Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review

Simple Summary Pancreatic ductal adenocarcinoma is one of the most lethal diseases, with an exceptionally poor prognosis. The successful clinical management of strongly related diabetes could significantly contribute to more efficient control of cancer development and progression. In this regard, various natural products have been explored. This review evaluates the therapeutic potential of four natural products (Curcumin—Curcuma longa L.; Thymoquinone—Nigella sativa L.; Genistein—Glycine max L.; Ginkgo biloba L.) and one nutritional intervention, in the form of a low-carbohydrate ketogenic diet in pancreatic cancer and diabetic patients, and discusses their possible integration in supportive cancer management. Although the results have shown their effectiveness in the treatment of diabetes, the therapeutic response and survival time were not significantly improved in pancreatic cancer patients, despite improvements in several biological parameters. Nevertheless, based on published data, the studied natural products and nutritional intervention can potentially become promising therapeutic approaches for pancreatic cancer risk reduction through early intervention at the onset of diabetic complications. Abstract The correlation between pancreatic ductal adenocarcinoma (PDAC) and diabetes-related mechanisms support the hypothesis that early therapeutic strategies targeting diabetes can contribute to PDAC risk reduction and treatment improvement. A systematic review was conducted, using PubMed, Embase and Cochrane Library databases, to evaluate the current evidence from clinical studies qualitatively examining the efficacy of four natural products: Curcumin—Curcuma longa L.; Thymoquinone—Nigella sativa L.; Genistein—Glycine max L.; Ginkgo biloba L.; and a low-carbohydrate ketogenic diet in type 2 diabetes (T2D) and PDAC treatment. A total of 28 clinical studies were included, showing strong evidence of inter-study heterogeneity. Used as a monotherapy or in combination with chemo-radiotherapy, the studied substances did not significantly improve the treatment response of PDAC patients. However, pronounced therapeutic efficacy was confirmed in T2D. The natural products and low-carbohydrate ketogenic diet, combined with the standard drugs, have the potential to improve T2D treatment and thus potentially reduce the risk of cancer development and improve multiple biological parameters in PDAC patients.

IR causes insulin oversecretion, β-cell overactivity and increased β-cell mass. The tissue of the exocrine pancreas becomes chronically exposed to elevated levels of secreted insulin [15]. Its mitogenic activity promotes cell proliferation and growth, increases utilization of glucose, and thus contributes to the development of a tumor and its progression. Insulin also increases the bioavailability of IGF-1 [17]. IGF-1 exhibits substantial mitogenic and anti-apoptotic effects and, furthermore, potentiates the growth of insulin and insulin receptor-expressing cells. IGF-1 and its receptor are over-expressed in PDAC cells and enhance their proliferation, invasion, angiogenesis, and inhibition of apoptosis [18]. The binding of insulin and IGF-1 to their receptors initiates signal transduction that activates MAPK (Ras-Raf-MEK-ERK) and PI3K/Akt/mTOR pathways, promotes proliferation, and downregulates apoptosis [15]. Hyperglycemia, attributed to excess carbohydrate availability, glycation, and impaired detoxification, upregulates the formation of free radicals and advanced glycation end products (AGEs) and increases inflammation [19]. AGEs upregulate AGEs receptor in PanIN and stimulate PDAC invasiveness [20]. Hyperglycemia might also be responsible for acquiring mesenchymal and cancer stem cell features necessary for tumor initiation and progression. It is mediated by the hyperglycemia-activated TGF-β signaling that might provide another explanation for T2D facilitating PDAC [7].
Hyperinsulinemia and IR, associated with increased adiposity, activate a plethora of inflammatory cells, and induce systemic inflammation that contributes to genomic aberrations and tumorigenesis [21]. Pro-inflammatory cytokines (adipocytokines), such as leptin, adiponectin, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL- 6), are involved in immune responses, inflammation, apoptosis, and metabolism. They increase IR and may trigger malignant transformation, angiogenesis, tumor growth, migration, and metastasis [21]. Pro-inflammatory cytokines, reactive oxygen species (ROS), and inflammatory pathway players, including COX-2 or NF-κB, contribute to DNA damage, genomic instability and mutations that prime carcinogenesis, suppression of apoptosis, immunosuppression, inhibition of DNA repair, and stimulation of the cell cycle. Inflammation also affects TME by immune cells releasing cytokines and growth factors that promote tumor growth [7,22].
Hyperglycemia is also associated with neural invasion and increased secretion of nerve growth factor (NGF) that ensure a loop of further neural infiltration and tumor growth [23,24]. In addition, immune cells express β-adrenoceptors and glucocorticoid receptors. Therefore, there is a direct correlation between excessive stress hormones (catecholamines and cortisol) during chronic exposure to stress and suppressing immune and inflammation surveillance. In concurrent obesity, stress hormones-stimulated β-adrenoceptors trigger the release of pro-inflammatory complexes by neutrophils, the oxidation of lipids, the upregulation of fibroblast growth factors, and the activation of mitogenic signaling and proliferation of dormant tumor cells [5].

Nutraceuticals-Based Treatment Strategies
Several supportive therapeutic approaches are being explored to manage T2D-related pathological mechanisms leading to PDAC. These include natural products (NPs), consisting of bioactive compounds which have shown the potential for the prevention and treatment of many diseases [25] and provide a framework for drug development [26,27]. More than 10,000 phytochemical constituents derived from various plants, valued for their bioactive properties, were suggested as supportive therapeutics for cancer patients, due to their efficacy and low toxicity [28,29]. NPs, in combination with conventional chemotherapeutic agents and radiotherapy as the supportive treatment strategy, may enhance anticancer activity and reduce adverse effects [30]. The anticancer activity of NPs includes reducing the levels of TNF-α, inflammatory cytokines, COX-2, cyclin D1, downregulation of NF-κB, suppression of Bcl-2, an anti-apoptotic protein, and activation of Bax, a pro-apoptotic protein, activation of caspase-3,9, and downregulation of PI3k-Akt and mTOR pathways. Some NPs have shown hypolipidemic and hypoglycemic properties, anti-inflammatory, antioxidant, immunomodulatory, anti-angiogenic, anticoagulant activity, or cardiovascular-protecting properties [28,29]. Such promising activity has been suggested for curcumin from Curcuma longa L., Nigella sativa L. or its constituent thymoquinone, Glycine max (L.) or genistein, Ginkgo biloba L., Gymnema sylvestre (R. Br.) or Momordica charantia L. Several adaptogenic medicinal plants have also been proposed for their ability to protect cells during stress-induced changes in the tissue environment, helping them to resist stress and having a homeostatic effect on various body systems, including the immune, nervous and endocrine systems [31][32][33]. In addition, curcumin, Nigella sativa L. and thymoquinone, and Ginkgo biloba L. have shown neuroprotective and cognitive-enhancing properties and partial capacity for restoring the sympathovagal balance and monoamine levels [34][35][36].
Another tested approach is nutritional ketosis as the therapeutic strategy for the metabolic management of cancer. Physiological ketosis, achieved by a restricted lowcarbohydrate ketogenic diet (LCKD), is aimed at the induction of an energy crisis and glucose deprivation in hyperglycemic and hyperinsulinemia-stressed tissues [37]. Several clinical trials have shown the efficacy of LCKD in different cancer types, particularly in glioblastoma, colorectal, breast, head and neck, and lung cancer [38]. Ketosis, a metabolic state, acts on multiple levels. It targets the Warburg effect, a modified metabolism in cancer cells which uses glycolysis, rather than oxidative phosphorylation, to produce ATP like normal cells. Cancer cells are unable to metabolize ketone bodies (KB) due to the mitochondrial altered morphology and dysfunction. LCKD can decrease glucose levels, deprive cancer cells of energy and create metabolic stress, while normal cells adapt and utilize KB for energy production and survival [39]. Nutritional ketosis reduces insulin and IGF-1 and thus downregulates the cancer cells' mitogenic activity, the proliferation and generation of inflammatory molecules, increases DNA repair mechanisms, autophagy and mitophagy, telomerase length, inhibits NF-kB, promotes apoptosis, and prevents tumorigenesis [40]. LCKD has been shown to significantly improve glycemic control and reverse T2D [41][42][43][44]. Additionally, signaling of β-hydroxybutyrate (BHB; commonly referred to as ketone) has neuroprotective effects, exhibits tumor-suppressing activity, and has an anti-inflammatory effect via downregulation of inflammatory molecules, such as TNF-α, IL-1,6,18, and prostaglandins. Calorie-restricted nutritional ketosis has shown an anti-angiogenic activity via reduction of HIF-1 and VEGF-receptor expression [38]. LCKD has also shown sympathovagal balance-modulating activity in obese individuals by reducing sympathetic activity (LF: low frequency parameter of heart rate variability (HRV)) and corticosteroid concentration, and increasing parasympathetic cardiac activation (mean RR interval and HF: high frequency parameter of HRV), thus promoting a higher HRV and positive affect on hypothalamic-pituitary-adrenal (HPA) axis and antioxidant capacity [45]. The increased sympathetic and decreased vagal nerve activity can be potentiated by stress and determined by various HRV parameters [46,47]. A lower HRV is often prevalent in cancer patients. Patients with higher HRV and coping mechanisms for stress have shown better adaptability [48,49] and more favorable prognosis, which has also been demonstrated in PDAC patients [50].
Limited meta-analyses or reviews have investigated the effect of nutritional or vitamin supplements and plants on PDAC patients. The favorable clinical outcomes and reduced PDAC risk were achieved in combination with chemotherapeutic agents [33,51,52]. The effect of nutraceuticals against PDAC is mediated via a number of mechanisms. The risk of PDAC development can be diminished by early prevention and the treatment of diabetic complications of impaired GT and insulin secretion, IR, or obesity [53]. However, the evidence investigating these common mechanisms with activities of nutraceuticals jointly in both PDAC and T2D is missing. Therefore, the aim of the study is to review available data on the treatment efficacy of NPs and LCKD in T2D and PDAC patients and discuss their possible integration in cancer management.

Methods
The literature search included collecting the available information on medicinal plants or phytochemicals used in conjunction with conventional therapies for the treatment of T2D and PDAC. Published original clinical studies for the NPs used in both diseases were identified by searching PubMed, Embase, and Cochrane Library databases. A similar search strategy was conducted for clinical studies of LCKD. Search terms were (pancreatic cancer OR pancreatic ductal adenocarcinoma) AND (type 2 diabetes) AND (curcuma longa OR curcumin) AND (nigella sativa OR black cumin OR thymoquinone) AND (glycine max OR genistein OR soy isoflavone) AND (ginkgo biloba) AND (low-carbohydrate ketogenic diet OR nutritional ketosis). Data were collected from 1998 until August 2021. Clinical studies were selected based on title and abstract first, and further following the selection criteria. The inclusion criteria included original clinical studies (clinical trial phase I-IV, (non)randomized (un)controlled clinical trial, observational or interventional study); NP/LCKD as a primary source of intervention, including the combination of nutraceuticals with chemo-/radiotherapy or current anti-diabetic medication; participants diagnosed with PDAC or T2D; and full-text articles in English. Studies were included only if LCKD and particular NPs were used as monotherapy, not combined with other NPs, and indicated in both PDAC and T2D. Given the scarcity of available data on NPs and LCKD for both conditions, a broader spectrum of clinical studies was acceptable, including one case series clinical study. Exclusion criteria were: studies in vitro or in vivo, reviews, meta-analyses; NP/LCKD in combination with other nutraceuticals; participants diagnosed with other types of cancer or primary disease; and non-full text and non-English language articles. Data collection, including the searching and analysis of clinical studies, was independently performed by two authors. Data were extracted using a self-designed framework, including the study design and duration, sample size, participants characteristics, intervention used, outcome measures, results, and adverse events. The methodological quality of included studies was assessed using a modified Jadad scale, evaluating the randomization, the blinding method, the description of withdrawals and dropouts, the inclusion/exclusion criteria, the description of the method used to assess adverse effects, and the statistical analysis. The scoring system ranged between 0 (0-3, indicating lower quality) and 8 (4-8, indicating higher quality) [54]. The study was conducted according to PRISMA guidelines [55].

Results
The selection process is presented in the flow diagram (Figure 2), and extracted data are provided in Table 2. The electronic search delivered 321 studies for NPs and 175 studies for LCKD used in PDAC and T2D management. After removing duplicates and screening titles and abstracts, 52 articles remained for full-text assessment. Twenty-four studies were excluded due to insufficient information, focusing on conditions associated with T2D and PDAC, or using a combination of nutraceutical products. The studies using a combination of curcumin products were accepted, due to their low bioavailability and rapid elimination from the body when used as a single agent [56]. Co-administration with piperine, phospholipids, or turmeric oil may increase curcumin absorption in the gut 20-fold and bring beneficial results during treatment [57][58][59]. The studies using micronutrients and other lifestyle recommendations alongside LCKD were also included. Nineteen studies were selected for review, among which eight studies, including 177 participants, used NPs for the management of PDAC [60][61][62][63][64][65][66][67] and 11 studies, including 617 participants, for T2D [68][69][70][71][72][73][74][75][76][77][78] (Table 2). Nine studies using LCKD were included, among which four studies were conducted on 27 patients with PDAC [79][80][81][82] and five studies on 422 diabetic patients [83][84][85][86][87] (Table 2). Aside from studies conducted on patients with T2D, one study [76] with pre-diabetic patients was also included. All 28 studies were peer-reviewed.

Participants' and Studies' Characteristics
The participants in all PDAC clinical studies were diagnosed with locally advanced or metastatic disease (or just specified as carcinoma). Participants' previous therapy varied, including surgery, radiotherapy, chemotherapy, immunotherapy, or none of the prior treatment was specified. Gemcitabine was the most frequent chemotherapeutic used. Other agents were nab-paclitaxel, S-1, FOLFIRINOX, erlotinib, dexamethasone or metoclopramide. The majority of studies (83%) conducted on PDAC patients were open-label, non-randomized uncontrolled interventional phase I or II clinical trials, except for two studies, among which one was a prospective controlled study [79] and one was conducted as a case series study [82]. They lasted from 1 week to 23 months.
Prior medication of participants with T2D was predominantly metformin, then sulfonylureas, a thiazolidinedione, insulin, glucagon-like-peptide-1 receptor agonists, dipeptidyl peptidase 4 and sodium-glucose cotransporter-2 inhibitors, statins, antihypertensives, or no prior treatment. Studies with diabetic patients included open-label non-randomized (12.5%), randomized (25%) controlled clinical trials and randomized double-blind (or participants-blind, n = 1) placebo-controlled clinical trials (62.5%), which are less prone to bias than other designs. The duration of these studies ranged from 10 days to 1 year. Except for two studies [63,78], all clinical trials were single-centered. methodological quality of included studies was assessed using a modified Jadad scale, evaluating the randomization, the blinding method, the description of withdrawals and dropouts, the inclusion/exclusion criteria, the description of the method used to assess adverse effects, and the statistical analysis. The scoring system ranged between 0 (0-3, indicating lower quality) and 8 (4-8, indicating higher quality) [54]. The study was conducted according to PRISMA guidelines [55].

Results
The selection process is presented in the flow diagram (Figure 2), and extracted data are provided in Tables 1 and 2. The electronic search delivered 321 studies for NPs and 175 studies for LCKD used in PDAC and T2D management. After removing duplicates and screening titles and abstracts, 52 articles remained for full-text assessment. Twentyfour studies were excluded due to insufficient information, focusing on conditions associated with T2D and PDAC, or using a combination of nutraceutical products. The studies using a combination of curcumin products were accepted, due to their low bioavailability and rapid elimination from the body when used as a single agent [56]. Co-administration with piperine, phospholipids, or turmeric oil may increase curcumin absorption in the gut 20-fold and bring beneficial results during treatment [57][58][59]. The studies using micronutrients and other lifestyle recommendations alongside LCKD were also included. Nineteen studies were selected for review, among which eight studies, including 177 participants, used NPs for the management of PDAC [60][61][62][63][64][65][66][67] and 11 studies, including 617 participants, for T2D [68][69][70][71][72][73][74][75][76][77][78] (Table 1). Nine studies using LCKD were included, among which four studies were conducted on 27 patients with PDAC [79][80][81][82] and five studies on 422 diabetic patients [83][84][85][86][87] (Table 2). Aside from studies conducted on patients with T2D, one study [76] with pre-diabetic patients was also included. All 28 studies were peerreviewed.    Mean change ± SD in curcumin and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):

Participants' and Studies' Characteristics
No serious side effects reported Mean baseline and post-treatment in hyperinsulinemic group of diet controlled and on medication and pancreatic exhaustion group, respectively (↓↓/↑↑ p < 0.05, significant difference):

Interventions
Active constituents of parental plants were used in all studies, except three studies with Nigella sativa, where the plant seeds were processed to a final product [72][73][74], and two studies with Glycine max, whose leaves were used without specified constituents [75,76]. The active constituents of Curcuma longa were curcuminoids (curcumin, desmethoxycurcumin, bisdesmethoxycurcumin). Curcuminoids were used alone or combined with piperine or turmeric oil or prepared as nano-micelle or phytosome (Meriva ® ) to enhance bioavailability. The other active compound used was thymoquinone from Nigella sativa [64]. Two studies used genistein [65], a constituent of Glycine max, and the combination of genistein, daidzin, glycitin, a Novasoy ® product [66]. Ginkgo biloba standardized extract EGb761 (ginkgo flavone glycosides, terpene lactones (ginkgolides, bilobalide) was used in all three studies [67,77,78].
All NPs were administered orally in the form of capsules, except for one study, in which 350 mg of Ginkgo biloba extract was administered intravenously in 250 mL physiologic saline solution as an infusion [69]. In one study, Glycine max leaf powder was incorporated into biscuits [75]. Dosages varied for each NP. They were 8 g, 2 g and 1.5 g of curcumin/curcuminoids per day. Two studies used a lower daily dose of 80 mg of curcumin in nano-micelle form [69] and 500 mg of curcumin with 5 mg of piperine [70]. The application of a nano-carrier allowed use of a lower dose of curcumin and its delivery with increased bioavailability. Nigella sativa was administered as seed oil extract capsules, with a dose of 1 g [72] and 5 g [73], and as seed powder capsules, with an overall dose of 2 g per day [74]. One phase-I study used the thymoquinone constituent of Nigella sativa in various escalating dosages for participants with different cancers. A dose of 85 mg and 500 mg per day was used in two patients with PDAC [64]. Genistein, a constituent of Glycine max, was used in escalating dosages, from 400 mg to 1600 mg [65], and in a dose of 531 mg (Novasoy ® ) per day [66]. A dose of Glycine max leaf powder was 10 g (in biscuits) [75] and 2 g (extracted in 70% ethanol) per day [76]. The oral daily dose of Ginkgo biloba was 120 mg [77,78].

Outcome Measures
The primary outcome parameters in studies on patients with PDAC differed across studies and for each NP. The common parameters measured were tumor response rate (TRR), overall and progression-free survival (PFS), tumor and inflammation markers, toxicity profile, and quality of life. Additional parameters measured depended on the study's character and included NF-kB, PSTAT3, liver and renal function, lipid profile or pharmacokinetics, and a maximum tolerated dose. The outcome parameters in studies on patients with T2D and NPs were more consistent, and they included fasting blood glucose, glycated hemoglobin (HbA1c), fasting insulin, IR and β-cell function, lipid profile, BMI, C-reactive protein and adiponectin levels, the function of liver enzymes (AST, ALT), antioxidant capacity and the levels of pro-inflammatory cytokines, measured in two studies [72,74]. Outcome parameters in studies with LCKD were similar to parameters in studies with NPs and diabetic patients. The level of diabetic medication use, inflammatory markers and immune cell profile were additionally measured in two studies [85,87] (Figure 3). Findings also reported the TRR and/or survival in PDAC patients [80][81][82].
Biology 2023, 12, x FOR PEER REVIEW 21 of 39 markers and immune cell profile were additionally measured in two studies [85,87] (Figure 3). Findings also reported the TRR and/or survival in PDAC patients [80][81][82]. Curcumin (Curcuma longa L.). Oral curcumin was well tolerated as a monotherapy [60] as well as in combination with gemcitabine [61][62][63]. Only five patients (29%) had to discontinue the treatment for a few days, due to abdominal fullness or pain, and an 8 g daily dose was reduced [61]. In PDAC patients with heterogeneous history of chemotherapy, radiotherapy or surgery, stable disease was achieved in 28-36% of cases [61][62][63], and a partial response was achieved in 9% of cases [61] with a concurrent treatment of curcumin and gemcitabine, achieving a disease control rate of 24% [61] and 61.4% [62]. There was no complete response. However, one patient on curcumin monotherapy experienced a marked tumor regression (73%), with significantly increased cytokine levels and recurrent tumor progression [60]. The median time to progression was 2.5-8.4 months (range 1-12 months) [61,62], and the median overall survival (OS) was 5-10.2 months (range 3.6-24 months) [61][62][63]. Tumor marker CA19-9 decreased in 18% of cases, and 12% of cases maintained normal marker levels [61]. A slow reduction of CA125 was achieved after 1 year in one patient [60]. Elevated levels of cytokines variably changed after treatment with curcumin [60]. However, curcumin significantly reduced the expression of NF-kB, COX-2, and phosphorylated STAT3, which are implicated in tumor-/angiogenesis and growth and are over-expressed in pancreatic and other cancers [60]. Quality of life slightly increased [62].
Curcumin achieved more profound changes in patients with T2D. There was a significant decrease in fasting blood glucose [69,71], glycated hemoglobin [69,70], low-density lipoprotein (LDL) cholesterol [69], and serum triglycerides [68]. Insulin levels did not show any significant difference after the treatment with curcumin. There was only a slight decrease in two studies [68,69] and an increase in another study, with slightly increased IR and β-cell function [71]. Total antioxidant capacity, measured in one study, did not show any difference from the baseline [71]. However, curcumin markedly reduced inflammatory C-reactive protein [68,70], increased adiponectin, and anti-inflammatory cytokines [68]. BMI was also significantly decreased in two of four studies [69,70].
Thymoquinone and Nigella sativa L. The only study published on this topic including PDAC patients was of poor quality, without outcome measures provided. Findings had a narrative character that included the outcomes for all patients and different types of cancer, including PDAC. The treatment with thymoquinone improved overall general condition and reduction of tumor markers (<25% decrease from baseline) in four of 21 patients. Other parameters, such as lipid profile, renal and liver function, and random blood glucose, did not show any significant changes from baseline [64].
The treatment with the Nigella sativa product in diabetic patients showed better results. Fasting blood glucose was significantly reduced in all three studies [72][73][74]. Other significant changes in the intervention groups were observed, in the reduction of glycated hemoglobin [73,74], BMI [73] and IR, and in the increase of β-cell function [74]. Despite the slight improvements in lipid profile and liver function, these changes were not significant [73]. Nigella sativa supplementation induced an antioxidant activity with more pronounced positive changes after 1 year [74] compared to 8 weeks of intervention [72]. Findings showed a significant elevation in total antioxidant capacity (p < 0.002), antioxidant biomarkers-superoxide dismutase (p < 0.04), catalase (p < 0.003), and glutathione (p < 0.03), and a marked reduction in thiobarbituric acid reactive substances (p < 0.02) [74], malondialdehyde and nitric oxide, the oxidative stress species [72]. A significant anti-inflammatory effect was not shown, as the TNF-α and interleukin-1β (IL-1β), pro-inflammatory cytokines were reduced only moderately [72].
Glycine max leaf extract intervention revealed a significant reduction in fasting and postprandial blood glucose and glycated hemoglobin in both diabetic [75] and pre-diabetic patients [76]. Another marked improvement in diabetic patients was a lipid profile (total cholesterol, LDL, high-density lipoproteins (HDL), triglycerides) [75], whereas there was no significant difference between pre-and post-treatment shown in pre-diabetic patients. In the latter group, insulin levels and IR were also only moderately decreased, but liver function showed a significant improvement by reducing the levels of transaminases (ALT, AST) [76].
Ginkgo biloba L. The Ginkgo biloba product, in combination with 5-FU, showed a good risk-benefit ratio in the treatment of PDAC, with a low level of adverse events and improvement of the treatment tolerability, with stable quality of life during the treatment period [67]. There was no complete response. Partial response and stable disease were achieved in 9.4% and 21.9% of cases, respectively. The median OS was 5.6 months (range 2.6-7.3 months). More than a 15-month survival was reached by only one patient [67].
Administration of Ginkgo biloba with metformin resulted in more significant changes [78] than in Ginkgo biloba monotherapy intervention [77] in patients with T2D. In the combination treatment, a marked reduction was observed in fasting blood glucose, glycated hemoglobin, serum insulin, BMI, visceral adiposity index, and urea and creatinine levels. Ginkgo biloba also significantly contributed to an increase in blood parameters, particularly hematocrit, hemoglobin, and red blood cell count [78]. Ginkgo biloba monotherapy studies differed in terms of control groups. There were hyperinsulinemia patients controlled on a diet; those already taking hypoglycemic medication; and patients with pancreatic exhaustion, also taking hypoglycemic medication. The only significant effect was observed during the response to glucose loading in the oral glucose tolerance test. Ingestion of Ginkgo biloba caused a marked reduction of plasma insulin in hyperinsulinemic diabetic patients taking hypoglycemic medication. The reducing effect on insulin levels in diet-controlled patients was only minor. In patients with pancreatic exhaustion, ingestion of Ginkgo biloba significantly improved β-cell function (increased C-peptide and insulin levels), which, however, did not reduce blood glucose [77].
Low-carbohydrate ketogenic diet. LCKD intervention also demonstrated variable outcomes in PDAC patients. In two studies, the patients were a part of a bigger group combining other cancer types [80,82]. Two PDAC patients experienced progressive disease and did not complete the study [80]. Four patients achieved a median OS of 10.7 months. This positive outcome might result from the synergistic effect of LCKD with prior patients' chemotherapy (gemcitabine or gemcitabine and S-1). Fasting blood glucose was significantly reduced in two of four patients. All four patients showed a marked increase in β-hydroxybutyrate levels and thus a significant reduction of glucose ketone index, which provides information about a state of ketosis and metabolic health [82]. In the study with control to general diet in patients after pancreatectomy, the LCKD group demonstrated significant changes in almost all measured parameters; however, changes between groups were not profound. A reduction of body cell mass was higher in the general diet group, while patients on LCKD had a higher energy intake, better meal compliance, and overall satisfaction. Although urine ketones and C-reactive protein levels increased, this change was insignificant [79]. In the study with concurrent chemo-/radiotherapy, one patient did not complete the LCKD intervention [81]. The patient was on ketosis for only 8 days, but achieved better results in PFS (5.3 months) and OS (10 months) than a patient who completed the study, whose time to progression and OS were 2 months [81].

Safety Issues
No serious adverse effect was reported for NPs in patients with T2D. Only four patients experienced mild transient nausea after intervention with a Nigella sativa product [73]. PDAC patients experienced adverse effects, mostly due to the concurrent chemotherapy, except in one study, where the curcumin dose had to be reduced or discontinued in some patients due to curcumin-specific grade 3 abdominal pain and fullness. However, toxicity related to curcumin did not affect gemcitabine dosing [61]. Hematological or non-hematological toxicity at grades 3-4 appeared in two other studies [62,63], which led to reduction of the curcumin dose or suspension of both gemcitabine and curcumin until recovery. The genistein product did not cause any adverse effects during product monotherapy, nor increased toxicity in combination with gemcitabine [65] or erlotinib [66]. Nevertheless, patients did experience grade 3-4 adverse effects specific to both chemotherapeutics. Similarly, the side effects in the treatment with Ginkgo biloba product were related to 5-FU, disease progression, or other medication [67].
More adverse events in patients with PDAC were related to chemotherapy or disease progression. LCKD-specific adverse effects included weight loss (73% of cases), hyperuricemia (64%) and, to a minor extent, hyperlipidemia, pedal oedema, anemia, halitosis, pruritus, hypoglycemia, hyperkaliemia, hypokalemia, hypomagnesaemia, and flu-like symptoms or fatigue [80]. Reduced compliance with LCKD intake during concurrent chemo-/radiotherapy was due to adverse effects of the overall treatment regimen [81]. One study reported grade 1-2 adverse effects related to LCKD; however, these were also experienced by patients with other cancer types, and the side effects exclusive to PDAC patients were not specified [82]. The frequency of meal intake-related adverse effects (anorexia, nausea and vomiting, constipation, diarrhea, abdominal pain) was lower in patients after pancreatectomy and on a LCKD than in patients on a general diet, which may suggest LCKD as a better adjuvant complementary treatment strategy [79].
Information about LCKD-related adverse events was not provided in two studies in patients with T2D [85,87]. One study reported problems with headaches, constipation, diarrhea, insomnia, or back pains [83], and another study reported issues with increased constipation [86]. On the contrary, in the latter study, patients with LCKD reported a decrease in headaches, bloating and gas compared to the control group [86]. Adverse effects in diabetic patients differed between two study groups: the continuous care intervention unit and the standard care unit. In the first group, patients experienced fewer side effects, particularly the increased blood urea nitrogen, possibly due to higher protein intake, even though this is not recommended, and two patients experienced subclinical hypothyroidism.
In the second group, more serious complications were experienced, including percutaneous coronary intervention (PCI) to left anterior descending stenosis, PCI to the right coronary artery, carotid artery disease, multifactorial encephalopathy, and diabetic ketoacidosis with pulmonary emboli. These adverse effects were not attributed to the intervention [84].

Discussion
Despite partial improvement in several biological parameters, treatment tolerability and stable wellbeing, the studied substances did not significantly improve the treatment response of PDAC patients. In contrast, it is apparent that T2D patients may benefit from the treatment with NPs and LCKD. However, numerous questions remain open, mainly regarding the reliability of reviewed compounds before their integration into clinical practice.

Mechanisms of Action
Curcuminoids are negative regulators of a transcription factor NF-κB, phosphorylation of STAT3 and an elevated COX-2, which are mediatory contributors to inflammatory processes through the activation of inflammatory cytokine cascade [60,90]. Such inhibition further decreases the expression of proteins implicated in cell proliferation and apoptosis, such as cyclin D1 or c-myc and Bcl-2 or survivin, respectively [91]. The positive effect of curcumin in in vitro and in vivo experiments has also been associated with the downregulation of EGFR, Notch-1 signaling pathways and p-Erk1/2 expressions, which are implicated in PDAC cell growth [92,93]. Curcumin-induced downregulation of elevated prostaglandins E2, TNF-α, interleukin-6,-8,-10, malondialdehyde free radicals and an increase of glutathione and other antioxidant molecules are supported by the additional clinical evidence [59]. However, studied clinical trials did not confirm the beneficial effect of curcumin on PDAC patients' outcomes.
Chronic inflammation is associated with hyperglycemia, obesity, metabolic syndrome or IR, and curcumin's anti-diabetic activity is partially linked to reducing inflammation [94]. Curcumin suppresses NF-kB activity, macrophage infiltration of adipose tissue and, consequently, the expression of C-reactive protein, and increases adiponectin production, which is involved in blood glucose regulation and fatty acid catabolism. Downregulation of serum-free fatty acids by increased oxidation and its utilization in tissues has a hypoglycemic effect, which makes curcumin an ameliorating agent of T2D [94]. Curcumin reduces inflammation by regulating arachidonic acid metabolism, leading to COX, LOX, and nitric oxide synthases suppression [68]. By reducing inflammatory processes, curcumin improves insulin signaling and prevents the progression of T2D [94]. Inflammation and oxidative stress promote glucose and lipid toxicity and deteriorate β-cells' function [95,96]. Curcuminoids are strong antioxidants and accomplish protective activity by free radical scavenging, performed predominantly by phenolic hydroxyl groups, and by reducing nitric oxide levels, which drives the reactive metabolites [97]. As shown in the reviewed studies, curcumin is capable of decreasing serum cholesterol via suppression of its absorption. The mechanism behind curcumin hypolipidemic activity is suggested by inhibiting the sterol regulatory element-binding transcription factor 1 and fatty acid synthase and by increasing β-oxidation and metabolism of fatty acids, which might prevent a rise of serum lipids [68].
Importantly, curcumin has the potential to act as an epigenetic modulator via inhibition of DNA methyl transferases (DNMTs) and regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Epigenetic inhibitors, such as curcumin, were shown to have the ability to reverse aberrant epigenetic modification and regulate gene expression [98]. Moreover, combined with other anticancer therapies, they could play an essential role in reversing acquired therapy resistance in solid tumors [99]. By regulating the balance of DNA methylation and histone modifications, curcumin and its analogues were shown to reverse T2D complications via modulation of inflammation, over-deposition of extracellular matrix and fibrosis [100].
Thymoquinone is the predominant biologically active essential oil constituent of Nigella sativa [101], showing insufficient activity in the reviewed study in patients with PDAC [64]. The reviewed studies revealed the anti-inflammatory and antioxidant activity of Nigella sativa, which can benefit both PDAC and diabetic patients. The activity is associated with decreasing the activity of NF-kB and HDACs, synthesis of monocyte chemoattractant protein-1, TNF-α, IL-1β, IL-8, COX-2 and prostaglandin-E2, expression of COX-1 and nitric oxide, increasing superoxide dismutase, catalase, glutathione antioxidants, and decreasing thiobarbituric acid reactive substances and malondialdehyde, the oxidative stress molecules [72,74,102,103]. The antihyperglycemic effect of Nigella sativa demonstrated by the reviewed studies might result from the improvement of the β-cell structure and the activity of carbohydrate metabolism enzymes. This mechanism increased insulin levels and decreased oxidative stress on pancreatic β-cells, thereby protecting their integrity and function [104], as well as reducing blood glucose and glycated hemoglobin levels in vivo [102].
Similarly to curcumin, genistein also affects tumorigenesis through epigenetic regulations [105]. Besides its effect on DNA methylation, it shows the ability to alter chromatin configuration. In vivo and in vitro studies demonstrated genistein's ability to inhibit the activation of NF-kB and Akt signaling pathways involved in growth, angiogenesis, cell death, and chemoresistance [106]. NF-kB is unintentionally activated by chemotherapeutic agents, which may explain the chemoresistance. In docetaxel and cisplatin treatment, NF-kB activation was eliminated in the cells with genistein pre-treatment [107]. Another study showed that genistein pre-treatment, followed by gemcitabine chemotherapy, inhibited tumor cell growth by 60-80%, compared to 25-30% when gemcitabine was used alone [108]. The administration of Glycine max leaf extract significantly reduced fasting blood glucose, glycated hemoglobin and triglyceride levels and an improved cholesterol profile in diabetic patients in the reviewed studies [75,76]. A high plasma concentration of genistein resulted in a lower risk of T2D or metabolic syndrome complications [109][110][111][112]. Genistein activity in glycemic control may be associated with an increase of glucokinase, an enzyme that phosphorylates glucose to glucose-6-phosphate, hence decreasing glucose-6-phosphate levels [113]. Another mechanism relates to genistein's binding ability to peroxisome proliferator-activated receptors (PPARs), which affects insulin activity and glucose metabolism [114]. Glucose clearance is regulated by estrogen, particularly insulin pathways-associated proteins, which increase the levels and translocation of GLUT4, the main glucose transporter [115]. Phytoestrogen genistein is able to increase glucose uptake through activation of AMP-activated protein kinase and GLUT4 translocation, thus providing an antihyperglycemic effect [116]. Hyperglycemia contributes to IR in adipose tissue, which results in the hydrolysis of triglycerides to free fatty acids and their release into the liver and blood circulation. Therefore, reduction of serum triglycerides might be associated with genistein hypoglycemic activity, as well as genistein's ability to increase fatty acid catabolism in the liver [109,117]. In addition, genistein administration showed a pronounced reduction of malondialdehyde levels and an increase in total antioxidant capacity in patients with T2D. It was enhanced through ROS scavenging ability and increased gene expression of antioxidant enzymes [109,118].
While the response rate of 5-FU monotherapy in PDAC patients was only 0-10%, gemcitabine alone or in combination therapy with other chemotherapeutics produced an additional response of 5.4-23%, which, however, brought additional toxicity [119]. The combination of Ginkgo biloba and 5-FU contributed to a 9.4% TRR, which is comparable with the abovementioned response rates. Co-treatment with Ginkgo biloba improved the treatment tolerability and overall quality of life [67]. Complete response in PDAC is scarce and does not influence the patients' survival rate. However, two cases with a non-resectable secondary and resected locally recurrent PDAC who experienced a complete response after the treatment with gemcitabine and the combination of 5-FU and Ginkgo biloba extract (350 mg daily dose intravenously), respectively, were reported. The patient who underwent combination therapy did not experience any severe therapy-associated adverse effects for 10 months since the diagnosis [120]. These favorable effects of Ginkgo biloba on PDAC cells have been shown in previous preclinical studies. Kaempferol, Ginkgo biloba flavonoid lowered PDAC cell number and inhibited cell proliferation by 70-90%. Decreased proliferation and activated cancer cell death were associated with the reduction of mitochondrial enzyme activity and an increase in apoptotic bodies. By this mechanism and in combination with 5-FU, Kaempferol can sensitize PDAC cells to chemotherapy and provide an additive action of the abrogation of cancer cell proliferation [121]. Similarly, ginkgolic acid, a phenolic compound of Ginkgo biloba, decreased the viability of PDAC cells and promoted their apoptosis in vitro and in vivo. It inhibited the tumor growth by decreasing proliferating cell nuclear antigen (PCNA) and abrogated the de novo lipogenesis of cancer cells by the initiation of AMP-activated protein kinase (AMPK) signaling and reduction of the lipogenesis enzymes levels (acetyl-CoA carboxylase, fatty acid synthase) [122]. AMPK, a serine/threonine protein kinase complex, is involved in cellular energy metabolism control and lipid and glucose metabolism regulation [123]. PDAC has been shown to have an increased rate of fatty acid synthesis, which is required for cancer development and survival [124].
The Ginkgo biloba effect on lipid and glucose metabolism in patients with T2D was demonstrated in one of two reviewed studies, showing a significant decrease in fasting serum glucose and insulin levels, IR, glycated hemoglobin, visceral adiposity, or BMI [78]. The mechanism of this effect is suggested to be associated with the improvement of β-cell function (increased insulin and C-peptide during increased glucose levels), transferring blood glucose to peripheral tissue while increasing insulin sensitivity and decreasing IR, as well as stimulating lipolytic enzymes [78,125,126]. However, in another reviewed study, 3-month Ginkgo biloba administration significantly improved pancreatic β-cell function only in diabetic patients with pancreatic exhaustion during a glucose loading [77]. In addition, Ginkgo biloba maintained euglycemia in both pre-diabetic and diabetic patients while decreasing the accumulation of platelet-free radicals, which makes ginkgo a potential platelet-activating factor antagonist and free radical scavenger [127]. Free radicals caused by hyperglycemia are implicated in LDL oxidation-induced atherosclerosis development and the impairment of platelet function, which contributes to micro-and macro-vascular complications. Therefore, administration of Ginkgo biloba could prevent such adverse effects in both diabetic and PDAC patients [127,128].
LCKD therapy demonstrated significant improvements in lipid profile, fasting serum glucose and insulin levels, liver function, metabolic health, C-reactive protein levels and some inflammatory markers and medication use, predominantly in patients with T2D [83][84][85][86][87]. Except for marked improvements in fasting glucose, β-hydroxybutyrate levels and lipid profile in four advanced PDAC patients and six patients after pancreatectomy [79,82], variable outcomes of LCKD therapy were achieved in patients with different types of cancer [80,82], including partial and a complete response in 19% and 8% of the patients [82].
Previous studies have shown that being in ketosis and producing β-hydroxybutyrate (one of the main ketone bodies) can improve glycemic control and reverse T2D and being overweight or obese. It can prevent and halt cancer progression, improve mild cognitive impairment and cardiovascular disease risk factors, such as atherogenic dyslipidemia and inflammation [129,130]. β-hydroxybutyrate production is inversely dependent on insulin levels, as hyperinsulinemia inhibits the rate of ketogenesis, and ketone bodies are cleared through their increased metabolism. On the contrary, low insulin concentration increases ketogenesis and ketone body levels [131]. Low carbohydrate composition of the LCKD and induced nutritional ketosis do not stimulate the pancreas to secrete insulin, resulting in a reduction of blood glucose, glycated hemoglobin and impaired oxygen saturation capacity, hyperglycemia-inhibited fibrinolysis and accumulation of clotting factors and inflammatory signaling [40]. Elevated insulin levels mediate the accelerated cell division through pro-inflammatory signaling molecules, including cytokines, chemokines, or growth factors, leading to prolonged, chronic inflammation, which is one of the mechanisms of neoplastic progression in PDAC [132]. Hyperinsulinemia leads to increased ROS, which further increases the production of inflammatory cytokines, including TNF-α, monocyte chemoattractant protein-1, interleukins, or prostaglandins. Under these conditions, mitochondrial DNA is more susceptible to mutations, and malfunctioned mitochondrial electron transport chain becomes the major producer of ROS in cancer cells [133,134]. Elevated intracellular levels of free radicals (O 2 −• , H 2 O 2 ) in cancer cell mitochondria might be a target for LCKD therapy, involving a mechanism combating oxidative stress, as the state of nutritional ketosis increases the endogenous production of antioxidants, such as glutathione peroxidase, superoxide dismutase, or catalase [135]. Furthermore, the endogenous production of BHB also leads to an increase in intracellular concentrations of nicotinamide adenine dinucleotide NAD + , which is vital for NAD + -sirtuin activity. NAD + sirtuins connection is responsible for autophagy, mitophagy, and longevity, driving cellular processes, including insulin action and sensitivity, pancreatic β-cells' function, energy expenditure, mitochondrial and cognitive function, or inflammatory reactions [136][137][138].
Most research studies examining the side effects of LCKD have been performed on patients with epilepsy or those aspiring to lose weight [40]. The successful results of these studies suggested LCKD as adjuvant therapy in cancer treatment [139]. Despite no serious adverse effects experienced with LCKD, there are possible risks which might be potentiated by PDAC or T2D. The most common acute side effect is gastrointestinal discomfort, including nausea and vomiting caused by higher fat intake [40]. An appropriate mineral supplementation can prevent the possible risk of a trace minerals deficiency [140]. As a long-term side effect, increased LDL cholesterol, kidney stones, and renal impairment might be experienced by diabetic patients [40], due to the increased elimination of nitrogenous waste products from protein metabolism. Although long-term daily protein intake and the related adaptive response of renal function did not show adverse effects in healthy individuals, these dietary changes might have an impact on kidney function in patients with T2D or PDAC, who are more susceptible than others [141].

Intervention's Quality and Safety
The popularity and consumption of NPs have increased worldwide, driving more research on their quality and safety profiles [142]. Both medicinal plants and single compounds were used in combination in the reviewed studies. Medicinal plants contain numerous compounds, whose complex interactions may potentially provide a powerful clinical effect. However, these interactions are difficult to and usually not thoroughly examined. The pharmaceutical model using a single active compound can fairly easily explain the mechanism behind a compound's activity and how can it be exploited for drug manufacturing; however, this could result in loss of beneficial multi-constituent mixtures of the whole plant [143]. Using the single compound or plant extract is also confounded by factors specific to each patient, including dosage and use of other medication, type and stage of disease, and medication-or disease-induced adverse effects or age [143]. In addition, for single compounds, semi-synthetic variants, co-administration with other compounds or in different formulations could often compensate for poor pharmacokinetic properties (poor absorption, fast metabolism, and elimination) and bioavailability of the parental compound [144]. Moreover, -omics technologies, particularly metabolomics and proteomics, can contribute to the standardization of plant extracts and determine the specific phytochemicals that can reduce adverse effects caused by pharmaceutical drugs or make drugs more efficient [145].

Clinical Perspectives
As shown by reviewed studies, the pharmacological synergy of standard chemotherapies combined with NPs may provide therapeutic advantages through phytochemical complexity and multiple constituents of herb-herb interactions [143]. The efficacy of the poly-NPs formula has already been demonstrated in clinical practice [146] within the management of some cancer types (such as colorectal, breast and prostate cancers, cervical neoplasia, Barrett's metaplasia, and other gastrointestinal malignancies) and T2D [29,[147][148][149][150].
However, in evaluated clinical studies, the results were more favorable for diabetics than for PDAC patients. PDAC development could potentially be prevented by early intervention at the onset of diabetic symptoms, particularly in type 3c diabetes, in which further prompt examinations can detect a potentially curable tumor [8,53]. Since diabetes is linked to PDAC, distinguishing between T2D and type 3c, and implementing pharmacological and non-pharmacological interventions might be a good preventative strategy [151].
The treatment combining LCKD, gemcitabine or FOLFIRINOX, hyperthermia and hyperbaric oxygen therapy in patients with metastatic PDAC achieved longer survival outcomes (median OS 15.8 (10.5-21.1) months) and PFS of 12.9 (11.2-14.6) months [152]. This approach targets impaired mitochondrial energy mechanisms in mutated cancer cells, which is glucose-dependent. LCKD, 12-hour fasting and insulin administration prior to chemotherapy enhanced the effect of chemotherapeutics by making the membranes more permeable, depriving cancer cells of glucose and developing metabolic oxidative stress on the cells [153,154]. Hyperthermia sensitizes cancer cells to radiotherapy and chemotherapy, and hyperbaric oxygen delivery under high pressure can resolve the problem of hypoxia in cancer cells [155,156]. A combination with curcumin could further radiosensitize pancreatic tumor cells and bring additional treatment benefits [157].
Enteral and parenteral LCKD could be offered as an option to cancer patients in hospitals. These patients usually receive higher glucose-containing feeds, leading to hyperglycemia that increases systemic inflammation, which might contribute to cancer progression or the increased incidence of infection [158,159]. Moreover, hyperglycemia-induced elevation of insulin might increase the activity of the sympathoadrenal system, which is known for its cancer-stimulating effect [160]. Low-carbohydrate, high monounsaturated fatty acids tube feeding has been associated with a significant improvement in glycemic control (HbA1c), fasting and postprandial blood glucose in diabetic patients who were also taking antidiabetic medication [161][162][163].
The combination of LCKD, silybin from Silybum marianum plant and omega-3 polyunsaturated fatty acids has been found to be a good nutritional strategy to prevent cachexia [164]. This is performed by reducing tumor growth and inflammatory cytokine secretion (IL-6,-8, TNF-α), activating pro-apoptotic molecules, reducing glycolysis proteins, regulating impaired metabolism and immune responses, or preserving skeletal muscle mass. However, decisions regarding the application of LCKD for advanced PDAC cachexic patients are still inconclusive [164,165].
The stimulating effect of nerves innervating cancer tissue on tumor growth and invasiveness results in augmentation of peripheral stress-inflammatory responses that give feedback to the CNS, thus affecting patients' mental state (e.g. emotional tension, depression, impaired cognition, sleep disturbances) and facilitating a vicious cycle of further stress responses [166]. Since adrenergic and inflammatory responses may work in a synergistic and mutually enhancing manner, in addition to combination therapy of NPs and LCKD, and their immune-inflammatory modulation activity, both β-blockers and COX-2 inhibitors can be suggested as promising treatment strategies for improving cancer outcomes. The clinical evidence has also shown the advantage of such an approach in the perioperative period, when the inhibition of perioperative stress-related inflammatory responses to surgery may prevent metastasis, eliminate residual disease, and improve survival [24,167]. To reduce perceived stress and physiological responses, curcumin has shown a beneficial effect in the activation of vagal afferent neurons and restoring the sympathovagal balance. It has been reported to possess antidepressant activity by increasing serotonergic and dopaminergic transmission and suppression of monoamine oxidase, ROS formation, and inflammatory signaling. The beneficial effect of curcumin has also been reported in diabetes-induced CNS dysfunction, caused by fluctuations of acetylcholine neurotransmitters levels, resulting in cognitive impairment [34,168,169]. Nigella sativa oil administration has increased 5-hydroxytryptamine (5-HT/serotonin) and tryptophan brain and plasma levels, hence offering antidepressant and anxiolytic activity, which has also been shown through the regulation of γ-aminobutyric acid (GABA) and nitric oxide (NO) levels by thymoquinone [35,170]. Administration of Ginkgo biloba extract significantly improved mental and physical activity, reduced fatigue and anxiety via regulation of dopamine and serotonin levels, and inflammatory glial-derived proteins, as well as reversing cerebral hypoperfusion by regulation of neuroinflammation and the cholinergic system [171,172].
Similarly to NPS, LCKD also exhibits sympathovagal balance-modulating activity, relating to promoting a higher HRV and antioxidant capacity [45,173]. HRV analysis has shown potential for monitoring physiological and psychological wellbeing, thus giving an opportunity for biofeedback intervention and improvement of survival [174]. HRV biofeedback has demonstrated positive outcomes through learning how to build up resilience against stress by training to achieve optimal performance or HRV coherence. Higher HRV coherence optimizes autonomic-cardio-respiratory homeostasis, which better helps to sustain the energy for recovery processes during and after treatment [175]. Thus, apart from the combination of NPs with standard chemo-and radio-therapy, a NPs-concomitant, stress-reducing or HRV-improving strategy (psychotherapy, HRV biofeedback, β-blocker treatment) may be of interest in the search for new supportive approaches that could bring additional benefit for PDAC patients through the synergy in described NPs effects and improved autonomic balance.

Study Limitation
The major limitation of this study lays in the heterogeneity of the administered treatments, as well as the studies being available only in English. A small sample size in the studies, especially in the ones with PDAC patients, and the short duration of treatment, in some cases for only few weeks, do not provide sufficient dose-or ketosis-response data for NPs or LCKD to be evaluated and implemented as adjuncts to the anticancer medication. More studies with a larger group of participants, of a longer duration, and with synergistic interventions are therefore needed to assess the effect of NPs and LCKD in integrative and supportive anticancer treatment.

Conclusions
The data obtained from clinical studies demonstrate the ability of NPs and LCKD to affect multiple biological parameters implicated in the pathology of PDAC and T2D. The few clinical studies in which NPs and LCKD were used as monotherapy or in combination with conventional anticancer medications did not improve response and survival in PDAC patients. However, both interventions showed significant efficacy in the treatment of T2D. Therefore, the present study indicates that NPs and LCKD can have a significant association with reduction of the risk of PDAC development and progression. The risk of PDAC development could be prevented by early intervention at the onset of diabetic symptoms, in which further prompt examinations can detect a tumor at a potentially curable stage. There is no population screening program for PDAC, due to its low incidence. Since T2D is linked to PDAC, implementing an early intervention might be a good screening therapeutic strategy. The interventions can further contribute to improvement in biological parameters and treatment tolerability, maintain stable quality of life, and may benefit patients with pancreatic neoplasms. With the discerned safety of NPs and LCKD, and the ongoing acceptability of nutraceuticals and advances in the field, we believe that supportive management of PDAC is warranted and should be supported further by clinical trials. However, larger-scale research studies and new approaches, with more effective combinations of interventions and the optimal therapeutic window, are needed to overcome current limitations and reliably assess the role of NPs and LCKD in PDAC prevention and treatment. Future studies may also consider initiating a debate with clinicians on using evidence-based nutraceuticals within supportive cancer management; encouraging and educating patients within early prevention programs; and designing the therapeutic protocols and practices of supportive cancer management and their implementation in a healthcare system.

Conflicts of Interest:
The authors have no relevant financial or non-financial interests to disclose.