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  • A Systematic Review on Management of Type 2 Diabetes Mellitus: Conventional Treatment Strategies v/s Phyto-Alkaloids as Natural Alternatives

  • Photo Raj Kumar* Photo Leena Thakur Photo Pardeep Kumar

  • Department of Plant Sciences, School of Life Sciences, Central University of Himachal Pradesh, Shahpur Campus – 176206, Kangra (HP), India.

Abstract

Diabetes mellitus is a multifactorial global pandemic that occurs due to an impaired production or action of insulin and is being prevalent at an alarming rate. The WHO supported organization NCD-RisC has reported that there are over 800 million diabetic individuals worldwide. Pharmacological and non-pharmacological treatment strategies aim to protect diabetic patients from various microvascular disorders, including retinopathy, nephropathy, neuropathy and dermopathy. The conducted systematic review adopted the methodology of Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) to conduct this systematic review and a flow chart has been used to provide a systematic search of included studies. Adhesion to intensive glycemic control methods also decreases the risk of macrovascular diseases such as cerebrovascular diseases, coronary artery disease (CAD), peripheral arterial disease, walking impairment, and amputations. This systematic review discusses the pathophysiology of T2DM and its current treatment strategies, including pharmacotherapy (biguanides, thiazolidinediones, sulphonylureas, meglinides, ?-glucosidase inhibitors, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1R agonists, amylin agonists and insulins) and non-pharmacological methods (bariatric surgery, insulin pumps, and CGM) along with their contraindications and limitations. The conducted study has compiled various antidiabetic plant-based alkaloids (e.g., berberine, cryptolepine, conophylline, magnoflorine, palmatine, trigonelline, vicine etc.) that have potential to be used as natural alternatives to the conventional anti-hyperglycemic drugs. Mechanisms of their antidiabetic action are also provided briefly. The review also anticipates the prospects of phyto-alkaloids with the potential to improve the standard of care and finding new formulations to improve the complications associated with T2DM.

Keywords

Type 2 Diabetes Mellitus, Insulin, Retinopathy, Biguanides, Sulphonylureas, Alkaloids, Natural Alternatives

Introduction

Insulin is a naturally occurring hormone produced by the pancreas that is responsible for regulating blood glucose levels in the body. An impaired insulin production or action that prevents the proper regulation of blood sugar levels causes a chronic disorder called diabetes mellitus (DM) or diabetes [1]. Diabetes is a noncommunicable progressive metabolic disease that is characterized by persistent hyperglycemia (or increased fasting plasma glucose (FPG) concentration), hypertension, dyslipidemia (encompasses elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol, and a transition to small & dense low-density lipoprotein (LDL) particles) etc [2]. Resulted due to an inadequate control of blood glucose levels and altered metabolism of biomacromolecules, mainly carbohydrates. Liver, adipose tissue and skeletal muscles are the tissues that most prominently show the signs of impaired insulin sensitivity [3]. DM has been diagnosed using a variety of measures. Currently, the impaired levels of 2-h postprandial glucose (2hPG), glycated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), are used as diagnostic markers for diabetes [4]. Several anti-hyperglycemic agents are available for the management of diabetes such as biguanides, thiazolidinediones, sulphonylureas, meglinides, etc. No doubt these agents are more or less effective in managing the disease but also exhibit some adverse effects that may negatively influence human health conditions.

Diabetes is affecting a huge number of population and becoming increasingly prevalent across nations worldwide. The statistical evidence of epidemiological data from the Global Health Estimates (GHE) of the World Health Organization has ranked it among ten leading causes of mortality [5, 6]. The 10th edition of IDF Atlas, 2021 of International Diabetes Federation (IDF) has estimated that 537 million adults are diabetic with the predictions of reaching up to 643 million by 2030 and 783.2 million by 2045 [7]. A global network of scientists and health researchers, known as Noncommunicable Disease-Risk Factor Collaboration (NCD-RisC) supported by the World Health Organization, has conducted an analysis on the epidemiological data on the disease. The new data released by this analysis on World Diabetes Day (November 14, 2024), reported that the global number of diabetes affected adults has dramatically surpassed 800 million and is rapidly increasing day by day [8, 9]. The research question that this review tried to answer is “How do plant-based alkaloids compared to conventional treatments are helpful in managing diabetes in terms of adverse effects and long term outcomes?.” The main objectives were:

  • To review the current pharmacological and non-pharmacological treatments and management strategies of T2DM.
  • Limitations and contraindications of available treatments.
  • To enlist various anti-diabetic alkaloids from different plants and their possible mechanisms of action in brief.
  • Summarizing the main findings and prospects.

METHODS

The conducted systematic review adopted the methodology of [10] for defining the PICO components (P-population of interest, I-intervention, C-comparison, and O-outcomes). The population of interest for this systematic review is the adult individuals that are diagnosed with T2DM and those at elevated risk of developing T2DM. Intervention involves the use of plant-derived alkaloids for managing T2DM. A comparison has been made between conventional treatment strategies and alkaloids as natural alternatives to these conventional methods. The outcome of conducted review suggests the use of plant-based alkaloids due their promising therapeutic potential in treating T2DM.

  1. Data Sources and Search Strategy

The literature related to diabetes mellitus was searched by performing electronic searches on various search engines and databases, including PubMed, Web of Science, Google Scholar, Semantic Scholar, ResearchGate, and Wiley Online Library. The search query used Boolean operators “AND” and “OR” paired with some key terms like “Diabetes Mellitus, T2DM, Pathophysiology of Diabetes, Microvascular and Macrovascular Complications in Diabetes, Diabetic Retinopathy, Diabetic Nephropathy, Diabetic Neuropathy, Peripheral Artery Disease, Cerebrovascular Disease, Cardiovascular Disease, Diabetes-related risk factors, Treatments and Management of T2DM, Anti-diabetic plants, Traditional anti-diabetic uses, Anti-diabetic Alkaloids, Mechanism of Action of Antidiabetic Alkaloids” etc. for precise and effective searches. Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines have been followed to conduct this systematic review and a flow chart has been used to provide a systematic search of included studies. The PRISMA flow chart shows the included studies by passing the various phases of identification, screening, and eligibility [11].

  1. Inclusion and Exclusion Criteria

Inclusion criteria included: (a) articles published between 2005-2025, (b) written in English, (c) full-texts available, (d) relevant peer-reviewed articles, research articles (e) studies that mainly focused on T2DM, associated complications and treatment (f) articles that mainly focused on anti-diabetic alkaloids. Exclusion criteria included: (a) articles published in language other than English (b) without the abstract (c) full-text unavailable (d) studies on other types of DM (e) studies involving non-alkaloidal remedies, such as phenolic compounds, flavonoids unless combined with alkaloids (f) articles with unclear outcomes.

  1. Evaluation of Eligibility

In the first phase of the PRISMA, called identification, the search queries were developed for literature search on databases and search engines. A total of 424 records were identified. In the second phase, called screening, the duplicates (n = 73) and those records that did not match the inclusion criteria (n = 36) were excluded by reading titles and abstracts. 315 records were assessed for eligibility of which 164 studies were excluded with reasons (n = 86 were not focused on T2DM, n = 16 were not written in English, n = 54 full texts were unavailable or not accessible freely, n = 8 were with unclear outcomes). In the final phase, called eligibility phase, 151 records met the inclusion criteria and were included in the conducted study (Figure 1).

  1. Synthesis of Systematic Review

The full texts of eligible studies were retrieved and read several times by the authors to synthesize a systematic review paper. The extracted data is summarized in the form of figures and tabular or textual descriptions in a thematic manner. The authors have tried their best to maintain a degree of consistency in each section of the paper.

Figure 1. PRISMA flow chart

Types And Pathophysiology of Diabetes Mellitus

Diabetes is often classified under two main categories: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Both types are characterized by progressive β-cell loss. Gestational diabetes is another type of DM that develops in pregnant women and the symptoms usually resolve following childbirth. However, those affected are at higher risk of developing type 2 DM in future [12, 13]. Monogenic diabetes syndrome, drug- or chemical-induced diabetes and diabetes related to cystic fibrosis are some specific conditions of diabetes mellitus [14].

  1. Type 1 DM

Type 1 DM is also identified as insulin-dependent diabetes mellitus (IDDM) or primary diabetes. It occurs due to an autoimmune disorder that causes production of anti-insulin immunoglobulins (Ig), destructing insulin secreting pancreatic β-cells, resulting in an absolute insulin deficiency [15, 16]. It is prevalent in 5-10% of diabetic cases. Severe hypoglycemia in type 1 DM causes diabetic ketoacidosis (DKA), producing toxic ketones [17]. The cell-mediated death of β-cells, called apoptosis is executed by CD4+ helper T-cells and CD8+ cytotoxic T-cells of immune system that is influenced by Major Histocompatibility Complex (MHC) I and II, respectively [18].

  1. Type 2 DM

Type 2 DM, formerly known as non-insulin-dependent diabetes mellitus (NIDDM) or secondary diabetes that occurs due to progressive loss of β-cells or when cellular tissues become resistant to insulin. This form of diabetes accounts for ~90-95% of total diabetes cases [19]. Excessive sugar consumption and fried foods are strongly associated with insulin resistance and the subsequent onset of type 2 diabetes [20]. Severe type 2 diabetic conditions cause some serious long term health complications, including microvascular and macrovascular disorders, called microangiopathy and macroangiopathy, respectively. The T2DM-related complications adversely affect almost all organ systems of the body. Microangiopathy involves diabetic retinopathy (vision loss) [21], nephropathy (kidney failure) [22], neuropathy (damage to blood capillaries) [23], dermopathy (damage to blood vessels of skin) [24] and encephalopathy (changes in brain function, often leading to confusion, behavioural changes, cognitive impairment and other neurological symptoms) [25]. Macroangiopathy includes cerebrovascular disease (brain strokes), coronary artery disease (heart attacks) and peripheral arterial disease (nerve damage, particularly in extremities such as limbs, causing walking impairment and amputation in severe cases) [26, 27] (Figure 2 ). Diabetic foot, osteoporosis and reduced resistance to other infections are some other clinical conditions associated with T2DM [28]. The prevalence of these complications may vary in type 1 and type 2 DM (Table 1). Genomic Wide Association Studies (GWAS) serve as the key tool for pinpointing the susceptibility loci associated with these diabetes-related complications [29, 30]. The genes encoding for risk-factors associated with diabetes-related complications are listed below in Table 2 [31].

Figure 2. Major Microvascular disorders associated with Type 2 DM

Table 1. Prevalence of diabetic complications in type 1 and type 2 DM

Complication

Type 2 DM

Type 2 DM

Reference(s)

Microvascular Complications

Retinopathy

Common after 10-15 years.

Often present at diagnosis.

[32]

Nephropathy

Leading cause of end-stage renal disease (ESRD).

Major cause of chronic kidney disease (CKD).

[33]

Neuropathy

Peripheral neuropathy is common.

Peripheral and autonomic neuropathy is frequent.

[34]

Macrovascular Complications

Cardiovascular Disease

Increased risk with duration.

Extremely elevated risk.

[35]

Cerebrovascular Disease

Increased risk of stroke.

Significantly higher risk of stroke.

 

Peripheral Artery Disease

Risk increases with duration.

Highly prevalent, leading to amputations.

[36]

Table 2. Genes encoding the risk-factors associated with diabetic complications

Diabetic Disease

Associated Risk-Factors

Encoding Gene

SNP(s)

Retinopathy

Extra ocular retinoblastoma, hyperkeratosis, adipose tissue expression, lipid profile, glycemic markers.

ACVR1C

 

rs4664229

Fasting blood glucose, metabolite levels, arterial stiffness.

ZFHX4

rs61729527

Pulse pressure, vision impairment.

WNT9B

rs4968281

Fibrinogen levels, platelet count.

SHANK3

rs9616915

Monocyte count, blood-retinal barrier integrity.

ZSCAN5A

rs7252603

Waist-to-hip ratio, obesity-related traits, IGFs.

DCP1B

rs715146, rs1044950, rs113147414

Neuropathy

Atherosclerosis, peripheral arterial narrowing.

GFY

rs4802605

Lipid measurements, fibrinogen levels, inflammatory response.

ADH4

rs4148883

BMI, T2DM, obesity-related traits.

LRFN2

rs61731010

Intraocular pressure, metabolic markers.

PKHD1

rs2499486

Iron metabolism, motor nerve conduction velocities.

SLC11A1

rs17235409

Extracellular matrix integrity, axonal health.

MATN4

rs2072788

Immune responses, glycolytic markers, BMI.

PPARA

rs4253772

Nephropathy

Cardiac serum proteins, nephron-related variables

TTN

rs72646845

Kidney expression, obesity traits.

PI16

rs113848006

Kidney expression, nephron-related variables.

DPY6

rs36027551

T2DM, proximal convoluted tubule thickening.

CROCC

rs41272737

Glycogen synthesis in kidney tubules.

PPP1R3A

rs1799999

CKD progression.

ZNF136

rs140861589

Oxidative stress markers, CKD risk.

HSPA12B

rs6076550

Kidney expression, cellular senescence.

FRMD4A

rs1541010

Cardiomyopathy

 

T2DM, coronary artery disease, cardiac troponin T levels.

PKHD1

rs62406032

Glycated hemoglobin levels.

MAST1

rs1078264

Carotid plaque build-up.

GFY

rs480265

Reactive oxygen species regulation.

SEPT14

rs146350220

Cardiac disorders, cataract.

PCNT

rs6518289, rs2839227, rs2839223

Obesity traits, peripheral arterial disease.

RILPL2

rs28434767

IGFs: Insulin-like Growth Factors; BMI: Body Mass Index; T2DM: Type II Diabetes Mellitus; CKD: Chronic Kidney Disease.

Management And Treatment of Type 2 DM

  1. Lifestyle Interventions

An effective management of diabetes is essential to prevent complications and improve patient outcomes. The treatment objectives should align with their ability to manage self-care and severity of the condition [37] (Figure 3). Efficient lifestyle interventions remain a cornerstone and are the first basic approach to treat T2DM. The two main lifestyle modifications include dietary changes (medical nutrition therapy) and physical activity that are related to weight management or obesity. Dietary modifications play a major role in controlling blood glucose levels. Adequate treatment can be accomplished by a controlled diet that is often low in energy density and high in dietary fibre. The optimal diet contains fresh fruits, vegetables, legumes, whole grains, limited refined carbohydrates along with healthy fats such as omega-3 and high-quality lean proteins [38]. The metabolism of excess glucose in hyperglycemic conditions can lead to excessive production of reactive oxygen species (ROS), contributing to various damages caused by oxidative stress. The pancreatic β-cells are more prone to oxidative stress. Furthermore, oxidative stress causes impaired insulin signalling, resulting in insulin resistance and subsequently T2DM [39]. Honey, a natural sweetener, has been used in treating diabetes for centuries due to its therapeutic and nutritional qualities [40]. The scavenger function of honey has been proved to be effective against oxidative stress [41].

Ayurveda, as an ancient medicine system, provides a body constitution-oriented and personalized approach to tackle diabetes. Ayurvedic practitioners adopt a multi-faceted approach to manage Madhumeha (derived from ‘madhu’ means honey and ‘meha’ means urine), encompassing dietary adjustments, herbal remedies, detoxification treatments through Panchakarma and incorporating yoga and pranayama techniques. The integration of Ayurveda with modern medicine is effectively addressing the complexities of type 2 diabetes, highlighting how ancient wisdom can meet contemporary healthcare needs [42, 43]. It could foster synergistic effects, optimize the therapeutic outcomes and improve patient’s quality of life.

The increasing prevalence of obesity is one of the main causes of the exponential growth of T2DM [44]. Physical activity is another considerable component for the management of T2DM as regular exercise helps improve insulin sensitivity and contributes to weight loss, aiding in the control of blood glucose levels. The ADA advises a moderate intensity aerobic exercise for at least 150 minutes per week for adults with diabetes [45]. Numerous high-quality technical tools are available for diabetic patients to assist them in self-management and health conditions. Monitoring physical activity levels using commercial applications can enhance adherence to management strategies. However, very few proportions of such tools have been appropriately evaluated for effectiveness [46].

Figure 3. Considerable factors for diabetes treatment

  1. Pharmacological Treatments

Several pharmacological interventions have antidiabetic potential for individuals with T2DM. The therapy field is continuously working on the development of more efficient pharmacological treatments. Targeting various aspects of glucose regulation is the most effective therapeutic strategy for treating microvascular disorders associated with T2DM [3]. The pharmacological treatments include both oral and injectable medications, often used individually or in combination. The anti-hyperglycemic drugs has been classified into various types- i) insulin secretagogues (Sulphonylureas & Meglitinides)-enhance insulin secretion; ii) insulin sensitizers (Biguanides & Thiazolidinediones)-enhance insulin sensitivity; iii) incretin-based therapies (glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptyl peptidase-4 (DPP-4) inhibitors) - stimulate pancreatic β-cells to release insulin; iv) insulin v) α-glucosidase inhibitors - delay the food absorption; vi) sodium-glucose cotransporter 2 (SGLT2) inhibitors - enhance urinary glucose excretion; vii) amylin agonists - slows digestion and reduces post-meal glucose production. The mechanisms of action of FDA-approved drug types along with their approval year and possible side-effects are summarized in Table 3 [47-69].

Table 3. FDA-approved antidiabetic pharmacological agents along with their mechanism of action and noted side-effects and contraindications

Sr. No.

Drug-Class

Mechanism of Action

FDA-approved Drugs

FDA approval (year)

Side-Effect(s) and Contraindications

Reference(s)

Insulin Secretagogues: Enhance insulin secretion.

1

SUs

Stimulate pancreatic β-cells for insulin secretion by closing ATP sensitive K+ channels.

Tolbutamide

Tolazamide

Chloropropamide

Acetohexamide

Glyburide

Glypizide

Glimepiride

1957

1982

1958

1964

1984

1984

1995

Weight gain, gastrointestinal issues, skin reaction and increased risk of secondary failure and cardiovascular risk.

[47, 48]

2

Meglitinides

Rapidly stimulate pancreatic β-cells to increase post-meal insulin secretion for a shorter period.

Mitiglinide

Nateglinide

Repaglinide

NA

2000

1997

Weight gain, hypoglycemia, uncertain cardiovascular safety.

[48-50]

Insulin Sensitizers: Improve insulin sensitivity.

3

Biguanides

Improve insulin sensitivity in peripheral tissues by reducing hepatic gluconeogenesis.

Metformin

1995

Stomach discomfort, diarrhoea, slight weight loss, active vit. B12 deficiency, lactic acidosis (rare).

[51, 52]

4

TZDs

Enhance insulin sensitivity in adipose tissue, muscle and liver by activating PPAR-γ.

Pioglitazone

Rosiglitazone

1999

1999

Weight gain due to fluid retention, increased adipose tissue burden, heart failure, considerable risk of fracture in postmenopausal women.

[53, 54]

Incretin (gut-derived hormones that promote insulin secretion)-based Therapies

5

GLP-1 Receptor Agonists

Mimic the action of GLP-1, enhance insulin secretion and suppress glucagon secretion.

Exenatide

Liraglutide

Semaglutide

2005

2010

2017

Gastrointestinal problems, nasopharyngitis, nausea, vomiting, influenza, cystitis, and viral infection, respiratory and urinary tract infections.

[55, 56]

6

DPP-4 Inhibitors

Inhibit DPP-4 enzyme and the release of glucagon and increase insulin secretion.

Sitagliptin

Saxagliptin

Linaglyptine

2006

2009

2011

Upper respiratory tract infections, urinary tract infections, headaches, nasopharyngitis. Rare conditions are thyroid cancer, pancreatic cancer, pancreatitis and sometimes severe allergic reactions.

[57,58]

SGLT 2-based Treatments

7

SGLT 2 Inhibitors

Inhibits SGLT 2 in renal tubules and reduces blood glucose by blocking glucose reabsorption in kidneys.

Canagliflozin

Dapagliflozin

Emphagliglozin

Ertugliflozin

2013

2014

2014

2017

Increased risk of hypotension, osmotic diuresis, such as volume depletion, dehydration, orthostatic hypotension, postural dizziness, syncope.

[59, 60]

Other Classes

8

Amylin Agonists

Reduce glucagon secretion and promote satiety for shorter period.

Pramlintide

2005

Mild to moderate gastrointestinal symptoms including anorexia, nausea, vomiting.

[61]

9

α-Glucosidase Inhibitors

Inhibit α-Glucosidase enzymes in the intestine and slow down the carbohydrate digestion, improve glycemic control.

Acarbose

Miglitol

Voglibose

1995

1998

NA

Gastrointestinal problems, such as diarrhoea and flatulence.

[62, 63]

10

Insulin Types

Ultra-Rapid Insulin Lispro

Ultra-rapid acting

Lyumjev

2020

Almost universal response, including reactions at injection sites, including itching, redness, swelling, severe hypoglycemia, expensive.

[64-69]

Insulin Lispro

Rapid acting

Humalog

1996

Insulin Aspart

Rapid acting

NovoLog

2000

Insulin Glulisine

Rapid acting

Apidra

2004

Faster-Acting Insulin Aspart

Rapid acting

Fiasp

2017

Regular Insulin

Short acting

Humulin R

Novolin R

1982

1991

Regular Insulin U-500

Short acting

Humulin R U-500

2016

Neutral Protamine Hagedorn (NPH) Insulin

Intermediate acting

Humulin N

Novolin N

1982

1981

Insulin Isophane

Intermediate acting

Humulin 70/30

Novolin 70/30

1999

2001

Insulin Glargine

Long-acting

Lantus,

Basaglar

2000

2015

Insulin Glargine U-300

Long-acting

Toujeo

2015

Insulin Detemir

Long-acting

Levemir

2005

Insulin Degludec

Long-acting

Tresiba

2015

Humalog Mix 75/25

Premixed insulins

(combination of rapid- and/or short-acting insulins)

-

1999

NovoLog Mix 70/30

-

2001

Humulin 70/30

-

1999

Inhaled Insulin

Rapid acting

Afrezza

2014

FDA: Food and Drug Association; SUs: Sulphonylureas; TZDs: Thiazolidinediones; PPAR-γ: Peroxisome Proliferator-Activated Receptor -γ; GLP-1: Glucagon-Like Peptide-1 Receptor; DPP-4: Dipeptyl Peptidase-4; SGLT 2: Sodium-Glucose Cotransporter 2; NA: Not Approved.

Non-Pharmacological Interventions

Bariatric Surgery

Obesity contributes to a number of life-threatening diseases, including type 2 diabetes mellitus. Traditional weight loss therapies, such as dietary modifications, physical activity and medication have been seen to be poor in treating obesity and obesity-related risks [70]. The increasing prevalence of obesity needs effective options, and bariatric surgery has evolved as transformative and viable intervention for managing the same. Bariatric surgery is recommended to obese patients having BMI ≥35-40 kg/m2 accompanied by T2DM [71]. Sleeve gastrectomy, roux-y gastric bypass, adjustable gastric band, and duodenal switch are different surgical procedures of bariatric surgery [72]. Due to safe and effective surgical trials, over 2, 50,000 patients have undergone bariatric surgeries alone in, 2019 and the figure was reduced to 1, 99,000 in 2020, in the United States. The decline in number is attributed to Covid-19 pandemic [73]. Despite its benefits, the technique also causes some adverse effects, including risk of gastric leak, weight regain, long term vitamin and/or mineral deficiencies, protein deficiency and micronutrient deficiency [38].

Continuous Glucose Monitoring

Finger pricking method is the traditional and popular method for monitoring blood glucose levels but can lead to pain and higher risk of infections from needle pricks. Continuous glucose monitoring (CGM) is an alternative to this method and has proved to be effective in providing accurate real-time data on glucose levels. The CGM devices employ a small sensor that is inserted into the subcutaneous tissue, monitoring the glucose levels continuously [74, 75]. The emergence of CGM technologies represents a shift towards personalized diabetes treatment. The wider adoption of CGM devices is limited by cost and accessibility, technical issues such as sensor adhesion, accuracy and calibration requirements [76].

Insulin Pumps

Insulin pumps are continuous subcutaneous insulin infusion systems (CSII), operating continuously to deliver rapid-acting insulin infusions. These devices eliminate the need for numerous daily subcutaneous insulin injections. Insulin pumps have been proved to reduce hemoglobin A1c (HbA1c) and extend the time during which the blood glucose remains within the range of 70-180 mg/dL [77]. The mismanagement of insulin pumps can cause technical failure, resulting in severe hypo- or hyper-glycemia [78]. Despite significant advancements in management and treatment of type 2 DM, current treatment strategies face several limitations that impact their efficacy, accessibility and long-term sustainability. Natural bioactive compounds from plants provide potential solutions to these challenges. Unlike many conventional anti-hyperglycemic drugs that target a single pathway, plant-derived alkaloids often exert their effect through multiple mechanisms. These compounds have capacity to enhance insulin sensitivity and improve glucose metabolism while typically exhibiting minimal adverse effects. The combination therapy of synthetic drugs and natural alkaloidal compounds could provide more effective and efficient treatment to T2DM.

Plant-Based Alkaloids as Natural Alternatives to Conventional Treatment Strategies OF T2DM

The medicinal plants are helpful in managing blood sugar levels and can compete with conventional drugs. They are rich sources of high-value and low-volume metabolites, both primary and secondary. The primary metabolites include carbohydrates, lipids, amino acids and nucleotides that are involved in the growth and maintenance of cellular structure [79]. On the other hand, the secondary metabolites are non-nutritive substances, such as alkaloids, terpenoids, phenolics etc. which are produced by plants in response to various biotic and abiotic factors. These are responsible for toxicity and other biological activities of the plants, including antidiabetic activity [80].

  1. Pharmacologically Screened Plants with Antidiabetic Alkaloids

The present review has collected all the available literature information on plants that contain anti-diabetic alkaloids responsible for their hypoglycemic activity. The enlisted plants were previously tested for their anti-diabetic activity in different in vivo or in vitro models. Moreover, we have summarized various antidiabetic alkaloids from more than 45 different plant species (Table 4). Alkaloidal phytoconstituents from these selected plants have shown promising results in preclinical studies for their potential to regulate blood sugar levels effectively, making them central target for further investigation.

Aegle marmelos

Family: Rutaceae

Vernacular Name(s): Bel, Bilva, Sriphal.

Traditional Antidiabetic Use: The leaves and fruits of A. marmelos are traditionally used in preparing various antidiabetic drug formulations and their references date back to Vedic times [81].

Morus alba

Family: Moraceae

Vernacular Name(s): Mulberry.

Traditional Antidiabetic Use: The plant has been extensively used in folk medicines and is effective in hypoglycemia [82].

Achyranthus aspera

Family: Amaranthaceae

Vernacular Name(s): Prickly chaff flower, Latjeera.

Traditional Antidiabetic Use: A. aspera var. A. rubrofuscais widely used for the treatment of diabetes mellitus [83].

Berberis aristata

Family: Berberidaceae

Vernacular Name(s): Tree Turmeric, Indian barberry, Daru Haldi, Daruharidra, Chitra.

Traditional Antidiabetic Use: The plant is used for treating diabetes mellitus in Sikkim and Darjeeling region of Indian subcontinent [84].

Catharanthus roseus

Family: Apocynaceae

Vernacular Name(s): Vinca, Madagascar periwinkle, Sadabahar.

Traditional Antidiabetic Use: Plant is widely used for preparing antidiabetic preparations like whole plant is soaked and steamed in water, dry powder is diluted in cow milk, leaf decoction is prepared, and stem is boiled in water [85].

Tinospora cordifolia

Family: Menispermaceae

Vernacular Name(s): Giloy, Guduchi.

Traditional Antidiabetic Use: T. cordifolia has been documented in various Ayurvedic scriptures and Ayurvedic materia medica such as Nighantu. Crushed stem mixed with water has antidiabetic effect [86].

Trigonella foenum-graecum

Family: Fabaceae (Leguminosae) 

Vernacular Name(s): Fenugreek.

Traditional Antidiabetic Use: The plant has been extensively used for treating various diseases since ancient times. Seeds are traditionally used for managing DM in Asia and Africa  [87].

Beta vulgaris

Family: Amaranthaceae

Vernacular Name(s): Beetroot, Sugar beet.

Traditional Antidiabetic Use: B. vulgaris has a history of traditional medicinal use in various cultures. Many recent studies have provided the evidences that ingestion of beetroot has improved clinical outcomes, including T2DM [88].

Peumus boldus

Family: Monimiaceae

Vernacular Name(s): Boldo.

Traditional Antidiabetic Use: P. boldus has been traditionally used as medicine by preparing tea from the leaves which is helpful in lowering blood glucose levels [89].

Coffea arabica

Family: Rubiaceae

Vernacular Name(s): Arabian coffee, Coffee.

Traditional Antidiabetic Use: The fruit decoction of C. arabica has been used as a beverage and is helpful in the management of diabetes [90].

Datura stramonium

Family: Solanaceae

Vernacular Name(s): Thornapple, Devil’s trumpet, Jimson weed.

Traditional Antidiabetic Use: None found.

Capsicum annuum

Family: Solanaceae

Vernacular Name(s): Sweet pepper, bell pepper, Jalapeno.

Traditional Antidiabetic Use: None found.

Colchicum autumnale

Family: Colchicaceae

Vernacular Name(s): Meadow saffron, Autum crocus.

Traditional Antidiabetic Use: The powdered bulb of C. autumnale is used as antidiabetic [91].

Ervatamia microphylla syn. Tabernaemontana divaricata

Family: Apocynaceae 

Vernacular Name(s): Pinwheel flower, Crape jasmine, Nero’s crown.

Traditional Antidiabetic Use: None found.

Rhizoma coptidis

Family: Ranunculaceae

Vernacular Name(s): Chinese goldthread.

Traditional Antidiabetic Use: The rhizome powder and decoction of R. coptidis have been used traditionally in the Asian countries for the treatment of diabetes along with anti-inflammatory disorders [92].

Cryptolepis sanguinolenta

Family: Apocynaceae 

Vernacular Name(s): Nibima.

Traditional Antidiabetic Use: None found.

Lupinus angustifolius

Family: Fabaceae

Vernacular Name(s): Blue lupin, Narrow-leaved lupin.

Traditional Antidiabetic Use: Lupin-kernel fibre from de-husked seeds of L. angustifolius is used to control obesity and cholesterol levels that directly influence diabetes [93].

Evodia rutaecarpa

Family: Rutaceae

Vernacular Name(s): - Evodia, Honey tree, Tree of thousand flowers.

Traditional Antidiabetic Use: None found.

Stephania tetrandra

Family: Menispermaceae

Vernacular Name(s): Han or Fen Fang Ji (Chinese).

Traditional Antidiabetic Use: In traditional Chinese medicine, the plant is used for treating diabetes in combination with other Chinese medicines, prescribed as Fangji Fuling decoction, Fangji Huangji decoction and Jijiao Lihuang pill [94].

Galanthus nivalis

Family: Amaryllidaceae

Vernacular Name(s): Flower of hope, Common snowdrop.

Traditional Antidiabetic Use: None found.

Leucojum aestivum

Family: Amaryllidaceae

Vernacular Name(s): Summer or giant snowflake, Snowbell, Dewdrop.

Traditional Antidiabetic Use: None found.

Tribulus terrestris

Family: Zygophyllaceae

Vernacular Name(s): Puncture vine, Caltrop, Gokhru.

Traditional Antidiabetic Use: In Northern India traditional practitioners use dried fruits of T. terrestris for treating diabetes mellitus [95].

Ariocarpus retusus

Family: Cactaceae

Vernacular Name(s): False peyote, Star or living rock.

Traditional Antidiabetic Use: None found.

Huperzia serrata

Family: Lycopodiaceae 

Vernacular Name(s): Chinese clubmoss, Toothed clubmoss.

Traditional Antidiabetic Use: None found.

Murraya koenigii

Family: Rutaceae 

Vernacular Name(s): Curry leaf tree or bush.

Traditional Antidiabetic Use: Various plant parts of M. koenigii have been traditionally used by folklore communities for the treatment of diabetes [96].

Leonurus cardiaca

Family: Lamiaceae

Vernacular Name(s): Motherwort, Lion’s ear.

Traditional Antidiabetic Use: None found.

Lepidium sativum

Family: Brassicaceae 

Vernacular Name(s): Garden cress.

Traditional Antidiabetic Use: The seeds of the plant are traditionally used for treating diabetes throughout the globe [97].

Lupinus albus

Family: Fabaceae 

Vernacular Name(s): White lupin, Field lupin.

Traditional Antidiabetic Use: Seeds of the plant are traditionally used in the treatment of diabetes [93].

Sophara alopecuroides

Family: Fabaceae 

Vernacular Name(s): Kudouzi (Chinese).

Traditional Antidiabetic Use: The seeds of Sophara species are consumed by diabetic patients to reduce their blood glucose level [98].

Helicteres isora

Family: Sterculiaceae 

Vernacular Name(s): East-Indian screw tree.

Traditional Antidiabetic Use: The root juice of plant has been consumed for curing diabetes by several ethnic groups in different parts of India [99].

Nelumbo nucifera

Family: Nelumbonaceae

Vernacular Name(s): Lotus, Sacred lotus.

Traditional Antidiabetic Use: N. nucifera has been frequently used by traditional healers and herbalists to treat diabetes [100].

Sophara favescens

Family: Fabaceae 

Vernacular Name(s): Shrubby saphora.

Traditional Antidiabetic Use: Sophara favescens possesses a potent antidiabetic activity and is ethnobotanically used as diabetes monotherapy [101].

Eurycoma longifolia

Family: Simaroubaceae 

Vernacular Name(s): Long jack, Tongkatali.

Traditional Antidiabetic Use: Various plant parts have been traditionally used as herbal medicine for the treatment of diabetes [102].

Piper longum

Family: Piperaceae 

Vernacular Name(s): Indian Long pepper, Pipli.

Traditional Antidiabetic Use: Various preparations such as juices, decoctions, infusions and powders from different parts of P. longum are used by ethnic groups to treat diabetes [103].

Piper nigrum

Family: Piperaceae 

Vernacular Name(s): Black pepper.

Traditional Antidiabetic Use: Decoction of leaves and seeds is orally consumed to treat diabetes [104].

Piper umbellatum

Family: Piperaceae 

Vernacular Name(s): Cow foot leaf.

Traditional Antidiabetic Use: the plant has been traditionally used by ethnic communities in Cameroon against diabetes [105].

Lobelia chinensis

Family: Campanulaceae

Vernacular Name(s): Half-sided lily, Chinese lobelia.

Traditional Antidiabetic Use: L. chinensis is a medicinal herb that is used in traditional Chinese medicine for treating diabetes mellitus for over 2000 years [106].

Sarcococca saligna

Family: Buxaceae 

Vernacular Name(s): Willow-Leaf Sweet-Box, Sweet box, Christmas box.

Traditional Antidiabetic Use: None found.

Theobroma cacoa

Family: Malvaceae 

Vernacular Name(s): Cocoa or Cacao tree.

Traditional Antidiabetic Use: None found.

Adhatoda vasica

Family: Acanthaceae 

Vernacular Name(s): Vasaka, Malabar nut.

Traditional Antidiabetic Use: Decoction of freshly collected roots of A. vasica mixed with cow milk is used as potential antidiabetic by rural communities of Dhemaji district of Assam.

Momordica charantia

Family: Cucurbitaceae 

Vernacular Name(s): Bitter gourd, Karela.

Traditional Antidiabetic Use: Blended fruit mixed with water is filtered and consumed before breakfast for curing diabetes.

Coptis chinensis

Family: Ranunculaceae

Vernacular Name(s): Golden tread, Chinese gold thread.

Traditional Antidiabetic Use: The traditional Chinese materia medica records explain the need of using C. chinensis for treating diabetes [107].

Amaranthus caudates

Family: Amaranthaceae 

Vernacular Name(s): Foxtail amaranth, Pendant amaranth, Velvet flower.

Traditional Antidiabetic Use: Amaranthus caudatus is nutraceutical rich traditional food source. In Chinese medicine system, the plant extract is used to treat various diseases, including diabetes and associated disorders such as urinary failure and cardiovascular complications [108].

Gossypium spp.

Family: Malvaceae

Vernacular Name(s): Cotton.

Traditional Antidiabetic Use: None found.

Camellia sinensis

Family: Theaceae 

Vernacular Name(s): Tea tree.

Traditional Antidiabetic Use: The plant has been traditionally used as a dietary supplement for the management of diabetes. It is consumed in various forms such as unfermented (green, white tea), semi-fermented (oolong tea) and fully fermented (black tea) all around the globe [109].

Paullinia cupana

Family: Sapindaceae 

Vernacular Name(s): Brazilian cocoa and zoom.

Traditional Antidiabetic Use: None found

  1. Alkaloids and Mechanisms of their Antidiabetic Action

Alkaloids are usually basic (alkaline) nitrogen containing heterocyclic organic compounds that represent one of the most valuable classes of natural bioactive compounds or secondary metabolites. They have held significant importance in human history, both for their medicinal and cultural value. Alkaloids have been extensively incorporated into folk medicine systems, including Indian Ayurvedic, Native American and Chinese medicine systems for treating a diverse array of diseases [110]. These phytochemicals exhibit numerous biological activities including antibacterial, anti-hypertensive, anti-asthmatic, anti-arrhythmic, anti-spasmodic, CNS-stimulant and anti-cancer. Many alkaloids were also found to have anti-hyperglycemic properties [111]. Alkaloids use a complex mechanism to control blood glucose levels in body by regulating or inhibiting the activities of different enzymes, including glucokinase (GK), AMP-activated protein kinase (AMPK), dipeptidyl peptidase-4 (DPP-4), glucose-6-phosphatase (G6Pase), glucose transporter 4(GLUT4), peroxisome proliferator-activated receptor (PPAR) and protein of tyrosine phosphatase 1B (PTP1B). Alkaloids can manage impaired glucose metabolism by increasing the insulin secretion, decreasing the tissues’ resistance to insulin, and inhibiting various digestive enzymes such as α- amylase and α-glucosidase (Figure 4).

Figure 4. Mechanisms of antidiabetic alkaloids

Table 4. Alkaloidal phytoconstituents with anti-diabetic potential.

Alkaloid

Source Plant

Chemical Structure

Primary Effect/ Mechanism of Action

Reference(s)

Achyranthine

Achyranthes aspera,

Amaranthus caudates,

Gossypium spp.

 

 

Plays role in carbohydrate digestion.

[112]

Vasicine

Adhatoda vasica

 

 

α-Glucosidase inhibition.

[113]

Vasicinol

Adhatoda vasica

 

 

α-Glucosidase inhibition.

[113]

Aegeline

Aegle marmelos

 

 

Reduces the activity of α-amylase and intestinal disaccharidase, delaying carbohydrate breakdown and glucose absorption.

[114]

β-sitosterol

Aegle marmelos

 

 

Reduces the activity of α-amylase and intestinal disaccharidase, delaying carbohydrate breakdown and glucose absorption.

[115]

Hordenine

Ariocarpus retusus

 

 

Protects from diabetic nephropathy.

[116]

Berberine

Berberis aristata

 

Inhibition of α-glucosidase, Decreases glucose transportation in intestinal epithelium.

[117]

Betaine

Beta vulgaris

 

 

Lowers fasting blood sugar,

Reduces HbA1c levels, serum glucose and fats.

[112]

Capsaicin

Capsicum annuum

 

 

Reduces blood glucose levels.

[118]

Catharanthine

Catharanthus roseus

 

 

Lowers the glucose absorption.

[119]

Vindoline

Catharanthus roseus

 

 

Suppresses protein tyrosine and phosphatase activity and enhances glucose-stimulated insulin secretion.

[120]

Vindolinine

Catharanthus roseus

 

Delays glucose absorption.

[121]

Caffein

Coffea arabica,

Camellia sinensis,

Theobroma cacao,

Paullinia cupana

 

 

Controls blood glucose and improves insulin sensitivity.

[122]

Colchicine

Colchicum autumnale

 

 

Reduces inflammation and improves metabolic dysregulation.

[123]

Worenine

Coptis chinensis

 

 

Stabilizes pancreatic islet cells, lowering blood glucose levels.

[124]

Cryptolepine

Cryptolepis sanguinolenta

 

 

Regeneration of pancreatic β-cells and enhances insulin receptor signaling.

[125]

Calystegine-B2

Datura stramonium,

 

 

Inhibition of α-galactosidase and β-glucosidase.

[126]

Muscimol

Helicteres isora

 

 

Lowers blood glucose levels.

[127]

Conophylline

Ervatamia microphylla

 

 

Changes pancreatic originator cells to insulin producing cells.

[128]

Picrasidine L

Eurycoma longifolia

 

 

Inhibits PTP1B.

[129]

Evodiamine

Evodia rutaecarpa

 

 

Improves glucose tolerance and prevents insulin resistance.

[130]

Galantamine

Galanthus nivalis,

Leucojum aestivum

 

 

Alleviates insulin resistance.

[131]

Huperzine A

Huperzia serrata

 

 

Modulates oxidative stress and inflammation.

[132]

Leonurine

Leonurus cardiac

 

 

Reduces fasting glucose and increases insulin levels.

[133]

Lepidine

Lepidium sativum

 

 

Improves insulin synthesis in pancreatic cells.

[113]

1,4-Dideoxy-1,4-imino-D-arabinitol

Morus alba

 

 

Inhibits α-glucosidase, trehalase, isomaltase and α-mannosidase.

[134]

Radicamin A

Lobelia chinensis

 

 

α-Glucosidase inhibition.

[135]

Radicarmine B

Lobelia chinensis

 

 

Inhibits α-Glucosidase.

[135]

Lupanine

Lupinus albus,

Lupinus angustifolius

 

 

α-Glucosidase inhibition and enhances insulin sensitization.

[136]

Vicine

Momordica charantia

 

 

Increases insulin secretion and decreases insulin resistance, inhibits glucose absorption in intestine and suppresses enzymes involved in gluconeogenic pathways.

[137]

Piperine

Piper longum,

Piper nigrum

 

 

Lowers blood sugar levels.

[138]

Koenidine

Murraya koenigii

 

 

Improves insulin sensitivity and lowers blood sugar levels.

[139]

Mahanimbine

Murraya koenigii

 

 

Reduces hyperglycemia viz AMPK activation.

[140]

Nuciferine

Nelumbo nucifera

 

 

Stimulates insulin secretion from pancreatic cells.

[141]

Boldine

Peumus boldus

 

 

Protects tissues from oxidative damage and improves blood sugar levels.

 

Theobromine

Theobroma cacoa

 

 

Improves metabolic condition via NAD+/Sirt-1 activity.

[142]

Piperumbellactam C

Piper umbellatum

 

 

α-Glucosidase inhibition.

[113]

Copticine

Rhizoma coptidis

 

 

Hypoglycemic effect.

[143]

Epiberberine

Rhizoma coptidis

 

 

Regulates lipid metabolism and lowers blood glucose levels.

[144]

Sarcodine

Sarcococca saligna

 

 

Reduces blood glucose levels.

[145]

Matrine

Sophara alopecuroides,

Sophara favescens

 

 

Lowers glucose tolerance and plasma insulin levels.

[146]

Oxymatrine

Sophara alopecuroides,

Sophara favescens

 

 

Reduces oxidative stress and blood glucose.

[147]

Fangchinoline

Stephania tetrandra

 

 

Reduces blood glucose levels.

[148]

Tetrandrine

Stephania tetrandra

 

 

Resolve pancreatic islet injury by reducing oxidative stress.

[149]

Harmane

Tribulus terrestris

 

 

Increases insulin synthesis in the pancreas.

[113]

Pinoline

Tribulus terrestris

 

 

Increases insulin discharge.

[150]

Jatrorrhizine

Tinospora cordifolia

 

 

Decreases glucose levels in serum,

Induces insulin secretion.

[113]

Palmatine

Tinospora cordifolia

 

 

Stimulates insulin secretion and acts as insulin-mimicking hormone.

[113]

Magnoflorine

Tinospora sp.

 

 

Inhibits α-glucosidase enzyme, promotes insulin secretion and reduces postprandial hyperglycemia.

[113]

Trigonelline

Trigonella foenum-graecum

 

 

 

Protects pancreatic β-cells from apoptosis and enhances glucose tolerance.

[151]

HbA1c: Hemoglobin A1c; PTP1B: Protein tyrosine phosphatase; AMPK: Adenosine monophosphate-activated protein Kinases; NAD+/Sirt-1: Nicotinamide adenine dinucleotide+/Sirtuin-1.

CONCLUSION AND FUTURE ASPECTS

Type 2 diabetes mellitus causes significant global health challenges. The management and treatment of this metabolic disorder requires multifaceted approaches. The present-day treatment strategies, including lifestyle interventions, pharmacological and non-pharmacological methods remain to be central to diabetes management. But their limitations, such as side-effects, progressive loss of efficacy and cost, highlight the need for alternative strategies. Plant-based remedies are often more affordable and accessible, particularly in developing countries where access to modern healthcare services may be limited. This review has provided a comprehensive understanding of T2DM and associated complications along with their risk-factors and has also synthesized the findings in the literature on various antidiabetic alkaloids in addressing the complexities of T2DM. The study suggests that certain alkaloids may offer valuable therapeutic benefits against various complications of T2DM. Future research should prioritize into elucidating the efficacy, safety profile and precise molecular mechanisms of these natural compounds. The integration of ‘omics’ technologies could reveal novel targets and biomarkers for personalized treatment approaches. Furthermore, by enhancing our understanding of phyto-alkaloids, we can develop more effective combination therapies, particularly in resource-limited settings. This approach has the potential to significantly improve global diabetes management and reduce the burden of T2DM worldwide.

ACKNOWLEDGEMENTS

This work is a part of M.Sc. Plant Sciences(Botany) degree of the first author. The author gratefully acknowledges the supervisor Prof. (Dr.) Pardeep Kumar and a PhD research scholar Ms. Leena Thakur from the Department of Plant Sciences. All the authors sincerely acknowledge the Central University of Himachal Pradesh for providing all the required facilities and support for the successful completion of the study.

Declarations

Author Contributions

Conceptualisation: Raj Kumar and Leena Thakur; Methodology, Data Curation, Writing original draft, Software:  Raj Kumar; Reviewing and writing: Leena Thakur; Review and Supervision: Pardeep Kumar.

Fundings

The work is not funded by any funding agency.

Conflict of Interest

The authors declare that the study was conducted without any kind of financial or other relationships that could be regarded as a potential conflict of interest.

Clinical Trial Number

Not applicable

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Raj Kumar
Corresponding author

Department of Plant Sciences, School of Life Sciences, Central University of Himachal Pradesh, Shahpur Campus - 176208, Kangra, H.P., India

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Leena Thakur
Co-author

Department of Plant Sciences, School of Life Sciences, Central University of Himachal Pradesh, Shahpur Campus - 176208, Kangra, H.P., India

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Pardeep Kumar
Co-author

Department of Plant Sciences, School of Life Sciences, Central University of Himachal Pradesh, Shahpur Campus - 176208, Kangra, H.P., India

Raj Kumar*, Pardeep Kumar, Leena Thakur, A Systematic Review on Management of Type 2 Diabetes Mellitus: Conventional Treatment Strategies v/s Phyto-Alkaloids as Natural Alternatives, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 452-488 https://doi.org/10.5281/zenodo.17053155

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