Alpha-glucosidase inhibitor

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Alpha-glucosidase inhibitors (AGIs) are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates (such as starch and table sugar). Naturally occurring AGIs are found in raw plants/herbs such as cinnamon and white mulberry as well as some bacteria. [1] [2] [3] [4] Carbohydrates are normally converted into simple sugars (monosaccharides) by alpha-glucosidase enzymes present on cells lining the intestine, enabling monosaccharides to be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of dietary carbohydrates on blood sugar. [5] [1]

Contents

Examples and differences

Examples of alpha-glucosidase inhibitors include:[ citation needed ]

Even though the drugs have a similar mechanism of action, there are subtle differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol is fairly well absorbed into the bloodstream, as opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to alpha-glucosidase, and is degraded by gut bacterial maltogenic alpha-amylase and cyclomaltodextrinase. [6] [7]

Natural alpha glucosidase inhibitors

There are a large number of natural products with alpha-glucosidase inhibitor action. [8] [9] [1] In fact, the prototypic drug of this class (acarbose) is discovered from soil bacteria. [10]

For example, research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect. [11] [12] [13] [14] [15] [16] The reason Maitake lowers blood sugar is because the mushroom naturally contains an alpha glucosidase inhibitor. [17]

All cinnamon species show acarbose-like activity. [5] A single dose of raw cinnamon before a meal containing complex carbohydrates decreases the postprandial hyperglycemia (higher than 140 mg/dL; >7.8 mmol/L) in patients with type II diabetes. [1] Another plant attracting a lot of attention is Salacia oblonga . [18]

Clinical use

Alpha-glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia. The intake of a single dose before a meal containing complex carbohydrates clearly suppresses the glucose spike and may decrease the postprandial hyperglycemia (higher than 140 mg/dL; >7.8 mmol/L) in patients with type II diabetes. [1] This ability is observed in the native/raw state of the alpha-amylase inhibitor; therefore, its consumption inside a meal that undergo heating (baking, frying or cooking/boiling) is expected to blunt its property to decrease the activity of carbohydrate digesting enzymes. [1] [19] They may be used as monotherapy in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs.[ citation needed ]

A Cochrane systematic review assessed the effect of AGIs in people with impaired glucose tolerance, impaired fasting blood glucose, elevated glycated hemoglobin A1c (HbA1c). [20] It was found that Acarbose appeared to reduce incidence of diabetes mellitus type 2 when compared to placebo, however there was no conclusive evidence that acarbose compare to diet and exercise, metformin, placebo, no intervention improved all-cause mortality, reducer or increased risk of cardiovascular mortality, serious or non-serious adverse events, non-fatal stroke, congestive heart failure, or non-fatal myocardial infarction. [20] The same review found that there was no conclusive evidence that voglibose compared to diet and exercise or placebo reduced incidence of diabetes mellitus type 2, or any of the other measured outcomes. [20]

In patients with diabetes mellitus type 1, alpha-glucosidase inhibitors use has not been officially approved by the Food and Drug Administration in the US but some data exists on the effectiveness in this population, showing potential benefits weighted against an increased risk of hypoglycemia. [21]

Mechanism of action

Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine.[ citation needed ]

Acarbose also blocks pancreatic alpha-amylase in addition to inhibiting membrane-bound alpha-glucosidases. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine.[ citation needed ]

Inhibition of these enzyme systems reduces the rate of digestion of carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drugs therapies is to decrease current blood glucose levels: the long-term effect is a small reduction in hemoglobin A1c level. [22]

Dosing

Since alpha-glucosidase inhibitors are competitive inhibitors of digestive enzymes, they must be taken at the start of main meals to have maximal effect. Their effects on blood sugar levels following meals will depend on the amount of complex carbohydrates in the meal.[ citation needed ]

Formulation

The health benefits of a alpha-glucosidase-inhibiting herb powder were shown to be stronger when the powder is consumed orally dissolved in water as a beverage in comparison to its intake as ordinary hard gelatin capsules. [1]

The package insert of acarbose tablet lists two ways to take it: chewing it down with the first bites of food, or swallowing it some time before eating. With the same brand of acarbose tablet, chewing food appears effective than swallowing in combating the blood sugar rise from drinking sucrose water. [23]

Side effects and precautions

Since alpha-glucosidase inhibitors prevent the degradation of complex carbohydrates into glucose, the carbohydrates will remain in the intestine. In the colon, bacteria will digest the complex carbohydrates, thereby causing gastrointestinal side effects such as flatulence and diarrhea. Since these effects are dose-related, it is generally advised to start with a low dose and gradually increase the dose to the desired amount. Pneumatosis intestinalis is another reported side effect. [24]

If a patient using an alpha-glucosidase inhibitor suffers from an episode of hypoglycemia, the patient should eat something containing monosaccharides such as glucose tablets or a soft drink containing HFCS. Since the drug will prevent the digestion of polysaccharides (or non-monosaccharides), non-monosaccharide foods may not effectively reverse a hypoglycemic episode in a patient taking an alpha-glucosidase inhibitor.[ citation needed ]

See also

References

  1. 1 2 3 4 5 6 7 Moreira, Fernanda Duarte; Reis, Caio Eduardo Gonçalves; Gallassi, Andrea Donatti; Moreira, Daniel Carneiro; Welker, Alexis Fonseca (2024-10-09). Dardari, Dured (ed.). "Suppression of the postprandial hyperglycemia in patients with type 2 diabetes by a raw medicinal herb powder is weakened when consumed in ordinary hard gelatin capsules: A randomized crossover clinical trial". PLOS ONE. 19 (10): e0311501. Bibcode:2024PLoSO..1911501M. doi: 10.1371/journal.pone.0311501 . ISSN   1932-6203. PMC   11463819 . PMID   39383145.
  2. ↑ Hayward, Nicholas J.; McDougall, Gordon J.; Farag, Sara; Allwood, J. William; Austin, Ceri; Campbell, Fiona; Horgan, Graham; Ranawana, Viren (December 2019). "Cinnamon Shows Antidiabetic Properties that Are Species-Specific: Effects on Enzyme Activity Inhibition and Starch Digestion". Plant Foods for Human Nutrition. 74 (4): 544–552. Bibcode:2019PFHN...74..544H. doi:10.1007/s11130-019-00760-8. ISSN   0921-9668. PMC   6900266 . PMID   31372918.
  3. ↑ Lown, Mark; Fuller, Richard; Lightowler, Helen (2017). "Mulberry-extract improves glucose tolerance and decreases insulin concentrations in normoglycaemic adults: Results of a randomised double-blind placebo-controlled study". PLOS ONE. 12 (2): e0172239. Bibcode:2017PLoSO..1272239L. doi: 10.1371/journal.pone.0172239 . PMC   5321430 . PMID   28225835.
  4. ↑ Lee, Hyunjin; Seo, Myung-Ji; Jang, Sungho (2024). "1‑Deoxynojirimycin‑producing bacteria: production, optimization, biosynthesis, biological activities". Biotechnology and Bioprocess Engineering. 29: 981–992. doi:10.1007/s12257-024-00159-6.
  5. 1 2 Hayward, Nicholas J.; McDougall, Gordon J.; Farag, Sara; Allwood, J. William; Austin, Ceri; Campbell, Fiona; Horgan, Graham; Ranawana, Viren (December 2019). "Cinnamon Shows Antidiabetic Properties that Are Species-Specific: Effects on Enzyme Activity Inhibition and Starch Digestion". Plant Foods for Human Nutrition. 74 (4): 544–552. Bibcode:2019PFHN...74..544H. doi:10.1007/s11130-019-00760-8. ISSN   0921-9668. PMC   6900266 . PMID   31372918.
  6. ↑ Jang MU, Kang HJ, Jeong CK, Kang Y, Park JE, Kim TJ (February 2018). "Functional expression and enzymatic characterization of Lactobacillus plantarum cyclomaltodextrinase catalyzing novel acarbose hydrolysis". Journal of Microbiology. 56 (2): 113–118. doi:10.1007/s12275-018-7551-3. PMID   29392561. S2CID   255583941.
  7. ↑ Kim TJ, Kim MJ, Kim BC, Kim JC, Cheong TK, Kim JW, Park KH (April 1999). "Modes of action of acarbose hydrolysis and transglycosylation catalyzed by a thermostable maltogenic amylase, the gene for which was cloned from a Thermus strain". Applied and Environmental Microbiology. 65 (4): 1644–1651. Bibcode:1999ApEnM..65.1644K. doi:10.1128/AEM.65.4.1644-1651.1999. PMC   91232 . PMID   10103262.
  8. ↑ Benalla W, Bellahcen S, Bnouham M (July 2010). "Antidiabetic medicinal plants as a source of alpha glucosidase inhibitors". Current Diabetes Reviews. 6 (4): 247–254. doi:10.2174/157339910791658826. PMID   20522017.
  9. ↑ Ji F, Xiao G, Dong L, Ma Z, Ni J (June 2010). "[Development of alpha-glucosidase inhibitor from medicinal herbs]" 药用植物来源的α-葡萄糖苷酶抑制剂研究进展[Development of α-glucosidase inhibitor from medicinal herbs]. Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica (in Chinese). 35 (12): 1633–1640. doi:10.4268/cjcmm20101229. PMID   20815224.
  10. ↑ Tsunoda T, Samadi A, Burade S, Mahmud T (June 2022). "Complete biosynthetic pathway to the antidiabetic drug acarbose". Nature Communications. 13 (1) 3455. Bibcode:2022NatCo..13.3455T. doi:10.1038/s41467-022-31232-4. PMC   9200736 . PMID   35705566.
  11. ↑ Konno S, Tortorelis DG, Fullerton SA, Samadi AA, Hettiarachchi J, Tazaki H (December 2001). "A possible hypoglycaemic effect of maitake mushroom on Type 2 diabetic patients". Diabetic Medicine. 18 (12): 1010. doi:10.1046/j.1464-5491.2001.00532-5.x. PMID   11903406. S2CID   34210764.
  12. ↑ Hong L, Xun M, Wutong W (April 2007). "Anti-diabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice". The Journal of Pharmacy and Pharmacology. 59 (4): 575–582. doi:10.1211/jpp.59.4.0013. PMID   17430642. S2CID   85987141.
  13. ↑ Kubo K, Aoki H, Nanba H (August 1994). "Anti-diabetic activity present in the fruit body of Grifola frondosa (Maitake). I". Biological & Pharmaceutical Bulletin. 17 (8): 1106–1110. doi: 10.1248/bpb.17.1106 . PMID   7820117.
  14. ↑ Lo HC, Hsu TH, Chen CY (2008). "Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic rats". The American Journal of Chinese Medicine. 36 (2): 265–285. doi:10.1142/S0192415X0800576X. PMID   18457360.
  15. ↑ Manohar V, Talpur NA, Echard BW, Lieberman S, Preuss HG (January 2002). "Effects of a water-soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice". Diabetes, Obesity & Metabolism. 4 (1): 43–48. doi:10.1046/j.1463-1326.2002.00180.x. PMID   11874441. S2CID   23788507.
  16. ↑ Horio H, Ohtsuru M (February 2001). "Maitake (Grifola frondosa) improve glucose tolerance of experimental diabetic rats". Journal of Nutritional Science and Vitaminology. 47 (1): 57–63. doi: 10.3177/jnsv.47.57 . PMID   11349892.
  17. ↑ Matsuur H, Asakawa C, Kurimoto M, Mizutani J (July 2002). "Alpha-glucosidase inhibitor from the seeds of balsam pear (Momordica charantia) and the fruit bodies of Grifola frondosa". Bioscience, Biotechnology, and Biochemistry. 66 (7): 1576–1578. doi: 10.1271/bbb.66.1576 . PMID   12224646.
  18. ↑ Vyas N, Mehra R, Makhija R. Salacia - The new multi-targeted approach in diabetics. Ayu. 2016;37(2):92-97. doi:10.4103/ayu.AYU_134_13
  19. ↑ Mulimani, V. H.; Supriya, D. (September 1993). "Effect of heat treatments on alpha-amylase inhibitor activity in sorghum (Sorghum bicolour L.)" . Plant Foods for Human Nutrition. 44 (2): 181–186. Bibcode:1993PFHN...44..181M. doi:10.1007/BF01088383. ISSN   0921-9668. PMID   8378275.
  20. 1 2 3 Moelands, Suzanne VL; Lucassen, Peter LBJ; Akkermans, Reinier P; De Grauw, Wim JC; Van de Laar, Floris A (2018-12-28). Cochrane Metabolic and Endocrine Disorders Group (ed.). "Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus". Cochrane Database of Systematic Reviews. 2018 (12): CD005061. doi:10.1002/14651858.CD005061.pub3. PMC   6517235 . PMID   30592787.
  21. ↑ Alternative Agents in Type 1 Diabetes in Addition to Insulin Therapy: Metformin, Alpha-Glucosidase Inhibitors, Pioglitazone, GLP-1 Agonists, DPP-IV Inhibitors, and SGLT-2 Inhibitors. Michelle DeGeeter, PharmD, CDE, Bobbie Williamson, PharmD, BCACP, CDE. Journal of Pharmacy Practice Vol 29, Issue 2, pp. 144 - 159. First Published October 13, 2014 https://doi.org/10.1177/0897190014549837
  22. ↑ Venable SJ, Aschenbrenner DS (2006). Drug Therapy In Nursing . Hagerstown, MD: Lippincott Williams & Wilkins. ISBN   0-7817-4839-9.[ page needed ]
  23. ↑ Ji, W.; Yang, S.; Zhang, W.; Sun, Z.; Wen, Q.; He, K. (2021). "Pharmacodynamic comparison of acarbose tablets in Chinese healthy volunteers under chewing and swallowing conditions". Journal of Clinical Pharmacy and Therapeutics. 46 (3): 814–819. doi:10.1111/jcpt.13361. PMID   33462825.
  24. ↑ McKinley, Blake; Santiago, Mariangela; Pak, Christi; Nguyen, Nataly; Zhong, Qing (2022-10-07). "Pneumatosis Intestinalis Induced by Alpha-Glucosidase Inhibitors in Patients with Diabetes Mellitus". Journal of Clinical Medicine. 11 (19): 5918. doi: 10.3390/jcm11195918 . PMC   9571713 . PMID   36233785.
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