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). 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.

Contents

Examples and differences

Examples of alpha-glucosidase inhibitors include:

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 by the body, 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. [1] [2]

Natural alpha glucosidase inhibitors

There are a large number of natural products with alpha-glucosidase inhibitor action. [3] [4]

For example, research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect. [5] [6] [7] [8] [9] [10] The reason Maitake lowers blood sugar is because the mushroom naturally contains an alpha glucosidase inhibitor. [11] Another plant attracting a lot of attention is Salacia oblonga . [12]

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. 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.

A Cochrane systematic review assessed the effect of AGIs in people with impaired glucose tolerance, impaired fasting blood glucose, elevated glycated hemoglobin A1c (HbA1c). [13] 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. [13] 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. [13]

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. [14]

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.

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.

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. [15]

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.

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 cystoides intestinalis is another reported side effect. [16] 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. 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

Related Research Articles

<span class="mw-page-title-main">Type 2 diabetes</span> Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Maltase</span> Enzyme

Maltase is one type of alpha-glucosidase enzymes located in the brush border of the small intestine. This enzyme catalyzes the hydrolysis of disaccharide maltose into two simple sugars of glucose. Maltase is found in plants, bacteria, yeast, humans, and other vertebrates. It is thought to be synthesized by cells of the mucous membrane lining the intestinal wall.

<span class="mw-page-title-main">Acarbose</span> Chemical compound

Acarbose (INN) is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay, in North America as Precose, and in Canada as Prandase.

Glycated hemoglobin is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously bond with hemoglobin when present in the bloodstream. However, glucose is only 21% as likely to do so as galactose and 13% as likely to do so as fructose, which may explain why glucose is used as the primary metabolic fuel in humans.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Tagatose</span> Chemical compound

Tagatose is a hexose monosaccharide. It is found in small quantities in a variety of foods, and has attracted attention as an alternative sweetener. It is often found in dairy products, because it is formed when milk is heated. It is similar in texture and appearance to sucrose :215 and is 92% as sweet,:198 but with only 38% of the calories.:209 Tagatose is generally recognized as safe by the Food and Agriculture Organization and the World Health Organization, and has been since 2001. Since it is metabolized differently from sucrose, tagatose has a minimal effect on blood glucose and insulin levels. Tagatose is also approved as a tooth-friendly ingredient for dental products. Consumption of more than about 30 grams of tagatose in a dose may cause gastric disturbance in some people, as it is mostly processed in the large intestine, similar to soluble fiber.:214

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

<span class="mw-page-title-main">Psicose</span> Chemical compound

D-Psicose (C6H12O6), also known as D-allulose, or simply allulose, is a low-calorie epimer of the monosaccharide sugar fructose, used by some major commercial food and beverage manufacturers as a low-calorie sweetener. First identified in wheat in the 1940s, allulose is naturally present in small quantities in certain foods.

<span class="mw-page-title-main">Isomaltulose</span> Chemical compound

Isomaltulose is a disaccharide carbohydrate composed of glucose and fructose. It is naturally present in honey and sugarcane extracts and is also produced industrially from table sugar (sucrose) and used as a sugar alternative.

α-Glucosidase Enzyme

α-Glucosidase (EC 3.2.1.20, is a glucosidase located in the brush border of the small intestine that acts upon α bonds:

A diabetic diet is a diet that is used by people with diabetes mellitus or high blood sugar to minimize symptoms and dangerous complications of long-term elevations in blood sugar.

<span class="mw-page-title-main">Glycoside hydrolase</span> Class of enzymes which break glycosidic bonds via hydrolysis

In biochemistry, glycoside hydrolases are a class of enzymes which catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes, with roles in nature including degradation of biomass such as cellulose (cellulase), hemicellulose, and starch (amylase), in anti-bacterial defense strategies, in pathogenesis mechanisms and in normal cellular function. Together with glycosyltransferases, glycosidases form the major catalytic machinery for the synthesis and breakage of glycosidic bonds.

<span class="mw-page-title-main">Miglitol</span> Chemical compound

Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to break down complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates into monosaccharides which can be absorbed by the body.

<span class="mw-page-title-main">Voglibose</span> Alpha-glucosidase inhibitor

Voglibose is an alpha-glucosidase inhibitor used for lowering postprandial blood glucose levels in people with diabetes mellitus. Voglibose is a research product of Takeda Pharmaceutical Company, Japan's largest pharmaceutical company. Vogilbose was discovered in 1981, and was first launched in Japan in 1994, under the trade name BASEN, to improve postprandial hyperglycemia in diabetes mellitus.

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<span class="mw-page-title-main">Glucosidases</span> Enzymes which hydrolyse glycosides

Glucosidases are the glycoside hydrolase enzymes categorized under the EC number 3.2.1.

<span class="mw-page-title-main">Remogliflozin etabonate</span> Chemical compound

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References

  1. ↑ 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.
  2. ↑ 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. doi:10.1128/AEM.65.4.1644-1651.1999. PMC   91232 . PMID   10103262.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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
  13. 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). doi:10.1002/14651858.CD005061.pub3. PMC   6517235 . PMID   30592787.
  14. ↑ 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
  15. ↑ Venable SJ, Aschenbrenner DS (2006). Drug Therapy In Nursing . Hagerstown, MD: Lippincott Williams & Wilkins. ISBN   0-7817-4839-9.[ page needed ]
  16. ↑ 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. doi: 10.3390/jcm11195918 . Retrieved 2024-05-01.
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