Berberine And Its Study as An Antidiabetic Compound

Abstract

A metabolic disease called diabetes mellitus (DM) results in hyperglycemia and a number of chronic consequences that can be fatal. The high toxicity levels of existing diabetic medications and the expected further rise in diabetes prevalence have led to extensive research into natural substances, such as berberine, as potential alternative diabetes treatments. Berberine and several other alkaloid compounds, including some of its derivatives, have shown many bioactivities, such as neuraminidase and hepatoprotective activity. properties. By activating the AMPK system, berberine, an antidiabetic substance, is known to lower blood glucose levels, boost insulin production, and impair insulin resistance and glucose tolerance. Apart from being an antidiabetic compound, berberine also exhibits various other activities such as being anti-adipogenic, anti-hyperlipidemic, anti-inflammatory, and antioxidant. Many studies have been conducted on berberine, but its exact mechanism still needs to be clarified and requires further investigation. As a naturally occurring substance with a variety of uses, mostly as an antidiabetic, berberine and its mechanism will be covered in this review[1]. A metabolic condition with a high death and morbidity rate is type 2 diabetes (T2D). Non-coding RNAs, which include both long and small non-coding RNAs, are a new class of functional RNA molecules that control a variety of biological processes [2].

Keywords

Introduction

Patients with diabetes mellitus (DM), a metabolic disease, have elevated blood sugar levels (also known as hyperglycemia), which are brought on by problems with the body's metabolism of proteins, lipids, and carbs.  Weight loss, wounds that are difficult to heal, chronic loose stools, skin issues, and eyesight impairment are some of the symptoms that define patients with diabetes mellitus.  Diabetes mellitus (DM) can lead to a number of organ issues, including blood vessel damage, diabetic retinopathy, kidney failure, diabetic neuropathy, vision impairment or blindness, diabetic neuropathy, nerve diseases, and cardiovascular illness, which includes heart attacks and strokes [3].According to estimates from the International Diabetes Federation in 2021 [4], 537 million adults worldwide between the ages of 20 and 79 have been diagnosed with diabetes; by 2030, that number is expected to rise to 643 million, and by 2045, it will reach 783 million. Up to 6.7 million fatalities annually have been attributed to diabetes up to this point.DM can be categorized into two types, namely type 1 DM and type 2 DM. T1DM is a type of DM that occurs due to damage to the β-pancreatic cells responsible for insulin production and secretion. Hence, the level of insulin the body needs becomes less or even absent. This condition is known as insulin deficiency. The lack of insulin levels in T1DM patients leads to the need for insulin injection as a treatment method. Therefore, T1DM is also known as Insulin-Dependent Diabetes Mellitus (IDDM). T1DM can be found at a young age, such as in children and adolescents. T2DM, on the other hand, is a metabolic disease that causes insulin resistance. Insulin resistance is the inability of the body’s cells to respond to insulin hormone signals, resulting in impaired glucose metabolism.

Fig: Berberine fruit

This condition occurs due to the influence of unhealthy lifestyles such as food, lack of exercise,obesity, increased high-fat diets and lack of fiber, age, and genetic factors [5]. In addition,the accumulation of fatty acids such as diacylglycerol (DAG) and ceramides can also cause insulin resistance [6]. T2DM usually appears at the age of over 30 years, but T2DM has also begun to be found at a young age in recent years [3,7].There is another type of diabetes mellitus called mitochondrial diabetes which is a part of T2DM. Mitochondria are cytoplasmic organelles where cellular respiration occurs,and mitochondria primarily produce Adenosine Triphosphate (ATP) as chemical energy.Unlike nuclear DNA, mitochondrial DNA (mtDNA) has a high mutation rate due to the absence of a DNA repair mechanism [8,9].Mitochondrial diabetes mainly occurs due to mutations in mitochondrial DNA (mtDNA),thus why it is called mitochondrial diabete. These mutations are then associated with reduced function of pancreatic β-cell insulin. One of the mutations found is the mutation of the A3243G nucleotide of the tRNALeu mtDNA gene, which is heteroplasmy that causes maternally inherited diabetes accompanied by hearing loss [8,10,11]. Some of the other mutations that are associated with diabetes are C3271T, C12258A, A8296G, which causes cardiomyopathy [12], and T4291T, which is associated with myopathy, hypomagnesemia, and hypokalemia [13]. There is also a G9053A mutation at the ATP6 gene that was found in T2DM patients with cataracts, and its assay detection research was conducted by Ilmi et al.in 2023 along with the T15663C mutation in the CYB gene [14,15]. It is known that a mutation of mtDNA is responsible for approximately 80% of adult mitochondrial diseases [9].One of the effects of mutations in mitochondrial functions results in a lack of ATP that causes dysfunction in the secretion of insulin [16].

Drug profile:

Morphological Characteristics:

*Leaf shape: basic, alternating, and frequently waxy.

* Flower shape: tiny, white or yellow, and frequently found in groups.

*Fruit shape: Small, berry-like, and often red or purple.

* Stem shape: Woody, frequently prickly[25].

Berberine as a Therapeutic Natural Compound :

Traditional medicine has made extensive use of alkaloid substances. Antimalarial, antihyperglycemic, anti-asthmatic,anticancer,antibacterial,and antidiabetic properties are among the many pharmacological actions of alkaloid substances.  Berberine, an isoquinoline alkaloid, is one of those alkaloid compounds that is used as a medicinal agent to treat type 2 diabetes[26,27,28].By activating the 5-adenosine monophosphate-activated protein kinase (AMPK) pathway, berberine is known to lower blood glucose levels, increase insulin secretion, lower body weight and lipid levels, attenuate glucose tolerance and insulin resistance, raise glucagon-like peptide-1 (GLP-1) levels, decrease the production of reactive oxygen species (ROS), reverse mitochondrial dysfunction, and suppress inflammation[29].

Fig 2. Structure of berberines.  Berberine, an isoquinoline alkaloid with a quartenery base structure that has been utilized in traditional medicine across multiple locations and is known to have antidiabetic properties.

• Berberine and Structure-Activity Relationship:

Berberine, a naturally occurring substance classified as an alkaloid group compound—more specifically, an isoquinoline alkaloid—has been utilized as traditional medicine in many parts of the world.  It is well known that berberine has antidiabetic properties.  Coptisin is another alkaloid molecule that has been shown to have antidiabetic properties.Coptisin, a bitter-tasting member of the isoquinoline alkaloid group, is frequently used in Chinese herbal medicine to treat bacterial infection-related digestive issues[30].

Berberine as an Antidiabetic Compound:

Numerous investigations have examined berberine's potential as an antidiabetic agent[26,27,29,30].Berberine, an antidiabetic substance, stimulates glycolysis by suppressing hepatic gluconeogenesis and adipogenesis, increasing insulin production, and increasing glucokinase activity.Although AMPK is the primary mechanism via which this activity takes place, additional research has suggested that berberine works through other routes or enzymes[26,31].

• Berberine as Anti-diabetic Agent via The AMPK Pthaway:

The AMP/ATP ratio, which measures the energy level in the cell, determines whether the AMPK anergy-sensing/signaling mechanism is engaged or inactivated.  AMPK activation controls mitochondrial activity and improves insulin sensitivity[26,32,33].By causing Thr172 on the α subunit of AMPK to get phosphorylated, berberine activates AMPK [34,35].By reducing ATP production in mitochondria and raising the AMP/ATP ratio, berberine can also activate AMPK [36,37].Berberine directly suppresses the monoamine oxidase (MAO) enzyme found on the outer membrane of mitochondria [38].

Berberine reduces mitochondrial function linked to AMPK activation, according to multiple studies.  Complex I of the electron transport chain, which is in charge of mitochondrial respiration, is known to be inhibited by berberine.  This inhibitory action is likewise shared by rosiglitazone and metformin, two popular antidiabetic medications[37].

1. Efficacy of berberine on diabetic patients:

Chinese literature contains a wealth of clinical studies regarding berberine's hypoglycemic effects.  Although the majority of the studies were poorly constructed, berberine was said to have similar blood glucose-lowering properties to metformin or sulphonureas.  Berberine has thus far been the subject of numerous clinical trials.  Our research shown that giving patients with recently diagnosed type 2 diabetes 0.5 g of berberine t.i.d. at the start of each meal could lower their fasting blood glucose (FBG) and postprandial blood glucose (PBG)[47].There was a 2.0% decrease in hemoglobin A1c (HbA1c) levels, which is similar to what metformin does.  Berberine decreased HbA1c by 0.8% in insulin-injecting diabetic individuals with poorly managed conditions.  Apart from the hypoglycemic effect, berberine therapy also reduced total cholesterol, low-density lipoprotein (LDL), and plasma triglycerides[47,48]. Another group likewise observed similar findings[49].Following berberine (0.5 g b.i.d.) medication, HbA1c dropped by 0.9% in this two-center, randomized, double-blind study.  Every metric, including cholesterol and blood sugar, saw a notable improvement.  Only mild gastrointestinal side effects, like diarrhea, flatulence, and constipation, were noted in brief clinical trials.  Plasma levels of creatinine, γ-glutamyl transpeptidase (γ-GT), and alanine aminotransferase (ALT) did not significantly alter during our investigation.  In a different investigation, the berberine group showed a significant decrease in serum ALT, aspartate aminotransaminase (AST), and γ-GT.  This suggests that at the dosage used in the aforementioned investigations, berberine had no toxicity to the liver or kidney.  Large-scale, long-term clinical trials are still required to assess the effectiveness of berberine in the treatment of diabetes, despite the fact that its hypoglycemic impact has been documented in growing Chinese literature.

8683511. I. Berberine on glucose metabolism in animals:

Both dietary and genetic rodent models of type 2 diabetes demonstrated that berberine reduced weight gain, improved insulin sensitivity, and decreased blood glucose.  Berberine reduced FBG, PBG, fasting insulin, body weight, and the homeostasis model of assessment-insulin resistance (HOMA-IR) in rats fed a high-fat diet that caused obesity[47,50,51].Berberine administration dramatically reduced FBG and enhanced insulin tolerance in rats with type 2 diabetes caused by a high-fat diet and a low dosage of streptozotocin (STZ)[51,52].

Mechanisms Of Action:

1)AMPK Pathway Activation: Berberine improves insulin sensitivity and muscle glucose absorption by activating the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway [40].

2)Increasing Insulin Secretion: Berberine lowers blood glucose levels by increasing insulin secretion [40].

3)Improving Insulin Sensitivity: Berberine increases muscle absorption of glucose and decreases hepatic synthesis of glucose, improving insulin sensitivity [41].

4)Reducing Glucose Absorption: Berberine reduces the absorption of glucose by inhibiting intestinal α-glucosidase [42].

5)Antioxidant and Anti-Inflammatory Effects: Berberine's anti-inflammatory and antioxidant qualities reduce inflammation and oxidative stress, which enhances insulin sensitivity[43].

6)Modulating Gut Microbiome: Berberine may alter glucose metabolism by modifying the gut microbiota [44].

7)Inhibiting Hepatic Glucose Production: Berberine inhibits hepatic glucose production, reducing glucose output[45].

8)Enhancing Glucose Uptake: Berberine enhances glucose uptake in skeletal muscle cells[46].

CONCLUSION:

A metabolic disease called diabetes mellitus results in hyperglycemia, which can cause a number of long-term problems and even death.  High-risk antidiabetic medications are used to treat type 2 diabetes brought on by insulin resistance. Berberine is one of the natural substances that have been explored as potential alternative antidiabetic medications.By enhancing the body's control over glucose and lipid metabolism, the isoquinoline alkaloid molecule berberine exhibits anti-hyperglycemia properties.  Berberine has the ability to suppress mitochondrial activity and trigger the AMPK pathway, which in turn interacts with a number of other processes linked to the metabolism of fat or glucose.  In addition to its anti-diabetic properties, berberine has been shown to have antioxidant properties via lowering the buildup of reactive oxygen species and to have anti-inflammatory properties. Numerous berberine mechanisms are yet unknown.  However, berberine has a lot of promise as an oral antidiabetic medication based on the mechanisms that have been suggested.  The limited absorption and high level of toxicity of berberine in its free form are some of its disadvantages, though.  Future research on berberine is required, particularly in the investigation of berberine derivatives or structural modification, in order to produce a berberine product with good pharmacokinetics in addition to good antidiabetic potential.

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