Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium-glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided.

Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus.

Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes.

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Recent Pharmacological Options in Type 2 Diabetes and Synergic Mechanism in Cardiovascular Disease

Cold press technology generates high quality value-added oil products along with highly stable oilseed cakes or meals. Hazelnut cakes are characterized by high concentrations of proteins that can be valorized in the manufacture of various protein products. Here, using an aqueous extraction scheme along with enzymatic proteolysis and FPLC-based fractionation, a variety of hazelnut peptide fractions with varying bioactive properties were manufactured and their sequences were determined based on LC-Q-TOF/MS techniques. DPP-IV inhibitory attributes were determined based on in vitro DPP-IV activity measurement assay and in silico prediction techniques including BIOPEP and PeptideRanker as well as molecular docking (HPEPDOCK) approaches. Based on these investigations, 256 peptides were identified in 81 different FPLC fractions. The majority of fractions were characterized with low to moderate DPP-IV inhibitory activity possibly due to the relative dilute nature of the fractions, while some hazelnut peptides were characterized by comparable IC50 values as the positive control and plant peptides in the current literature. All peptide sequences were further tested in silico for their bioactive potential and DPP-IV inhibitory characteristics. The most influential 7 sequences were shown to generate higher docking scores than the positive control. While the further concentration of samples could enhance the DPP-IV inhibitory attributes of hazelnut peptides, valorization of cold press hazelnut meals represent a valid methodology to generate potentially antidiabetic peptides and their corresponding fractions.

Tombul hazelnut (Corylus avellana L.) peptides with DPP-IV inhibitory activity: In vitro and in silico studies

This study aims to determine the potential antioxidant, antihypertensive, hypoglycaemic and nootropic activity of a purified polyphenolic extract from the halophyte ice plant (Mesembryanthemum crystallinum). The ice plant extract showed good antioxidant activity measured by DPPH, ORAC, TEAC, FRAP and ferrous ion chelating activity. Moreover, the extract showed potent ACE, DPP-IV and PEP-inhibitory activity (90.5%, 98.6% and 73.1%, respectively, at a final concentration of 1 mg/mL). The extract was fractionated and the fraction with the highest content of total phenolic compounds showed the highest bioactivity, suggesting that polyphenols could be mainly responsible for the abovementioned activities. The tentative polyphenol identification by HPLC-ESI-QTOF-MS in this fraction revealed that flavones (>65%) are the major group, with apigenin (38%) predominating, followed by diosmin (17.7%) and luteolin (11.9%). They could presumably be the main elements responsible for the enzymatic inhibition activity. Additionally, 4-hydroxybenzoic acid, p-coumaric acid and a hydroxycinnamic acid derivative (2-O-(p-cumaroyl)-l-malic acid) were found in the extract. To our knowledge, this is the first time that some of these activities have been reported for halophyte extracts.

https://www.mdpi.com/2304-8158/11/11/1581/pdf?version=1653913890

Antioxidant, Antihypertensive, Hypoglycaemic and Nootropic Activity of a Polyphenolic Extract from the Halophyte Ice Plant (Mesembryanthemum crystallinum)

Type 2 diabetes mellitus is a metabolic disorder resulting from impaired insulin secretion and resistance. Dipeptidyl peptidase (DPP)-IV is an enzyme known to trigger the catalysis of insulinotropic hormones, further abating the endogenous insulin levels and elevating the glucose levels in blood plasma. In the field of drug development, DPP-IV inhibitors have opened up numerous opportunities for leveraging this target to generate compounds as hypoglycemic agents by regulating incretin activity and subsequently decreasing blood glucose levels. However, the practice of synthetic drugs is an apparent choice but poses a great pharmacovigilance issue due to their incessant undesirable effects. The ideology was set to inventively look upon different ethnomedicinal plants for their anti-diabetic properties to address these issues. To date, myriads of phytochemicals are characterized, eliciting an anti-diabetic response by targeting various enzymes and augmenting glucose homeostasis. Antioxidants have played a crucial role in alleviating the symptoms of diabetes by scavenging free radicals or treating the underlying causes of metabolic disorders and reducing free radical formation. Plant-based DPP-IV inhibitors, including alkaloids, phenolic acid, flavonoids, quercetin, and coumarin, also possess antioxidant capabilities, providing anti-diabetic and antioxidative protection. This review article provides a new gateway for exploring the ability of plant-based DPP-IV inhibitors to withstand oxidative stress under pathological conditions related to diabetes and for reforming the strategic role of ethnomedicinal plants as potent DPP-IV inhibitors through the development of polyherbal formulations and nanophytomedicines to regulate incretin activity.

https://www.frontiersin.org/articles/10.3389/fendo.2022.1027237/pdf

A review on phytochemical and pharmacological facets of tropical ethnomedicinal plants as reformed DPP-IV inhibitors to regulate incretin activity

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia that is predominantly caused by insulin resistance or impaired insulin secretion, along with disturbances in carbohydrate, fat and protein metabolism. Various therapeutic approaches have been used to treat diabetes, including improvement of insulin sensitivity, inhibition of gluconeogenesis, and decreasing glucose absorption from the intestines. Recently, a novel approach has emerged using dipeptidyl peptidase-IV (DPP-IV) inhibitors as a possible agent for the treatment of T2DM without producing any side effects, such as hypoglycemia and exhaustion of pancreatic β-cells. DPP-IV inhibitors improve hyperglycemic conditions by stabilizing the postprandial level of gut hormones such as glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptides, which function as incretins to help upregulate insulin secretion and β-cell mass. In this review, we summarized DPP-IV inhibitors and their mechanism of inhibition, activities of those isolated from various natural sources, and their capacity to overcome oxidative stress in disease conditions.

Neha Sharma

Papers

Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes