Pancreatic Cancer and Diabetes Mellitus

Sharma, Ayush; Chari, Suresh T.

doi:10.1007/s11938-018-0197-8

Cited by 35 publications

(33 citation statements)

References 57 publications

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“…T2DM was shown to be an independent risk factor for pancreatic cancer in many studies [273][274][275][276][277][278] and some authors have implicated hyperglycemia in cancer pathogenesis [279,280]. However, inferring causality for this observation is further complicated by the fact that PDAC itself and PDAC treatment regimens can cause diabetes [281][282][283]. Nevertheless, a Mendelian randomization study pointed to causal roles for BMI and fasting insulin, but not T2DM or dyslipidemia, in PDAC [284].…”

Section: Hyperinsulinemia and Pancreatic Cancermentioning

confidence: 99%

Hyperinsulinemia in Obesity, Inflammation, and Cancer

et al. 2021

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The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

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Section: Hyperinsulinemia and Pancreatic Cancermentioning

confidence: 99%

Hyperinsulinemia in Obesity, Inflammation, and Cancer

et al. 2021

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“…More than two-thirds of individuals with pancreatic cancer have diabetes or prediabetes (11). Some populationbased studies showed a significantly lower mortality risk associated with the use of metformin (12)(13)(14)(15)(16), whereas others (17)(18)(19) found no significant survival benefit of metformin in individuals with PCRD.…”

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confidence: 99%

Antidiabetic Medications and Mortality Risk in Individuals With Pancreatic Cancer–Related Diabetes and Postpancreatitis Diabetes: A Nationwide Cohort Study

et al. 2019

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There are no specific treatment guidelines for diabetes of the exocrine pancreas. High-quality studies are warranted to investigate whether the use of antidiabetic medications has survival benefit in individuals with diabetes of the exocrine pancreas. The objective was to determine the risk of mortality associated with the use of antidiabetic medications in individuals with pancreatic cancer-related diabetes (PCRD) and postpancreatitis diabetes mellitus (PPDM). RESEARCH DESIGN AND METHODS Nationwide pharmaceutical dispensing data (2006-2015) linked to hospital discharge data were used to identify 1,862 individuals with PCRD or PPDM. Multivariable Cox regression analysis was conducted, and the risk was expressed as hazard ratios and 95% CIs. A 6-month lag was used to minimize reverse causality. RESULTS In individuals with PCRD, ever users of metformin (adjusted hazard ratio 0.54; 95% CI 0.46-0.63) and ever users of insulin (adjusted hazard ratio 0.46; 95% CI 0.39-0.55) had significantly lower risks of mortality compared with never users of antidiabetic medications. These associations attenuated toward the null with the use of a 6-month lag. In individuals with PPDM, ever users of metformin had a significantly lower risk of mortality (adjusted hazard ratio 0.51; 95% CI 0.36-0.70), whereas everusers of insulin did not have a significantly changed risk of mortality (adjusted hazard ratio 0.75; 95% CI 0.49-1.14) compared with never users of antidiabetic medications. The former association remained significant with the use of a 6-month lag. CONCLUSIONS Metformin promotes a survival benefit in individuals with PPDM but not PCRD. Reverse causality may play a role in the association between insulin use and mortality in PCRD.

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“…Unfortunately, even in this case, no definitive conclusions have as yet been reached. It is not entirely clear whether, how much, and in which direction diabetes treatments affect the association between diabetes and PDAC [ 23 , 25 , 64 , 65 , 66 , 67 ]. To give a couple of examples, the protection provided by metformin, the most commonly drug used to treat T2DM, is currently under vigorous discussion, together with its mechanistic implications [ 67 , 68 , 69 , 70 , 71 , 72 , 73 ], and even the increased risk of PDAC observed in insulin-treated patients in some case-control studies [ 27 , 74 ] can be misleading [ 26 , 72 ].…”

Section: Relationship Between Diabetes and Pancreatic Cancermentioning

confidence: 99%

Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

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Iacobini

Vitale

et al. 2021

Cancers

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Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.

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Pancreatic Cancer and Diabetes Mellitus

Cited by 35 publications

References 57 publications

Hyperinsulinemia in Obesity, Inflammation, and Cancer

Hyperinsulinemia in Obesity, Inflammation, and Cancer

Antidiabetic Medications and Mortality Risk in Individuals With Pancreatic Cancer–Related Diabetes and Postpancreatitis Diabetes: A Nationwide Cohort Study

Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

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