INTRODUCTION:

Diabetes mellitus:

High blood glucose, insulin resistance, lower insulin production are the hallmarks of diabetes mellitus, a multifactorial, complicated metabolic illness. It is a major health problem across the world¹. Before nineteenth century, William Osler depicit that diabetes is a rare disorder mostly to develops in fatty people and patients with gout. He estimated its incidence as approximately two to nine cases per 100,000 populations in the western countries being more common in the latter¹. More than two hundred million around the globe affected from diabetes, which is one of the main causes of death in the country². One of the community white population Heart study, is a proof that there is doubling in the incidence of type 2 diabetes over the last 30 years³.

Identifying the root cause of type 2 diabetes is a key to its prevention. High weight and abdominal fat accumulation triggers Insulin resistance^4,5. This suggests that other risk factors besides obesity might play a role in the epidemic of type 2 diabetes.

Fructose and glucose combine to form the disaccharide sucrose. Fructose and glucose are released when sucrase breaks down sucrose in the gut after consumption, and these are subsequently absorbed.

The other main source of fructose, outside sucrose, is high fructose corn syrup (HFCS), which was first used as a sweetener in the early 1970s. Although it can be found in a range of quantities, HFCS is typically composed of 55% fructose and 45% glucose. The main dietary sources of fructose in the US are sucrose and HFCS, with HFCS being a common component of many processed foods, soft drinks, and pastries and desserts⁶.

Fructose:

Fruits and honey contain fructose, a simple sugar that gives them their sweetness. But the primary global source of fructose is sucrose, or table sugar, which comes from sugar beets and sugar cane. A rare and costly item, it was first created in New Guinea and the Indian subcontinent before being brought to Europe through Venice, Italy, and other trading ports throughout the Middle Ages.

Fructose is thought to absorb more slowly than Glucose from the gastrointestinal tract. A sodium-Glucose co-transporter absorbs Glucose produced when Sucrose is cleaved. Fructose, on the other hand, has no active absorption mechanism in the intestinal mucosa and is instead absorbed slowly and incompletely by enhanced diffusion⁷.

The blood Glucose increasing effect of Fructose is lower than that of most other carbohydrate sources due to its sluggish, Glucose and Fructose enter the portal circulation after absorption and are carried to the liver, where Fructose can either be taken up and converted to Glucose or be released into the general circulation^8-14 Fructose is mostly processed by the liver, with the kidney and intestinal mucosa playing a minor role¹⁵. GLUT 5 and GLUT 2 commence Fructose transepithelial transport in the intestine, while GLUT 2 is thought to release Fructose through the basolateral membrane and hence it is said to be¹⁶. The first process in the metabolism of Fructose is mediated by fructokinase, an enzyme that is not Insulin-dependent. Fructose does not cause pancreatic cells to secrete Insulin. The lack of Fructose stimulation is most likely due to reduced levels of the Fructose transporter GLUT5 in cells¹⁷.

Glucose:

Glucose, is a simple monosaccharide found in plants. Together with fructose and galactose, it is one of the three dietary monosaccharides that are taken up straight into the bloodstream during digestion. Glucose detection and metabolism by beta cells are required for Glucose-stimulated Insulin release. Glucose enters beta cells via the Glucose transporter GLUT 2, where it is phosphorylated to Glucose-6-phosphate (G6P) by glucokinase, resulting in the production of ATP. This occurs when ATP-sensitive potassium (K⁺) channels close, letting sodium (Na⁺) into the beta cell, resulting in a Na⁺/K⁺ ion imbalance. Membrane depolarization and activation of voltage-dependent (T-type) calcium (Ca²⁺) and Na⁺ channels arise from these two processes. Ca²⁺ and Na^{+ e}nter the beta cell, producing additional membrane depolarization and the activation of voltage-gated Ca²⁺ channels, resulting in a rise in intracellular Ca²⁺concentration and pulsatile Insulin production, which regulates carbohydrate, lipid, and protein metabolism¹⁸.

Correlation Between Fructose-Glucose and Diabetes Mellitus:

In many respects, Fructose metabolism differs from that of Glucose. First, the body uses Fructose at a faster rate than Glucose; second, Fructose uptake lacks a negative feedback mechanism, which explains why large doses of Fructose cause excessive catabolism¹⁹. The liver is the primary site of dietary fructose metabolism, following intestinal absorption in the jejunum. The glucose-fructose transporter GLUT2 and the fructose-specific transporter GLUT5 mediate the transport of fructose.²⁰ and occurs through the portal vein, with GLUT2 providing access to hepatocytes. Fructose is also processed by the kidneys and intestines, which have high levels of GLUT5 and ketohexokinase. Large doses of Fructose alone can cause diarrhoea by exceeding the capacity of intestinal Fructose absorption. Consumption of Glucose in combination with Fructose, as found in beverages and meals, enhances the Fructose metabolism. This impact is presumably mediated by the translocation of the Glucose-Fructose transporter GLUT2 to the enterocyte apical membrane domain, which increases Fructose absorption^20,21.

Furthermore, because Fructose up-regulates the intestinal Fructose transporter, Glut 5, as well as hepatic and intestinal KHK-C in response to Fructose exposure, Fructose absorption increases after long-term Fructose consumption. Fructose-rich meals, on the other hand, are well documented to raise plasma triglyceride levels. This impact is mediated by various processes that boost glycogen buildup, increase hepatic de novo fatty acid synthesis, and decrease oxidation in the mitochondria, as recently discovered²².

In summary, KHK-C phosphorylates Fructose to Fructose 1-phosphate, which is subsequently metabolised by aldolase B to triose phosphates, glyceraldehyde, and dihydroxyacetone phosphate. The gluconeogenic pathway to Glucose and Glycogen production is driven by the phosphorylation of glyceraldehyde to glyceraldehydes 3-phosphate¹⁹. The intermediates of Fructose metabolism are directed toward triglyceride synthesis once liver glycogen is replenished. Because Fructose is frequently consumed with Glucose, Fructose intermediates diverge quickly to this route. Thus, dietary Fructose derived carbons can be identified in both free fatty acids and plasma triglycerides¹⁹. The latter are combined into very low-density lipoproteins, which are then released from the liver and stored in fat and muscle¹⁹. In mitochondria, Fructose intermediates can be further converted to pyruvate, acetyl-CoA, and citrate via pyruvate dehydrogenase, providing substrates for de novo lipogenesis²³. The creation of UA (uric acid) as a byproduct is a unique feature of Fructose metabolism. When Fructose is first phosphorylated by KHK-C to Fructose 1–phosphate, the metabolic pathway involved in this action begins.

Because this enzyme is not regulated by intracellular negative feedback systems, the ATP required to complete this reaction is quickly depleted when a substantial amount of Fructose is consumed. The enzyme xanthine oxidase deaminates adenosine monophosphate (AMP) to inosine monophosphate (IMP) or dephosphorylates it to adenosine, both of which are eventually reduced to hypoxanthine and UA. Furthermore, depletion of phosphate, which is sequestered in Fructose 1–phosphate, enhances AMP deaminase activity, which promotes further AMP breakdown to IMP and eventually UA. The fact that Fructose concentration may be a key risk factor for ATP depletion shows that how Fructose is taken could have significant repercussions²⁴.

Although their chemical structures are similar, glucose and fructose use different GLUT transporters²⁵ and undergo entirely different metabolisms. Fructose avoids the two highly controlled stages of glycolysis in the liver, which are catalyzed by phosphofructokinase and glucokinase/hexokinase. Both of these processes are inhibited by rising levels of their byproducts. Rather, fructokinase or ketohexokinase (KHK)²⁶ metabolize fructose, which enters the pathway at an unregulated level, to fructose-1-phosphate. Hexokinase can also metabolize fructose, but because its Km is significantly higher than glucoses, only trace amounts of fructose are metabolized via this. Since fructokinase lacks a negative feedback mechanism, phosphorylation is accomplished by ATP. Consequently, ongoing fructose metabolism leads to intracellular phosphate depletion, AMP deaminase activation, and uric acid production, all of which are detrimental to cellular level²⁷.

DISCUSSION:

Across the globe, there is increase in the consumption of these sweeteners, Fructose intake has quadrupled since the early 1900s.The past 30 years we have witnessed an even greater acceleration in consumption, in part because of the introduction of HFCS; this phenomenon parallels the rise in multiple organelle disease²⁸. Although correlations do not establish causation, animal experiments have demonstrated that fructose can produce the majority of the metabolic syndrome's symptoms, such as insulin resistance, increased triglycerides, abdominal obesity, elevated blood pressure, inflammation, oxidative stress, endothelial dysfunction, microvascular disease, hyperuricemia, glomerular hypertension and renal injury, and fatty liver²⁹.

These effects are not seen in animal’s pair-fed Glucose or starch, which proves that the mechanism is not mediated by excessive caloric intake³⁰. Eating of large amounts of dietary Fructose also can increasingly induce Insulin resistance, linked to other metabolic disorders in humans more than starch (or Glucose) does in controls^31.It may also be a risk factor for fatty liver disease. Due to fructose's distinct metabolism, which results in uric acid production, endothelial dysfunction, oxidative stress, and lipogenesis³², it is known to cause metabolic syndrome. A comprehension of the mechanisms elucidates the variation in reactions documented in scholarly works. Because rodent studies usually employ high supraphysiological dosages (60%) they are frequently criticised. However, due to their high endothelial function, low uric acid concentrations, and ability to synthesise vitamin C, rats are resistant to fructose³³. Insulin resistance can be easily produced by increasing uric acid concentrations or by prolonging low doses. A clarification of fructose metabolism³³ can also account for the heterogeneity observed in human research³³. For instance, the more fructose consumed, the more susceptible one becomes to its effects because it specifically up-regulates its own transporter (Glut5) and metabolism (fructokinase). This could be the reason why people who are obese seem to be more vulnerable than people who are not to the lipogenic effects of acute fructose consumption^34-36.

CONCLUSION:

In India, the prevalence of diabetes mellitus is potentially epidemic. Diabetes has a very high rate of morbidity and death, as well as possible complications^37-40. As a result, families and society as a whole must bear heavy medical costs. Alas, research indicates that diabetes is emerging at a comparatively younger age in the nation and is linked to a wide range of complications. Diabetes rates are being impacted in India by a number of factors, including the country's ongoing rural-to-urban population migration, economic expansion, and ensuing lifestyle changes. The geographical, socioeconomic, and racial diversity of such a vast and heterogeneous nation means that, despite the rise in diabetes, there are still few studies examining the exact condition of the illness^41-43. Given the disease is now highly visible across all sections of society within India, there is now the demand for urgent research and intervention at regional and national levels to try to mitigate the potentially catastrophic increase in diabetes that is predicted for the upcoming years.

Because it is unregulated, the metabolism of fructose is extremely unusual. Cells may suffer from increased uric acid synthesis, endothelial dysfunction, oxidative stress, and increased lipogenesis as a result of unchecked fructose metabolism^44,45. In several animal models, fructose rich diet causes insulin resistance and other metabolic syndrome symptoms. An animal with high food diet of either glucose or starch does not exhibit these effects. Because study design, methods, and length are inconsistent, human epidemiological data are typically of low quality. It is yet unknown if inhibiting the transport or metabolism of fructose might have any positive therapeutic effects.

REFERENCES:

1. Osler W. The Principles and Practice of Medicine. 2nd ed. 1895.

2. Cory S, Ussery-Hall A, Griffin-Blake S, et al. Prevalence of selected risk behaviors and chronic diseases and conditions–steps communities, United States, 2006–2007. MMWR Morb Mortal Wkly Rep. 2010; 59(8): 1–37.

3. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, D'Agostino RB. Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s: The Framingham Heart Study. Circulation. 2006; 113(25): 2914–2918.

4. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000; 106(4): 473–481.

5. Pan WH, Flegal KM, Chang HY, Yeh WT, Yeh CJ, Lee WC. Body mass index and obesity-related metabolic disorders in Taiwanese and US whites and blacks: implications for definitions of overweight and obesity for Asians. Am J Clin Nutr. 2004; 79(1): 31–39.

6. Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 2009; 30(1): 96–116.

7. Zhao FQ, Keating AF. Functional properties and genomics of glucose transporters. Curr Genomics. 2007; 8(2): 113–128.

8. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004; 79: 537–543.

9. Bantle JP, Laine DC, Thomas JW. Metabolic effects of dietary fructose and sucrose in types I and II diabetic subjects. JAMA. 1983; 254(23): 3245–3248.

10. Cannon G, Einzig H, Heald FP. The impact of fructose on human blood glucose and insulin response. Diabetes Care. 1986; 9(1): 1–5.

11. Crapo PA, Kolterman OG. The metabolic effects of dietary fructose in diabetic and normal individuals. Diabetes Care. 1984; 7(5): 462–472.

12. Henry RR, Crapo PA, Thorburn AW. Current issues in fructose metabolism. Annu Rev Nutr. 1991; 11: 21–39.

13. Jenkins DJA, Wolever TMS, Taylor RH, et al. Glycemic index of foods: A physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981; 34(3): 362–366.

14. Swan MD, Shultz TD, Brigham SA, McGill JB. Comparative effects of sucrose and fructose on glucose and insulin levels in normal and diabetic patients. Lancet. 1966; 287(7432): 457–459.

15. Ludwig DS, Pereira MA, Kroenke CH, et al. Dietary fiber, weight gain, and cardiovascular risk factors in young adults. JAMA. 1999; 282: 1539–1546.

16. Kellett GL, Brot-Laroche E. Apical GLUT2: a major pathway of intestinal sugar absorption. Diabetes. 2005; 54: 3056–3062.

17. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab. 2005; 2: 1–14.

18. Straub SG, Sharp GW. Glucose-stimulated signalling pathways in biphasic insulin secretion. Diabetes Metab Res Rev. 2002; 18: 451–463.

19. Frayn KN, Kingman SM. Dietary sugars and lipid metabolism in humans. Am J Clin Nutr. 1995; 62(1): 250S–263S.

20. Le GM, Tobin V, Stolarczyk E, et al. Sugar sensing by enterocytes combines polarity, membrane bound detectors and sugar metabolism. J Cell Physiol. 2007; 213: 834–843.

21. Leturque A, Brot-Laroche E, Le GM. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am J Physiol Endocrinol Metab. 2009; 296–992.

22. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7:251–264.

23. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7(5): 251–264.

24. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7(5): 251–264.

25. Khan A, Watts GF. Fructose and glucose: A metabolic perspective. Nutr Metab. 2015; 12(1): 1–9.

26. Tappy L, Lê KA. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care. 2010; 13(4): 434–438.

27. Hughes J, Riddell MC. Fructose consumption and its impact on metabolic syndrome and related disorders. Curr Diabetes Rep. 2013; 13(5): 665–671.

28. George JA, Seshadri P. High fructose corn syrup: A review of the health implications. J Clin Nutr. 2010;92(4):897–904.

29. Tappy L, Lê KA. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care. 2010; 13(4): 434–438.

30. Schröder H, Marquez D. Comparative effects of fructose and glucose on metabolic syndrome features in animal models. Nutr Rev. 2014; 72(10): 655–667.

31. Havel PJ. Dietary fructose: Implications for dyslipidemia, hypertension, and obesity. Curr Opin Lipidol. 2005; 16(1): 12–19.

32. Tappy L, Lê KA. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care. 2010; 13(4): 434–438.

33. Lustig RH, Nadeau JH. The role of fructose in the development of obesity and metabolic syndrome: A review. Metabolism. 2014; 63(5): 651–661.

34. Stanhope KL, Havel PJ, Hagan LL. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2008; 88(6): 1733–1739.

35. Palaksha MN, Tamizh MT, Manjunatha E, Kumar GS. Comparative study of In-Vivo effects of Glipizide and Metformin HCl on plasma concentration of Aminophylline in healthy rabbits. Asian J Pharma Res. 2020 Jun 1; 10(2).

36. Manjunatha E, Nandeesh R, Ahmed SM. Antiulcer and ulcer healing potential of some medicinal plants: A review. Res J Pharmacog and Phytochem. 2022; 14(1): 37-42.

37. Mahesh Babasaheb Kolap, Nandini Maruti Bhise, Nisha Vasant Poojary, Rajesh Keshav Bhadke. Diabetes mellitus A Case Study. Res J Pharmacol Pharmacodynamics 2023; 15(1): 6-8.

38. Mansuri Sajid, Goswami Raksha, Jain Neetesh Kumar. In vitro Alpha glucosidase and Aldolase reductase Inhibitory activity of Holoptelea integrifolia. Res J Pharmacol Pharmacodynamics. 2021; 13(2): 35-40.

39. Aditya Mathur, Shweta Asthana, Samir Patra, Pulak Jana. A Review on Current Type-2 Diabetes Mellitus Treatment by selected Phytoconstituents. Res J Pharmacol Pharmacodynamics. 2023; 15(4): 205-1.

40. Indrayani D. Raut, Akshada N. Kakade, Jadhav Snehal, Jadhav Priyanka, Kabir Amruta. Survey on Antidiabetic Drugs. Res. J. Pharmacol Pharmacodynamics. 2017; 9(1): 10-12.

41. Bhavimani Guru, Nitin M. Pharmacological Studies on Drug-Drug Interactions between Antidiabetic Drug (Glibenclamide) and Selective Anti-HIV Drug (Lamivudine) in Rats and Rabbits. Res. J. Pharmacology & Pharmacodynamics. 2017; 9(3): 117-121

42. Vadivelan R, Dhanabal SP, Raja Rajeswari, Shanish A, Elango K, Suresh B. Oxidative Stress in Diabetes- A Key Therapeutic Agent. Research J Pharmacol & Pharmacodynamics. 2010; 2(3): 221-227.

43. SM Bhanushali, KM Modh, IS Anand, CN Patel, JB Dave. Novel Approaches for Diabetes Mellitus: A Review. Res J. Pharmacol & Pharmacodynamics. 2010; 2(2): 141-147.

44. AR Umarkar, AK Raut, SS Sonone, SS Pawar, RS Deshmukh, NV Bharude. Dibetes in India: A Review. Res J Pharmacology & Pharmacodynamics. 2011; 3(6): 345-352.

45. Vandna Dewangan, Himanshu Pandey. Pathophysiology and Management of Diabetes: A Review. Res J Pharmacol & Pharmacodynamics.2016; 8(3): 219-222.

Received on 22.08.2024 Revised on 14.11.2024

Accepted on 18.01.2025 Published on 14.05.2025

Available online from May 16, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(2):102-106.

DOI: 10.52711/2321-5836.2025.00016

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