Cellular metabolism involves a series of enzyme-driven biochemical reactions that generate or consume energy. The activity and speed of these reactions fluctuate constantly. Diverse cellular energy requirements, proliferative activities, environmental stressors, and overall functions govern these fluctuations. Nevertheless, metabolism is now perceived in much broader terms than mere biochemistry; it permeates all facets of biology ^[1][2][1,2].

Under healthy conditions, cells can balance anabolism, catabolism, and waste removal by monitoring and coordinating different metabolic pathways. In various disease states, this intricate balance is lost, resulting in altered metabolism. Usually, genetic reprogramming underlies dysfunctional metabolic switching in cells and tissues. These perturbing shifts in metabolism are different in each disease.

In 1923, Otto Warburg first postulated the Warburg phenomenon, suggesting metabolic rewiring to be one of the hallmarks of cancer after observing that tumors demonstrate increased glucose uptake. He further hypothesized that cancer cells, due to dysfunctional mitochondria, primarily utilize aerobic glycolysis instead of OXPHOS for rapid energy release, which is required by proliferating cells ^[3][4][4,5]. The Warburg effect involves cytoplasmic anaerobic fermentation of glucose into lactate, despite regular oxygen availability. Aerobic glycolysis ultimately increases cellular anabolism and decreases catabolism. Researchers' knowledge of this phenomenon and its driving forces has been refined and expanded over the past decades. Nevertheless, two features of the Warburg effect remain unaltered: increased glucose uptake and lactate production ^[5][6][6,7]. Aerobic glycolysis is markedly heightened in over 70% of cancer types, such as lung ^[7][8], breast ^[8][9], liver ^[9][10][10,11], brain ^[11][12], prostate ^[12][13], gynecologic ^[13][14], and pancreatic cancer ^[3][14][15][4,15,16]. Similar to solid tumors, hematologic malignancies, such as lymphomas ^[15][16][17][16,17,18] and leukemias ^[15][18][19][16,19,20], also demonstrate high aerobic glycolysis and low OXPHOS rates. In certain tumors, the accelerated Warburg effect occurs even in the presence of active or partially active mitochondrial OXPHOS ^{[20][21][22][23]}[21,22,23,24]. It is argued that, in cancer, minimal activity of mitochondrial OXPHOS is crucial for tumor cell survival ^{[21][24][25][26]}[22,25,26,27] and metastasis ^[27][28].

In addition to the Warburg effect, cancer cells simultaneously adopt another metabolic pathway called glutaminolysis as part of a metabolic reprogramming strategy to meet their specific energy and biosynthetic demands. With heightened energy demands, cancer cells absorb and utilize more glutamine than normal cells, supplementing glucose as an additional energy source ^[28][29]. Glutaminase converts glutamine to glutamate and ammonia ^[29][30]. The resultant glutamate enters the tricarboxylic acid (TCA) cycle within mitochondria, supporting energy production and biosynthetic precursor synthesis ^[30][31]. Notably, increased glutaminolysis in cancer cell mitochondria induces a metabolic shift from canonical OXPHOS and ATP production to the synthesis of anabolic intermediates for lipid and amino acid production. Malate, an intermediate in the TCA cycle, is metabolized to pyruvate and lactate, whereas citrate contributes to lipid metabolism. Both processes generate NADPH molecules, countering specific reactive oxygen species and averting oxidative stress ^[31][32]. Furthermore, glutamine serves as a crucial nitrogen source for nucleotide biosynthesis in the cytosol. In purine biosynthesis, two glutamine molecules provide nitrogen atoms for the purine ring formation in inosine monophosphate, a precursor to both adenosine monophosphate and guanosine monophosphate ^[32][33]. In pyrimidine biosynthesis, one glutamine molecule provides the nitrogen atom necessary for the formation of cytidine triphosphate from uridine triphosphate ^[33][34]. Collectively, glutamine acts as a signaling molecule, activating essential pathways that promote survival, proliferation, and differentiation.

Notably, a pivotal 2020 study by K.I. Nakayama found a significant shift in the fate of glutamine-derived nitrogen in cancer, which is crucial for cell proliferation and survival ^[34][35]. The nitrogen’s fate shifts away from the anaplerotic pathway supporting the TCA cycle, redirecting towards nucleotide biosynthesis. The regulation of this shift lies in the enzymes glutaminase (GLS1) and phosphoribosyl pyrophosphate amidotransferase (PPAT) ^[34][35]. A higher PPAT/GLS1 ratio orchestrates this transition, with PPAT steering nitrogen metabolism towards nucleotide synthesis and reduced GLS1 expression. GLS1, on the other hand, guides nitrogen metabolism to produce glutamate and ammonia, a pivotal step influencing the TCA cycle. Heightened GLS1 activity hinders tumor growth, whereas increased PPAT activity supports cell proliferation. Consequently, the determining factor for the metabolic shift is not solely glutamine availability but rather the PPAT/GLS1 ratio, as emphasized in the study ^[34][35]. In cancer, a prevalent pattern is observed with elevated PPAT expression and diminished GLS1 expression, particularly during malignant transformation ^[34][35]

In certain cancers, dysregulation of these pathways may contribute to cancer development and metastasis.

In contrast, the elaborate metabolic alterations characterizing T2D diverge from those associated with cancer. Despite these variances, there are shared signaling molecules at the crossroads of both conditions that influence shifts in OXPHOS and/or glycolysis.

In established T2D, insulin resistance arises in peripheral tissues, primarily in the skeletal muscle (SKM) ^[35][36], and decreases glucose-induced insulin secretion by pancreatic β cells ^{[36][37][38][39]}[37,38,39,40]. In healthy SKM, insulin increases the mitochondrial capacity for OXPHOS via increased expression of mitochondrial OXPHOS-related genes and the posttranslational modification of mitochondrial proteins in the form of phosphorylation ^{[40][41][42][43]}[41,42,43,44]. Hyperglycemia induces the release of insulin, activating mitochondrial respiration ^[44][45]. However, chronic hyperglycemia in individuals, due to continuous nutritional overload and decreased physical activity, leads to prolonged hyperactivity of the OXPHOS machinery. This is associated with a consistently excessive release of reactive oxygen species (ROS), leading to oxidative toxicity and insulin resistance in peripheral tissues, which eventually results in the development of T2D ^[45][46][47][46,47,48]. However, in established T2D, contradictory findings have been reported on mitochondrial OXPHOS in SKM ^[42][43]. Several researchers reported mitochondrial dysfunction and low OXPHOS in SKM ^[48][49][49,50], whereas others reported normal OXPHOS ^[50][51][52][51,52,53]. A few studies reported that the liver exhibited normal to even increased mitochondrial OXPHOS ^[53][54][55][54,55,56]. Some researchers argue that mitochondrial dysfunction contributes to the development of insulin resistance and T2D ^[48][49][56][49,50,57]. However, the opposite is more often believed to be true, i.e., insulin resistance leads to mitochondrial dysfunction in peripheral tissues ^[42][57][43,58]. In contrast, in T2D, a Warburg-like effect and lactate production also occur in pancreatic β cells ^[58][59][59,60]. The released lactate could cause insulin resistance by suppressing glycolysis and impairing insulin signaling in SKM ^[60][61].

2. Metabolic Therapeutic Approaches in Cancer and T2D

Cancer and T2D are metabolic disorders characterized by opposing metabolic switches and divergent underlying signaling pathways, yet they intertwine towards the master regulator AMPK. In cancer, the Warburg glycolytic shift promotes malignant transformation, tumor progression, invasiveness, and resistance to chemotherapy and/or radiotherapy ^[61][62][63][121,240,241]. Nonetheless, during the pathogenesis of T2D, there is hyperactivity and dominance of mitochondrial OXPHOS. Therapeutic and/or nutritional targeting of either of the two metabolic shifts is a promising approach to correcting the metabolic imbalance and restoring homeostasis ^{[20][63][64][65]}[21,241,242,243]. Although tumors are predominately glycolytic, they vary in their phenotypic features associated with proliferation, invasion, metastasis, and resistance to therapy. The characteristics of the metabolic phenotype of each cancer determine its rate of proliferation and resistance to chemotherapy ^[66][153]. Thus, cancer therapy needs to be customized to target the underlying causative metabolic dysfunction. Therapeutic attempts to target cellular metabolism in cancer are aimed at the inhibition of Warburg glycolysis and/or the activation of OXPHOS to confer antiproliferative activity. In addition, metabolic inhibition has shown the ability to sensitize chemo-resistant tumor cells to treatment. Furthermore, based on previous research, there have been suggestions to reestablish the metabolic imbalance in cancer by targeting tumor microenvironment symbiotic crosstalk. Certain pharmacological agents and nutrients have been shown to have the potential to correct and reverse metabolic imbalances in cancer. Some of these are gaining validation through in vitro and in vivo analyses, as well as in clinical trials. However, in T2D, targeted metabolic inhibition using nutritional and/or pharmacological compounds could prevent insulin resistance and improve insulin sensitivity in prediabetic and diabetic animal models and in diabetic patients. These therapies aim to inhibit mitochondrial OXPHOS activity ^[42][67][43,220]. The use of certain nutrients and dietary supplements as metabolic treatments or adjuvants in T2D is gaining attention owing to the encouraging results obtained in the past decade.

2.1. Pharmacological-Based Approaches Targeting Mitochondrial Metabolism in Cancer

2.1.1. BACH1 Depletion Activates OXPHOS and Sensitizes Tumor Cells to Metformin

Among the genes related to ROS homeostasis, BTB domain and CNC homolog 1 (BACH1) is a heme-binding transcription factor that combats the oxidative stress response by repressing the heme oxygenase 1 gene and is a negative regulator of ROS-induced cellular senescence directed by p53 ^[68][69][244,245]. BACH1 is upregulated in breast and other types of cancer; it is proposed to be a marker of poor prognosis and a high metastatic rate in breast cancer. For instance, triple-negative breast cancer (TNBC) cells reprogram their metabolism by increasing BACH1 expression to direct their metabolism away from the TCA cycle, which could be a protective mechanism that enhances their proliferative potential. On the one hand, it prevents the accumulation of ROS by shutting down mitochondrial metabolism. Thus, BACH1 may provide a mechanism by which tumor cells evade oxidative stress-induced senescence. In 2019, Rosner et al. ^[70][246] showed that the combined therapeutic use of metformin with BACH1 inhibitor (hemin) could reverse chemoresistance in TNBC cells. BACH1 targets mitochondrial metabolism by repressing key ETC genes (UQCRC1 and ATP5D, both negatively correlated with BACH1 in TNBC), which are predominantly involved in the OXPHOS pathway. Metformin is known to mainly inhibit mitochondrial ETC complex I, along with other metabolic targets. Metformin was able to inhibit the growth of tumor cells and decrease tumor cell viability in BACH1-depleted TNBC cells. However, control cells that expressed BACH1 did not respond to metformin treatment, and the TNBC cells continued to grow and proliferate. Downregulating BACH1 in tumors using hemin, both in vitro and in vivo, resulted in an increased expression of mitochondrial inner membrane genes involved in ETC and promoted mitochondrial respiration. TNBC cells that were depleted of BACH1 exhibited higher oxygen consumption, lower lactate production, higher glucose utilization in the TCA cycle, increased ATP generation, higher TCA cycle intermediate production, and decreased glycolysis-related intermediates ^[70][246]. Rosner attempted to reprogram the metabolic pathway in TNBC tumors resistant to ETC inhibition therapy because of high BACH1 expression. Inhibiting BACH1 expression sensitized tumor cells to metformin both in vitro and in vivo. For further details regarding interventional clinical trials investigating the impact of metformin on various types of cancer, researchers compiled a table retrieved from clinicaltrials.gov on 23 November 2023. This table encompasses both completed and ongoing studies that have reached phase 2 or phase 3. It is important to note that trials that were withdrawn, suspended, or terminated were excluded. Cellular senescence is mainly mediated by tumor suppressor p53, which serves as a barrier to malignant transformation ^[71][247]. The upregulation of BACH1 in TNBC cells has been suggested to prevent oxidative stress-induced senescence. This rationale is supported by the findings of Dohi et al., who demonstrated that BACH1 forms a complex with p53, histone deacetylase 1, and a nuclear co-repressor. The formation of this complex prevents p53 from inducing an effective oxidative stress response by promoting histone deacetylation ^[69][245]. Furthermore, Wiel et al. showed that stabilizing BACH1 using antioxidants in a p53-/- background in lung cancer models increased metastasis, glucose uptake, glycolysis rate, and lactate secretion in mouse and human lung cancer cells. Hence, in scenarios marked by lower oxidative stress, BACH1 promotes glycolysis-dependent lung cancer metastasis independently of p53 ^[72][248]. Multiple microRNAs (miRs) were found to target the post-transcriptional regulation of BACH1 and reduce cancer progression, such as miR-142-3p, which can target BACH1 in breast cancer cells, leading to reduced cellular proliferation, invasion, and migration ^[73][249]. The induction of miR-330 also inhibits the proliferation of colorectal cancer cells by suppressing BACH1 gene expression ^[74][250]. In addition to these studies, BACH1 was also found to be linked to an age-dependent decline in adaptive homeostasis. Its levels were elevated in various tissues, including the heart, liver, and lungs, in aging mice ^[71][247]. Furthermore, BACH1 expression was higher in human bronchial epithelial cells obtained from older adults compared to those from young adult donors ^[75][251]. Thus, BACH1 attenuates adaptive redox homeostasis in both aging mice and older individuals. Taken together, these studies show that BACH1 is a potential metabolism-targeting therapy for cancer. This suggests that the inhibition of BACH1 can modulate the metabolic profile in resistant cancers such that the OXPHOS pathway is restored, glycolysis is reduced or omitted, cancer growth is halted, and cancer cells are sensitized to therapy.

2.1.2. Dichloroacetate and EGFR-Inhibitors Reverse the Warburg Effect in Cancer

Sun et al. demonstrated that the generic drug dichloroacetate (DCA) can reverse the glycolytic phenotype in metastatic breast cancer cells both in vitro and in vivo and can inhibit tumor growth and metastasis ^[76][252]. DCA works by inhibiting PDK activity, wherein PDK inactivates PDH via phosphorylation. PDH controls the conversion of pyruvate to acetyl Co-A, which in turn enters the TCA cycle and generates ATP via the action of OXPHOS. Thus, treatment with DCA stops the inhibition of PDH, increases the flux of pyruvate into the mitochondria, and promotes mitochondrial OXPHOS over glycolysis ^[76][252]. In 2015, De Rosa et al. demonstrated that the use of EGFR inhibitors, including erlotinib or WZ4002 in human non-small cell lung cancer cell lines (H1975, HCC827, and H1993) and PHA-665,752 in the H1993 cell line, succeeded in the reversal of the Warburg effect and reactivation of OXPHOS in these cell lines ^[77][253]. This effect was mediated through the upregulation of ETC mitochondrial complexes, in addition to reduced expression levels of key glycolysis enzymes, such as hexokinase II and p-PKM2 Tyr105. Concomitantly, decreased lactate secretion and increased intracellular ATP levels were observed in response to EGFR inhibition ^[77][253]. In conclusion, these results revealed that the effective inhibition of EGFR signaling can reverse the Warburg effect in cancer cell lines and restore OXPHOS.

2.1.3. Metformin Activates AMPK to Induce Apoptosis in Cancer

Targeting AMPK in cancer cells to either sensitize tumor cells to chemotherapy, cause cell cycle arrest, or induce apoptosis is a promising therapeutic approach. For instance, the activation of AMPK inhibited cervical cancer cell proliferation through the AKT/FOXO3a/FOXM1 signaling cascade by counteracting the function of Forkhead box M1 (FOXM1) ^[78][192]. Previously, several pharmacological AMPK activators, such as metformin, the AMP-mimetic 5-aminoimidazole-4-carboxamide (AICAR), and the ATPase inhibitor A23187, were able to suppress cervical cancer cell growth by activating AMPK ^[78][192]. In 2008, Keith et al. were able to induce cell cycle arrest in the MDA-MB-231 breast cancer cell line by treating the cells with metformin only in the presence of cyclin-dependent kinase inhibitors (p27^kip and/or p21^cip1). Metformin was able to activate the AMPK pathway and downregulate cyclin D1 ^[79][254]. Mills et al. further demonstrated that the LKB1-AMPK pathway regulates p27^kip1 phosphorylation; they were able to induce apoptosis in cell lines after AMPK activation in the absence of p27^kip1. Downstream of AMPK, p27^Kip1 is phosphorylated at Thr198, which stabilizes p27, leading to autophagy and cell-cycle progression. When p27 was knocked down in the cancer cell line, LKB1-AMPK activation induced apoptosis ^[80][255].

2.1.4. Targeting PI3K/AKT Pathway in Cancer

The dysregulation of the PI3K/AKT pathway is a common feature in many cancers ^[81][256]. Evidence indicates that inhibiting the PI3K/AKT pathway hinders tumor progression ^[81][256]. However, the use of PI3K-AKT-mTOR inhibitors in treating various cancer types has been observed to induce hyperglycemia in patients ^[82][257]. A study by Khan et al. investigated the clinical data of 341 cancer patients from 12 phase I clinical trials treated with PI3K, AKT, or mTOR inhibitors as well as dual inhibitors. There was evident hyperglycemia in 87.4% of these patients. However, grade-three hyperglycemia was only seen in 6.7% of these patients. Hence, hyperglycemia was mostly manageable in those patients. Thus, caution is necessary when treating cancer patients who are also diabetics with PI3K-AKT-MTOR inhibitors ^[82][257]. This study may seem paradoxical, as the inhibition of the PI3K-AKT-mTOR pathway, which generally leads to inhibition of cell proliferation, is expected to activate the AMPK pathway. AMPK activation would exhibit beneficial effects in diabetes and lower glucose levels. However, this is not the case with PI3K-AKT-mTOR inhibitors alone. Nevertheless, the combination of metformin and PI3K-AKT-mTOR inhibitors in vitro enhances the apoptosis of ovarian cancer cells ^[83][258] and induces drug sensitivity in pancreatic cancer cells ^[84][259]. To understand how PI3K-AKT-mTOR inhibitors work, researchers will take a quick look at PI3K signaling. PI3K produces phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which in turn activates phospholipase D (PLD) ^[85][260]. PLD catalyzes the hydrolysis of the membrane phospholipid phosphatidylcholine to generate choline and metabolically active phosphatidic acid (PA) ^[86][261]. PA is a signaling lipid involved in processes such as cell proliferation and vesicular trafficking. PLD can influence mTOR activity by generating PA ^[87][262], which directly activates mTOR complex 1 (mTORC1) under certain conditions ^[88][263]. PA stimulates mTORC1 function and suppresses the activation of mTORC2 as part of a mTORC1/2 feedback loop ^[89][264]. PI3K inhibitors decrease PLD activation after insulin receptor stimulation ^[90][265], and the mutation of the PIP3 binding site on PLD prevents PLD activation and membrane recruitment ^[91][266]. A study by Toschi et al. demonstrated that by inhibiting PLD activity, mTORC2 could be targeted therapeutically with rapamycin ^[92][267]. Thus, the combination of rapamycin, metformin, and PI3K/PLD inhibitors can have a favorable therapeutic outcome in cancer therapy. PIP3 generation mediates downstream signaling events that inhibit glycogen synthase kinase-3β (GSK-3β) ^[93][94][268,269]. GSK-3β in turn hinders NRF2 by directing it towards ubiquitination and subsequent degradation ^[95][270]. NRF2 plays a pivotal role in combating oxidative stress and regulating redox homeostasis, thereby safeguarding cells against carcinogenesis ^[96][271]. However, studies over the last decade reveal a “dark side” of NRF2 ^[97][272], where its constitutive stabilization leads to increased glutaminolysis ^[98][273], cancer progression ^[99][274], metastasis ^[100][275], and chemoresistance ^[101][102][276,277]. Indeed, NRF2 redirects glucose and glutamine into anabolic pathways during metabolic reprogramming ^[98][103][273,278]. Consequently, strategies such as inhibiting PI3K and NRF2 or activating GSK-3β, along with NRF2 repressor Kelch-like ECH-associated protein 1 (KEAP1) ^[104][279], hold promising therapeutic potential against cancer.

2.2. Pharmacological-Based Approaches Targeting Mitochondrial Metabolism in T2D

2.2.1. Apoptosis-Inducing Factor Ablation in Diabetic Mice Inhibited OXPHOS

A study by Penninger‘s team in 2007 showed that global or tissue-specific gene ablation (liver and muscle) of apoptosis-inducing factor (AIF) in mice caused a deficiency in OXPHOS, which was accompanied by improved glucose tolerance, increased insulin sensitivity, and reduced fat mass ^[67][220]. AIF has been known to cause progressive OXPHOS dysfunction in mice ^[105][106][280,281]. Mutation analysis performed in several model organisms found that AIF was an essential regulatory gene for maintaining fully active and functional mitochondrial ETC ^[107][108][282,283]. Therefore, AIF deletion caused a progressive loss of ETC activity and function ^[105][107][280,282]. In the study by Penninger’s team, impaired OXPHOS prevented weight gain, insulin resistance, and T2D, which is contrary to other studies reporting that OXPHOS deficiency is associated with insulin resistance and T2D ^[67][220].

2.2.2. Targeting PI3K/AKT Pathway in T2D

Su et al., in a comprehensive review, explain the effects of PI3K-AKT signaling on obesity and T2D. The review summarizes the findings of many studies done in vitro and in vivo on diabetic cells and mouse models in which the activity of the PI3K-AKT was targeted ^[109][284]. Su et al. argue that, under normal physiologic conditions, the PI3K-AKT pathway actively regulates body functions, including metabolism and proliferation. The PI3K-AKT pathway regulates glucose metabolism through FOXO1 and GSK-3. PI3K-AKT also regulates lipid metabolism through mTORC1 and SREBP. Active AKT inhibits FOXO1, which reduces glucose levels ^[110][111][285,286]. Similarly, active AKT inhibits mTOR complex 1, which consequently reduces lipid and protein production ^[112][287]. GSK-3 is also inhibited by AKT, which leads to glycogen synthesis, thus reducing glucose levels ^[113][288]. Lipid metabolism is regulated by AKT activity through sterol regulatory element-binding proteins (SREBP). SREBP increases fatty acid and cholesterol accumulation ^{[109][112][114]}[284,287,289]. However, when there is chronic excessive energy intake, as in obesity, PI3K-AKT signaling becomes suppressed, a state in which re-activating PI3K-AKT would lessen obesity and insulin resistance. Nevertheless, it is in the established disease states of cancer and/or obesity where there is dysregulation and/or overexpression of PI3K-AKT. At this point, therapeutic inhibition of PI3K-AKT becomes an effective anti-obesity and anti-cancer treatment approach ^[109][284]. Thus, Su et al. detail the mechanism by which the PI3K-AKT pathway acts in an organ-specific manner ^[109][284]. That further explains why targeting PI3K, whether by inhibition or activation, would be favorable depending on the context ^[109][284]. For instance, one study showed that pharmacological inhibition of PI3K-AKT activity reduced adiposity and metabolic syndrome in obese mice and rhesus monkeys ^[115][290]. They used two small molecules with selective inhibitory action on PI3K (CNIO-PI3Ki and GDC-0941) as pharmacological inhibitors ^[115][290]. In contrast, overexpression of FAM3A in the liver activates PI3K p110α-AKT signaling in the liver and decreases hepatic gluconeogenesis and lipogenesis ^[116][291].

2.2.3. Metformin as a Metabolic Inhibitor in T2D

For decades, metformin has shown great success in the treatment of T2D. Metformin can stimulate glucose uptake and glycolysis in patients with T2D ^[117][203]. Glycolysis plays two major roles in glucose homeostasis. The first role is through inhibiting hepatic gluconeogenesis, thereby decreasing the amount of glucose released into the blood ^[117][118][203,292], and the second role is through enhancing insulin secretion by pancreatic β cells ^{[117][119][120]}[203,208,293]. In this context, metformin works by augmenting glycolysis, which leads to a decrease in liver gluconeogenesis. Metformin exerts its effects by suppressing mitochondrial OXPHOS by inhibiting complex I (NADH dehydrogenase) of the ETC ^[121][122][294,295]. Inhibiting complex I increases the AMP/ATP ratio, which further activates AMPK ^[123][185]. The idea behind metabolic inhibition is that any injury caused to the mitochondrial metabolic machinery leads to the activation of AMPK to compensate for the mitochondrial dysfunction. Metformin was also found to exert its function by upregulating UCP2 in adipocytes in mouse models, thus playing a protective role against oxidative damage ^[124][296]. Therefore, AMPK activation is an effective therapeutic strategy for enhancing insulin sensitivity in T2D ^[42][43].

2.3. Metformin and Other AMPK-Activators in Cancer Clinical Trials

Metformin, a standard anti-diabetic medication, has been an attractive therapeutic target in cancer patients. Clinical data on the effect of metformin and other AMPK activators in cancer patients strengthen researchers' argument about targeting the metabolic shifts in both diabetes and cancer. Several meta-analysis studies over the last decade have reported that diabetic patients receiving metformin are at lower risk of developing cancer ^{[125][126][127]}[3,297,298]. Moreover, metformin was able to improve survival and response to treatment in cancer patients ^{[126][127][128][129]}[297,298,299,300]. These studies corroborated previous in vitro and in vivo studies in animal models that showed metformin exhibiting anti-cancer effects ^{[78][126][127][130]}[192,297,298,301]. For instance, Noto et al. (2012) conducted a systematic meta-analysis on 6 studies (4 cohort studies, 2 RCTs), with data from a total of 210,829 diabetic patients ^[125][3]. They found that diabetic patients taking metformin had a significantly lower risk of cancer incidence and cancer mortality using pooled relative risk measures. One of the earliest meta-analysis studies, conducted by DeCensi et al. in 2010, showed a 31% reduction in overall relative risk of cancer incidence in subjects receiving metformin compared to other anti-diabetic treatments ^[131][302]. Another meta-analysis study, by Wang et al. (2014) ^[132][303], performed on data from 13 observational studies (10 cohort, 3 case-control), found that the use of metformin was associated with reduced risk of pancreatic cancer in T2D patients. In another observational study, by Kim et al. (2020), involving a Korean cohort of 323,430 individuals with a median follow-up of 12.7 years, data were extracted from national health records spanning from 2002 to 2015. The findings indicated that diabetic individuals undergoing metformin treatment had a reduced risk of cancer incidence compared to diabetic patients not receiving metformin, with an incidence percentage of 10.3% in metformin users compared to 11.1% in non-metformin users ^[133][304]. Similar results have been reported in other retrospective meta-analysis studies ^{[134][135][136][137][138][139]}[305,306,307,308,309,310]. However, a study conducted in the UK showed no protective effect of metformin against cancer incidence in diabetic patients ^[140][311]. An insightful review by Saraei et al. (2019) aimed to explain the mechanisms by which metformin exerts its beneficial effects in cancer ^[126][297]. The review also encompassed clinical trials conducted to confirm the beneficial effects of metformin on cancer. Based on this analysis, several clinical trials took place in non-diabetic patients to test the effects of metformin, but the results were inconclusive in proving a protective anti-cancer effect in non-diabetic patients. Therefore, further investigations are needed. An inquiry arises regarding the potential anti-cancer effects in diabetic patients of other AMPK activators similar to metformin. Although metformin is extensively studied as an AMPK activator, there exist additional physiological and pharmacological agents that can activate AMPK either directly or indirectly. For instance, thiazolidinediones (TZDs), such as troglitazone, pioglitazone, and rosiglitazone, belong to another class of anti-diabetic medications recognized for their ability to activate AMPK. Some studies showed the absence of any significant association between cancer risk and taking TZDs in diabetic patients ^{[141][142][143]}[312,313,314]. Other studies have shown that T2D patients who are taking TZD have lower cancer risk in certain cancer types ^{[141][143][144][145]}[312,314,315,316]. Interestingly, some clinical studies have shown that patients taking TZD have an increased risk of cancer ^[146][147][317,318]. Thus, observations and associations have been conflicting and inconclusive in meta-analysis studies. This is attributed to methodological variations within these studies and the intricacy of the disease ^[148][319]. Thus, more studies are needed. However, the evidence that associates metformin use in T2D patients with a lower risk of cancer is stronger and more consistent among studies ^[148][319]. Although metformin (belonging to biguanides) and TZDs can indirectly activate AMPK by inhibiting complex 1 in the mitochondrial respiratory chain (ETC cycle), metformin also acts in a non-AMPK-dependent manner ^[149][320]. Metformin’s impact on the liver is mediated by antagonizing glucagon signaling through cyclic AMP and PKA, operating independently of AMPK ^[150][151][321,322]. In contrast, TZDs activate AMPK by targeting the nuclear hormone receptor peroxisome proliferator-activated receptors (PPARs), which in turn stimulate the secretion of adiponectin and, consequently, activate AMPK ^[152][323]. Other AMPK activators, such as polyphenols and 5-aminoimidazole-4-carboxamide riboside (AICAR), have not been studied in the context of anti-diabetic drugs and the risk of cancer. Yet, it is worth noting that similar anti-cancer effects to those of metformin have also been observed with other AMPK activators in vitro and in vivo. This suggests that metformin may not be the only drug with dual effects and that other AMPK activators might exhibit promising anti-cancer effects as well as anti-diabetic ones ^[152][323].