The present study was conducted to ascertain how cigarette smoke affects the exocrine–endocrine interactions of the human pancreas with diabetes mellitus secondary to pancreatic diseases (type 3c). Blood has been collected from smoking and non-smoking healthy individuals as well as from patients with diagnosed chronic pancreatitis and diabetes type 3c. The concentrations of interleukin-6, endothelin-1 and insulin in the plasma were determined by enzyme-linked immunosorbent assay (ELISA) tests. The activities of amylase and lipase in the serum, as well as the lipid profile, creatinine, uric acid and urea concentrations, were measured using colorimetric methods. Samples of normal pancreatic tissue and chronic pancreatitis were verified histopathologically and then interleukin-6, endothelin-1, insulin and glucagon were localized by immunohistochemical staining using a monoclonal anti-human antibody. The highest levels of interleukin-6 and endothelin-1 and the lowest levels of insulin and glucagon intensity from the immunostaining were observed in smoking patients with diabetes. In all smoking patients with pancreatitis and diabetes, there was a significant elevation in interleukin-6 and endothelin-1 concentration and amylase and lipase activities, hyperlipidaemia and a lower value of estimated glomerular filtration rate and blood urea nitrogen when compared to non-smokers. Our study confirmed that smoking exerts a pro-inflammatory effect and disturbs the exocrine–endocrine interactions of the pancreas.