The Role of Type 2 Diabetes in Pancreatic Cancer

Overview of Pancreatic Cancer and Type 2 Diabetes Mellitus (T2DM)

• The incidence of T2DM and its associated complications, such as cancer, is rising globally.
• Pancreatic cancer (PC) is becoming a leading cause of cancer mortality in the U.S.
• Predisposing factors include obesity, sedentary lifestyles, and alcohol consumption.
• PC often presents late and is characterized by rapid metastasis.

Relation between T2DM and Pancreatic Cancer

• There is a complex relationship between T2DM and the risk of developing PC.
• Major contributing factors include:
  • Chronic inflammation
  • Insulin resistance (IR)
  • Hyperinsulinemia
  • Hyperglycemia
• Abnormalities in the insulin and IGF (insulin-like growth factor) axis are also implicated in this connection.

Incidence and Survival Rates of Pancreatic Cancer

• PDAC is the most prevalent and lethal form of pancreatic cancer, accounting for over 90% of cases.
• The five-year survival rate for PDAC is currently around 11.5%.
• PC is projected to become the second leading cause of cancer deaths in the U.S. by 2030.
• In 2022, an estimated 62,210 new cases of PC are expected in the U.S.
• PC is notably aggressive, often presenting late due to vague symptoms and lack of screening tools.

Definitions of Diabetes Mellitus

• Diabetes Mellitus (DM): a group of metabolic diseases marked by chronic hyperglycemia due to impaired carbohydrate, fat, and protein metabolism.
• Type 2 Diabetes Mellitus (T2DM): when insulin resistance predominates, comprising around 90-95% of diabetes cases. It is linked to a higher body mass index (BMI).
• Type 3c Diabetes (T3cDM): secondary diabetes stemming from pancreatic damage and refers to diabetes arising from conditions like chronic pancreatitis.

Risk Factors for Pancreatic Cancer

• Common risk factors include:
  • Family history of PC
  • Genetic mutations (e.g., BRCA2)
  • Cigarette smoking
  • Sedentary lifestyle
  • Obesity
  • Diabetes Mellitus
  • Chronic pancreatitis

Mechanisms Connecting T2DM and Pancreatic Cancer

• Insulin Resistance & Hyperinsulinemia: Promotes cancer cell metabolism by activating the insulin/IGF-1R signaling pathway, often leading to increased proliferation and reduced apoptosis of cancer cells.
• Chronic Inflammation: Associated with metabolic dysregulation in T2DM creates a tumor-favorable environment. Produced cytokines can activate signaling pathways enhancing cancer development.
• Dietary Impact: Diets high in sugars and fats (Western diet) exacerbate inflammation, while a Mediterranean diet is associated with a reduced risk of PC.
• Genetic Mutations: Certain pancreatic developmental genes correlate with susceptibility to PC in T2DM patients.

Role of Antidiabetic Agents in Pancreatic Cancer

• Metformin:
  • Widely used for managing T2DM; it reduces hepatic glucose production.
  • Associated with a lower risk of developing PC compared to those using insulin.
  • Acts via the LKB1-AMPK pathway to inhibit cancer growth and inflammation.
• Insulin:
  • Linked to an increased risk of PC, particularly in patients treated with exogenous insulin.
• Other Anti-diabetic Agents: The effects of glucagon-like peptide-1 (GLP-1) analogs and DPP-IV inhibitors on pancreatic health are still under investigation due to potential pancreatitis risks.

Conclusions and Implications

• PC continues to have a dire prognosis, particularly for individuals with T2DM.
• Ongoing research is vital to understand the interplay between diabetes and pancreatic cancer development.
• Preventive measures focusing on modifiable risk factors, like diet and obesity, are essential in mitigating the risks associated with PC.
• Further studies are required to identify beneficial and potentially harmful effects of various antidiabetic therapies on pancreatic cancer progression.