Pancreatic ductal adenocarcinoma (PDA), or pancreatic cancer, is a devastating exogenous pancreatic disease that ranks the fourth leading cause of cancer mortality and is projected to be the second leading cause of death by 2030 in the United States (Rahib et al., 2014; Siegel et al., 2020). PDA patients often have a dismal fate that only 10% of them could survive longer than 5 years. At present, over 80% of pancreatic cancer cases are in the unresectable tumor stage when diagnosed with extensive local invasion and metastases to distant organs (such as liver, lung, bone, etc.) (Klaiber et al., 2018).

Due to the high prevalence of prediabetic hyperglycemia and diabetes mellitus (DM) in pancreatic cancer patients (over 75% in high glucose status and 50% in diabetic status), a peripheral increase of insulin level and exogenous insulin injection can often be seen in PDA cases (Cetin et al., 2002; Korc, 2007; Dugnani et al., 2016; Andersen et al., 2017; Dev et al., 2018). In prediabetic status, increased blood glucose level stimulates the pancreatic islets to produce more insulin, leading to endogenous hyperinsulinemia in the human body. This compensatory insulin overexpression was gradually decreased with the apoptosis caused by hyperglycemia in pancreatic islet beta cells. Finally, long-standing diabetes patients require an exogenous insulin injection to sustain high-insulin concentration, which is the so-called “exogenous hyperinsulinemia.” Moreover, a unique portal structure enables insulin secreted from the pancreatic islet to perfuse the exocrine pancreas first, significantly increasing the regional insulin concentration in PDA tissue. As a result, pancreatic cancer is often exposed to a high insulin concentration environment. In the past decades, it has been generally accepted that insulin was a risk factor in many types of cancer, including colorectal cancer, breast cancer, liver cancer, and pancreatic cancer (Pollak, 2008). In PDA cases, hyperinsulinemia or exogenous insulin use is related to the elevated PDA incidence and increased tumor volume (Stolzenberg-Solomon et al., 2005; Zyromski et al., 2009; White et al., 2010; Wolpin et al., 2013; Boursi et al., 2017; Carreras-Torres et al., 2017). Thus, insulin has been considered decisive in developing PDA. However, the failure of clinical trials targeting insulin and its related signal pathway indicates there is still lacks a systemic understanding of how insulin interferes with PDA development. And, as a malignant disease initiating from the pancreas, it is not clear how pancreatic cancer influences insulin production and synthesis in the pancreas. A clear elucidation of the crosstalk between insulin and pancreatic cancer is needed at present.

This review summarizes the published clinical and experimental evidence of how insulin interacts with PDA to promote hyperinsulinemia, PDA initiation, and progression. We also concluded the current ways of lowering insulin levels and clinical advances targeting the insulin signal pathway in pancreatic cancer.

The peculiar correlation between diabetes and pancreatic cancer was observed as early as 1833 (Iqbal et al., 2013). Diabetes mellitus develops pancreatic cancer, while pancreatic cancer also strengthens hyperglycemic status. According to the diagnostic interval between type 2 diabetes mellitus (T2DM) and PDA, DM was divided as the long-standing diabetes mellitus (time interval longer than 3 years) and the new-onset diabetes mellitus (time interval shorter than 3 years) (Jeon et al., 2018). PDA risk is slightly increased in the LSDM group compared with the euglycemic group. However, LSDM is considered to be a relatively low PDA risk group because PDA was reported to have no causal relationship with LSDM(Molina-Montes et al., 2021). Moreover, the prevalence of PDA is low in the LSDM group, and the PDA risk is similar to other common cancers.

But the situation is totally changed in the new-onset diabetes mellitus (NODM) group, which is believed to be a high-risk signal of PDA. NODM is more likely to be a clinical manifestation of PDA and pancreatic precursor lesions because more than 50% PDA related diabetic cases developed diabetes in the 36 months preceding the PDA diagnosis (Setiawan et al., 2019). Moreover, studies also observed a significantly higher PDA risk in the NODM population compared with the LSDM population (Jeon et al., 2018). After removing tumorous tissue, hyperglycemic status and insulin resistance rate were significantly relieved in NODM patients. As for the DM prevalence in cancer, the prevalence of diabetes in the PDA population is significantly higher than noncancer population, whereas DM prevalence in other common cancers is no different from that in normal controls (Aggarwal et al., 2013). Therefore, the relationship between DM and PDA is close and peculiar according to epidemical and clinical studies.

As the first-line antidiabetic drug, insulin is essential for most diabetic patients to control blood glucose. Based on this, the assessment of PDA risk in insulin users is critical, and many studies have been done previously to solve this problem. For long-standing diabetes patients, a relatively low PDA risk population, insulin use is safe and long duration of insulin use is associated with a decreased PDA risk. (Bosetti et al., 2014; Molina-Montes et al., 2021). Unlike other types of cancer, PDA risk in insulin users does not increase with a longer insulin duration. PDA risk in short-term insulin use (less than 3 years) is significantly increased, while people who started insulin more than 5 years showed a relatively lower risk (0.5–0.7 folds) than new starters (Li et al., 2009; Colmers et al., 2012; Singh et al., 2013; But et al., 2017). Laboratory evidence also confirmed that single insulin stimulation could not initiate PDA under low PDA risk circumstances. In primary human pancreatic ductal cells, increased insulin concentration neither enhanced cell survives nor induced cell proliferation (Chan et al., 2014). Knocking out KRAS (the most common gene mutation in 95% PDA patients) in cancer cells even made insulin lose the ability to promote cancer cell viability, and insulin even turned to induced tumor cell dormancy in vitro experiments (Rajbhandari et al., 2017). With the introduction of the mutant KRAS gene, insulin regained the ability to induce invasion and proliferation in pancreatic ductal cells (Wang et al., 2019). Based on this, the tumorigenic effect of insulin is primarily driven by mutated cancer genes. Insulin injection or endogenous hyperinsulinemia is safe in long-duration diabetic patients.

However, the situation is changed in high-risk PDA patients. According to the American gastroenterology association (AGA) guideline, the high-risk population of PDA consisted of family history, genetic mutation carriers (including BRCA1, BRCA2, STK11, CDKN2A, etc.), and the NODM population (Aslanian et al., 2020). Although currently there is no direct evidence demonstrating the risk of insulin in initiating PDA in genetic mutation carriers and family history, the activation of insulin signal pathway and circulating hyperinsulinemia elevated the cancer risk in mutated gene carriers (Ding et al., 2012; Argirion et al., 2017). Moreover, hyperinsulinemia predicts PDA in new-onset diabetes mellitus (NODM) patients. As we have discussed before, NODM may be an early symptom of pancreatic precursor lesion or pancreatic cancer. For NODM patients, insulin use or high insulin receptor expression in tumor cells is associated with higher malignancy rates in pancreatic precursor lesions. Thus, insulin accelerates the malignancy of PDA precursor which manifests as a highly increased PDA risk in NODM insulin users (Li et al., 2009; Colmers et al., 2012; Singh et al., 2013; But et al., 2017). Especially in diabetic patients who initiated insulin use less than 0.5 years had the highest PDA risk in short-term cohorts (Colmers et al., 2012; Zanders et al., 2018). As for diabetic PDA patients, insulin is a definite tumor-promoting factor. The mechanism of how insulin influences PDA progression will be discussed later.

Unlike other cancer, a unique phenomenon is that PDA actively induces hyperglycemia or even diabetes through inducing peripheral insulin resistance as early as the PanIN (a precursor of pancreatic cancer) period. PDA does not directly stimulate insulin overexpression at pancreatic islet beta cells but synthesizes products to elicit insulin resistance in the human body. Reduced insulin sensitivity was observed in pancreatic cancer patients’ muscle, adipose, and liver tissue, which is believed to result from exosomes secreted from pancreatic cancer cells (Basso et al., 1997; Record et al., 2014; Wang et al., 2017). Figure 1. demonstrates the primary mechanism of how PDA induces insulin resistance and blunts glucose sensitivity to cause hyperinsulinemia.

Under physical conditions, insulin stimulates insulin receptors in muscle, adipose, and liver tissue to transport blood glucose into myotube cells, adipocytes, and hepatic cells. Under pancreatic cancer conditions, micro-RNAs (miRNAs) secreted from PDA activate PI3K/Akt/FoxO1 signal pathway to suppress myotube cells’ response to insulin in muscle tissue (Wang et al., 2017). Aside from miRNAs, pancreatic cancer cell generates galectin-3 and S100A9 to suppress glucose up-taking ability in myotube cells (Liao et al., 2019).

Moreover, adipose tissue is also the target of pancreatic cancer. In the pancreatic cancer microenvironment, pancreatic cancer cells and fibroblasts produce adrenomedullin to inhibit adipocyte response to insulin signals. Despite interfering with insulin response in human muscle and adipose tissue, the synthesis of glucagon-like peptide-1 (GLP-1), a well-known glucose-lowering hormone, can also be influenced by pancreatic cancer cells. miRNAs released from exosomes inhibit PCSK1/3 expression by suppressing the production of GLP-1 and glucose-dependent insulinotropic peptide (GIP) in enteroendocrine cells, which finally leads to increased insulin resistance (Valerio et al., 1999; Cases et al., 2015; Zhang et al., 2018). PDA also induces reduced insulin sensitivity in hepatic cells, which represents as a decreased liver gluconeogenesis level (Basso et al., 1997). When a delayed and blunted insulin response happens in PDA patients, elevated blood glucose levels then stimulate insulin synthesis and secretion in pancreatic islet beta cells, leading to endogenous hyperinsulinemia. What is more, because of the high insulin resistance rate, a worsened glucose control was found in diabetic PDA patients who take insulin as a regular regimen to control blood sugar. Increased insulin resistance caused by PDA will subsequently result in a higher dose of insulin use, leading to increased exogenous hyperinsulinemia.

Interestingly, hyperinsulinemia caused by pancreatic cancer might not effectively lower peripheral blood glucose levels. PDA produces multiple factors to inhibit glucose sensitivity in pancreatic islet beta cells which finally leads to a delayed insulin secretion peak (Tan et al., 2014; Parajuli et al., 2020; Wang et al., 2020). As a result, hyperinsulinemia couldn’t effectively control blood glucose levels in pancreatic cancer patients. A dual increase of glucose and insulin is typical in PDA patients and is essential for cancer development and progression.

Insulin has long been regarded as a promoter for cancer metabolism and proliferation in many types of cancer, including breast, prostate, colorectal and pancreatic cancer (Wang et al., 2007). There is a causal relationship between hyperinsulinemia and pancreatic cancer events under an inflammatory environment (Gao et al., 2015). High insulin receptor expression was found in pancreatic cancer tissue, and a high circular insulin level often predicts poor prognosis in PDA cases (Kim et al., 2020; Heckl et al., 2021). Mechanically, insulin mainly activates two signal pathways: insulin receptor (IR)-insulin receptor substrates (IRS)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signal pathway (Bergmann et al., 1996; Pollak, 2008); and extracellular signal-regulated kinase (ERK) 1/2- mitogen-activated protein kinase (MAPK). Based on these two signal pathways, insulin enhances PDA development through mediating metabolic reprogram, crosstalk with IGF-1, strengthening drug resistance, and stimulating tumor microenvironment (inflammation, fibrosis, and neo-angiogenesis) formation. By targeting insulin, PI3K-AKT signal pathway and chemoresistance are inhibited, and the development of PDAC is also inhibited (Metz et al., 2016; Xu et al., 2018). And we summarized the main signal pathway activated by insulin in pancreatic cancer cells in Figure 2.

In diabetic PDA patients, hyperglycemia and high insulin level are both signals for poor prognosis, but insulin is an essential drug in regulating blood glucose levels (Tseng, 2013; Cho et al., 2019). Singly reducing insulin dosage will cause worse blood glucose control that may kill PDA patients. Two ways to inhibit insulin-related tumorigenic effect with good glucose control are applied in clinical trials and clinical practice: the first is using other safe antidiabetic drugs to lower blood insulin concentration and blood glucose simultaneously; the second is designing new drugs targeting insulin-related signal pathways.

Over a long period, insulin has been regarded as a compensatory hormone of IGF-1 in cancer development and progression. But recently, more and more studies indicated that insulin might have an independent effect on cancer initiation and metabolic regulation. The relationship between insulin and pancreatic cancer is complex and important. Pancreatic cancer initiates hyperinsulinemia and delays insulin secretion peak, while insulin mediates cancer cell metabolism to maintain PDA survival with proliferation, and insulin also stimulates the formation of a tumor-promoting microenvironment around cancer cells. This reciprocal relationship between cancer and insulin reveals that insulin plays an essential role in pancreatic cancer onset and development. The intricate relationship between pancreatic cancer and insulin allows us to have a better understanding of the PDA initiation, metabolic reprogramming, development, chemoresistance, and metastasis.

Due to the low prevalence of pancreatic cancer in the whole population, insulin is safe for most diabetic patients. In contrast, insulin use should be more careful in high PDA risk people, especially NODM population, and PDA patients. More importantly, the tumor-promoting effect of insulin in pancreatic cancer cells and the TME is essential, which makes insulin and its related signal pathway a potential novel target for cancer therapies. Lowering peripheral insulin level via using other antidiabetic drugs is feasible, but therapies targeting insulin signal pathways still needs a long way to go at present. Cancer could use insulin to compensatorily activates multiple signal pathways to escape from IGF-1R inhibitors. This mechanism indicates that combining various drugs aimed at different targets in the insulin signal pathway with dual IR/IGF-1R inhibitor may be an excellent way to overcome drug resistance caused by alternative insulin related pathways activation.