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). They are found in raw plants/herbs such as cinnamon and bacteria (containing the inhibitor acarbose). [1] [2] 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. [3] [1]

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. [4] [5]

Natural alpha glucosidase inhibitors

There are a large number of natural products with alpha-glucosidase inhibitor action [6] [7] [1]

For example, research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect. [8] [9] [10] [11] [12] [13] The reason Maitake lowers blood sugar is because the mushroom naturally contains an alpha glucosidase inhibitor. [14] All cinnamon species show acarbose-like activity. [3] 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 . [15]

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] [16] 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). [17] 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. [17] 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. [17]

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. [18]

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. [19]

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.

Formulation

The benefits of alpha-glucosidase inhibitors on health 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]

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. [20] 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">Hyperglycemia</span> Too much blood sugar, usually because of diabetes

Hyperglycemia or hyperglycaemia is the situation in which blood glucose level is higher than in a healthy subject. A fasting healthy human shows blood glucose level up to 5.6 mmol/L. After a meal (postprandial) containing carbohydrates, healthy subjects show postpandrial euglycemic peaks of less than 140 mg/dL. Therefore, fasting hyperglycemia are values of blood glucose higher than 5.6 mmol/L whereas postprandial hyperglycemia are values higher than 140 mg/dL. Postprandial hyperglycemic levels as high as 155 mg/dL at 1-h are associated with T2DM-related complications, which worsen as the degree of hyperglycemia increases. Patients with diabetes are oriented to avoid exceeding the recommended postprandial threshold of 160 mg/dL for optimal glycemic control. Values of blood glucose higher than 160 mg/dL are classified as ‘very high’ hyperglycemia, a condition in which an excessive amount of glucose (glucotoxicity) circulates in the blood plasma. These values are higher than the renal threshold of 180 mg/dL up to which glucose reabsorption is preserved at physiological rates and insulin therapy is not necessary. Blood glucose values higher than the cutoff level of 200 mg/dL are used to diagnose T2DM and strongly associated with metabolic disturbances, although symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/L (~250–300 mg/dL). A subject with a consistent fasting blood glucose range between ~5.6 and ~7 mmol/L is considered slightly hyperglycemic, and above 7 mmol/L is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dL) can produce noticeable organ damage over time.

<span class="mw-page-title-main">Type 2 diabetes</span> Form of diabetes mellitus

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. Other symptoms include increased hunger, having a sensation of pins and needles, and sores (wounds) that heal slowly. Symptoms often develop slowly. Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy, which can result in blindness, kidney failure, and poor blood flow in the lower-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">Blood sugar level</span> Concentration of glucose present in the blood (Glycaemia)

The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis.

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

Maltase is an informal name for a family of enzymes that catalyze the hydrolysis of disaccharide maltose into two simple sugars of glucose. Maltases are found in plants, bacteria, yeast, humans, and other vertebrates.

<span class="mw-page-title-main">Digestive enzyme</span> Class of enzymes

Digestive enzymes take part in the chemical process of digestion, which follows the mechanical process of digestion. Food consists of macromolecules of proteins, carbohydrates, and fats that need to be broken down chemically by digestive enzymes in the mouth, stomach, pancreas, and duodenum, before being able to be absorbed into the bloodstream. Initial breakdown is achieved by chewing (mastication) and the use of digestive enzymes of saliva. Once in the stomach further mechanical churning takes place mixing the food with secreted gastric acid. Digestive gastric enzymes take part in some of the chemical process needed for absorption. Most of the enzymatic activity, and hence absorption takes place in the duodenum.

<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.

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

D-Psicose (C6H12O6), also known as D-allulose or simply allulose, is an epimer of fructose that is used by some commercial food and beverage manufacturers as a low-calorie sweetener. Allulose occurs naturally in small quantities in a variety of foods. It was first identified in the 1940s, although the enzymes needed to produce it on an industrial scale were not discovered until the 1990s.

<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:

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

Miglitol is an oral alpha-glucosidase inhibitor used in the treatment of type 2 diabetes. It works by reversibly inhibiting alpha-glucosidase enzymes in the small intestine, which delays the digestion of complex carbohydrates and subsequently reduces postprandial glucose levels. Approved for clinical use since 1998, miglitol has demonstrated efficacy in improving glycemic control, reducing HbA1c levels, and decreasing both fasting and postprandial plasma glucose concentrations in long-term clinical trials. Additionally, recent studies have suggested that miglitol may have potential as an anti-obesity agent, showing promise in reducing body weight and body mass index in obese or diabetic patients. While generally well-tolerated, the most common side effects associated with miglitol are gastrointestinal disturbances, which are typically mild to moderate and tend to decrease over time.

<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.

Chronic Somogyi rebound is a contested explanation of phenomena of elevated blood sugars experienced by diabetics in the morning. Also called the Somogyi effect and posthypoglycemic hyperglycemia, it is a rebounding high blood sugar that is a response to low blood sugar. When managing the blood glucose level with insulin injections, this effect is counter-intuitive to people who experience high blood sugar in the morning as a result of an overabundance of insulin at night.

α-Amylase Enzyme that hydrolyses α bonds of large α-linked polysaccharides

α-Amylase is an enzyme that hydrolyses α bonds of large, α-linked polysaccharides, such as starch and glycogen, yielding shorter chains thereof, dextrins, and maltose, through the following biochemical process:

The dawn phenomenon, sometimes called the dawn effect, is an observed increase in blood sugar (glucose) levels that takes place in the early-morning, often between 2 a.m. and 8 a.m. First described by Schmidt in 1981 as an increase of blood glucose or insulin demand occurring at dawn, this naturally occurring phenomenon is frequently seen among the general population and is clinically relevant for patients with diabetes as it can affect their medical management. In contrast to Chronic Somogyi rebound, the dawn phenomenon is not associated with nocturnal hypoglycemia.

<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">Postprandial glucose test</span> Medical test

A postprandial glucose (PPG) test is a blood glucose test that determines the amount of glucose in the plasma after a meal. The diagnosis is typically restricted to postprandial hyperglycemia due to lack of strong evidence of co-relation with a diagnosis of diabetes.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">1,5-Anhydroglucitol</span> Chemical compound

1,5-Anhydroglucitol, also known as 1,5-AG, is a naturally occurring monosaccharide found in nearly all foods. Blood concentrations of 1,5-anhydroglucitol decrease during times of hyperglycemia above 180 mg/dL, and return to normal levels after approximately 2 weeks in the absence of hyperglycemia. As a result, it can be used for people with either type-1 or type-2 diabetes mellitus to identify glycemic variability or a history of high blood glucose even if current glycemic measurements such as hemoglobin A1c (HbA1c) and blood glucose monitoring have near normal values. Despite this possible use and its approval by the FDA, 1,5-AG tests are rarely ordered. There is some data suggesting that 1,5-AG values are useful to fill the gap and offer complementary information to HbA1c and fructosamine tests.

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

In molecular biology, alpha-amylase inhibitor is a protein family which inhibits mammalian alpha-amylases specifically, by forming a tight stoichiometric 1:1 complex with alpha-amylase. This family of inhibitors has no action on plant and microbial alpha amylases.

References

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  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. doi:10.1007/s11130-019-00760-8. ISSN   0921-9668. PMC   6900266 . PMID   31372918.
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  4. ↑ 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.
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  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
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  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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
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  18. ↑ 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
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  20. ↑ 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 . PMC   9571713 . Retrieved 2024-05-01.
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