all are play a vital role in the future research pathway on the Type 2 diabetes research and pharmaceutical drug discovery and development programme.

References:

1. David L Nelson and Michael M Cox . Lehninger Principles of Biochemistry. USA: Worth Publishers. p. 2000: 724.

2. Young JW.Gluconeogenesis in cattle: significance and methodology. J. Dairy Sci. 60 (1).1977.pP: 1–15.

3. Miles B. Gluconeogenesis. International Journal of Physiology.2003.pP:212

4. Amanda Mather and Carol Pollock. Glucose handling by the kidney. International Society of Nephrology.2011.pP:S2-S6

5. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counter regulation. Diabetes .1999; 48.pP: 943–948.

6. Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans. Diabetes. 2000; pP:1186–1193.

7. Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin induced hypoglycemia in humans. Diabetes. 1999; pP: 261–266.

8. Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation. Diabetes 1999; pP: 943–948.

9. Basile J. A new approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibition. Postgrad Med.123(4).2011.pP:38–45.

10. Kruger DF, Bode B, Spollett GR. Understanding GLP-1 analogs and enhancing patients success. Diabetes Educ.36. 2010.pP: 44S–72S.

11. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010. P:125

12. Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis.53(5).2009.pP:875–883

13. Basile J. A new approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibitions. Postgrad Med. 123(4).2011.pP: 38–45.

14. Kruger DF, Bode B, Spollett GR. Understanding GLP-1 analogs and enhancing patients success. Diabetes Educ. 2010: 44S–72S.

15. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010.

16. Basile J. A new approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibition. Postgrad Med. 123(4).2011.pP: 38–45.

17. Kruger DF, Bode B, Spollett GR. Understanding GLP-1 analogs and enhancing patients success. Diabetes Educ. 2010.pP: 44S–72S.

18. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010.

19. Amanda Mather and Carol Pollock. Glucose handling by the kidney. International Socity of nephology.2011.pP:S3-S4.

20. Kuhnau J. The flavonoids: A class of semi-essential food components: their role in human nutrition. World Res Nut Diet. 1976.pP:117-91

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23. Romagnolo DF, Selmin OI. “Flavonoids and cancer prevention: a review of the evidence”. J NutrGerontolGeriatr 31 (3). 2012.pP: 206–38.

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