In 2014, the American Diabetes Association named diabetes caused by exocrine disorders of the pancreas pancreatic diabetes mellitus or type 3c diabetes. The combined incidence of pancreatic diabetes mellitus is about 6 per 100,000 cases, accounting for about 8% of all diabetes mellitus. The most common cause of pancreatic diabetes is chronic pancreatitis, which accounts for about 79%; This is followed by pancreatic ductal adenocarcinoma, which accounts for about 8%. According to statistics, the prevalence of pancreatic diabetes is significantly higher than that of type 1 diabetes, but it is still significantly lower than that of type 2 diabetes. Patients with pancreatic diabetes are more likely to develop hypoglycemia-related complications and even death due to the lack of β cells or α cells due to various reasons, and their blood sugar levels are difficult to control. Studies have shown that people with pancreatic diabetes have a higher risk of death and readmission than those with type 2 diabetes. As a type of diabetes caused by exocrine diseases of the pancreas, pancreatic diabetes is often misdiagnosed as type 2 diabetes. Studies have shown that 45%~90% of patients with pancreatic diabetes are mistakenly classified as type 2 diabetes. At present, there are few studies on pancreatic diabetes mellitus in China, and it is of great significance to fully understand, correctly identify and diagnose pancreatic diabetes to improve the survival and quality of life of patients.
1. Pathogenesis
1.1 Pancreatic islet dysfunction and insufficient insulin secretion
Immune-mediated islet dysfunction is a key mechanism in the development of pancreatic diabetes. In the early stages of pancreatitis, high levels of cytokines and a stressful inflammatory environment lead to β cell dysfunction. Due to severe fibrosis of the pancreatic parenchyma, functional pancreatic tissues such as pancreatic acinars, ducts, and nerve bundles are eventually replaced by connective tissues, thus losing vascular and secretory functions. Diabetes secondary to pancreatic cancer differs from diabetes caused by other causes in that it is not caused by fibrographic destruction or pancreatic resection, but by paraneoplastic effects caused by mediators released by the cancer. Studies have shown improvements in insulin resistance and β cell dysfunction in patients with pancreatic cancer surgery. Weighted gene co-expression network analysis confirmed that macrophage activation and Toll-like receptor signaling pathway are important pathophysiological features of pancreatic diabetes mellitus, and the expressions of ITGAM (integrin αM), ITGB2 (integrin β2), PTPRC (protein tyrosine phosphatase receptor C) and CSF-1R (colony-stimulating factor-1 receptor) in pancreatic islets were significantly up-regulated during macrophage activation in patients with pancreatic diabetes.
The occurrence and development of pancreatitis-related diabetes mellitus is related to the recruitment and activation of macrophages, which leads to the release of a large number of inflammatory cells, which in turn leads to changes in pancreatic islet function. Studies have shown that the early recruitment and activation of macrophages is one of the important links in aggravating pancreatic cell damage. Macrophages are the main inflammatory cells that infiltrate the pancreas during the development of chronic pancreatitis and play an important role in the progression of pancreatic fibrosis. In the pathogenesis of macrophages and chronic pancreatitis, nuclear factor kappa B (NF-κB) is one of the main participants in the recruitment of macrophages to the pancreas, and damaged acinar cells can release chemokines and inflammatory factors that activate macrophages, promote the activation of pro-inflammatory cytokines such as NF-κB subunit P65 and IL-6, TNF-α, and monocyte chemoattractant protein-1, causing a strong inflammatory response. Pro-inflammatory cytokines such as IL-10, TNF-α, IFN-γ inhibit glucose-stimulated insulin release. High concentrations of IL-1 receptor and IL-1β induce apoptosis in β cells, while high concentrations of IFN-γ can lead to reduced transcription factor translocations of pancreaticoduodenal homology box 1 (PDX-1) or insulin promoter factor 1. Studies have shown that PDX-1 is essential for the development of pancreatic cells, which are involved in the maturation of β cells and the differentiation of the duodenum. In patients with chronic pancreatitis, the differentiation and survival of β cells are also reduced due to reduced PDX-1 levels, resulting in impaired insulin production. Adrenal medullin and pantothylethylamine hydrolase have also been found to be a consequence of inflammation and may alter islet cell function in patients with pancreatic diabetes. In addition, the interaction between macrophages and pancreatic stellate cells (PSCs) can promote the progression of chronic pancreatitis, and the transforming growth factor-β and platelet-derived growth factor (PDGF) produced by macrophages are effective activators of PSCs, and the cytokines released by activated PSCs may induce pancreatic macrophages to polarize to the M2 phenotype, while the activated M2 macrophages have high expression of transforming growth factor-β and PDGF, which directly interact with PSCs and promote the proliferation and activation of PSCs. Eventually, pancreatic fibrosis is caused.
High levels of calprotectin (S100A6/A8/A9) and connexins are present in the pancreatic tissue of patients with pancreatic cancer-associated diabetes. The above proteins are overexpressed in pancreatic islets in patients with pancreatic ductal carcinoma, and a large number of S100A6/A8/A9 can be seen in neutrophils and activated macrophages, which may be due to the aggregation of monocytes, macrophages, neutrophils and other cells in early pancreatic cancer. The study found that the expression of S100A6 in pancreatic tissue of patients with pancreatic cancer and diabetes mellitus was upregulated compared with healthy people. It has been proposed that galectin-3, matrix metalloproteinase-9, adiponectin, and IL-1 receptor antagonists can be used as biomarkers to distinguish type 2 diabetes from pancreatic cancer-related diabetes.
1.2 Insulin resistance
Insulin resistance is a prominent feature of diabetes and may also be a factor in diabetes secondary to pancreatitis. Studies have confirmed that patients with pancreatic diabetes mellitus have hepatic insulin resistance, and insufficient pancreatic peptide response plays a key role in this. At present, pancreatic polypeptide has been shown to be a blood glucose regulating hormone that regulates hepatic insulin sensitivity, which can reverse the reduction of insulin receptors in pancreatitis, and the administration of pancreatic polypeptide to pancreatitis patients with pancreatic polypeptide deficiency can reverse hepatic insulin resistance. In addition to changes in insulin receptor availability, changes in hepatic insulin function in patients with chronic pancreatitis are also associated with inflammatory activation of hepatocytes IκBβ and NF-κB, and blocking NF-κB activation can improve insulin sensitivity in the liver.
1.3 Decreased insulinotropic effect – a decrease in incretin hormone
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones released by the intestine during digestion and absorption of nutrients. GLP-1 has the functions of regulating insulin secretion, delaying gastric emptying, stimulating the release of insulin, inhibiting glucagon secretion, reducing appetite, and slowing down gastric emptying. Studies have found that GLP-1 can also promote the growth and differentiation of pancreatic β cells and protect the role of β cells. GIP promotes insulin release and inhibits glucagon secretion by α cells. Both hormones are rapidly inactivated by dipeptidyl peptidase-4. In pancreatic insufficiency, nutrient absorption is impaired, incretin release is reduced, postprandial insulin is reduced, and blood glucose is correspondingly increased.
1.4 Disruption of the fungus
The gut microbiota plays a unique role in promoting the development of type 2 diabetes. The gut microbiota has a regulatory function for the body's metabolic and inflammatory responses. Microbiota disturbances are associated with dysregulation of immune cells as well as the levels of inflammatory cytokines and are therefore considered important factors in different inflammation-mediated diseases. Pancreatic injury and inflammation in the context of chronic pancreatitis can lead to impaired integrity of the intestinal mucosal barrier, which in turn leads to changes in the gut microbiota. Changes in the intestinal ecosystem and bacterial metabolism, in turn, lead to diabetes and metabolic abnormalities. Therefore, the gut microbiota has the potential to play a role in the occurrence and development of pancreatic diabetes. A study in India recruited healthy controls with type 1 diabetes, type 2 diabetes, and pancreatic diabetes secondary to chronic pancreatitis showed significant between-group differences in the abundance of certain bacterial species, including Ruminococcus species and Faecalibacterium phylum. In other studies, decreased abundance of faecalibacterium and increased plasma endotoxin were observed in patients with non-diabetic chronic pancreatitis, which was more obvious in diabetic chronic pancreatitis. Fasting and postprandial blood glucose were inversely correlated with faecalibacter abundance, while endotoxin was positively correlated with blood glucose and negatively correlated with insulin. These results suggest that gut microbial diseases are associated with metabolic changes in chronic pancreatitis.
1.5 Genetic factors
Studies have identified specific genes for chronic pancreatitis, such as PRSS1 (serine protease 1), SPINK1 (serine peptidase inhibitor Kazal type 1), CFTR (cystic fibrosis transmembrane conductance regulator), CTRC (chymotrypsin-C), and CASR (calcium-sensing receptor). Mutations in the PRSS1 gene enhance trypsinogen autoactivation. Studies have shown that mutations in the PRSS1 exon region are associated with diabetes secondary to chronic pancreatitis. In patients with chronic pancreatitis, there is a 60% chance of developing diabetes mellitus with exome abnormalities. Pancreatic cancer is also genetically heterogeneous, including CFTR, BRCA1, BRCA2, CDKN2A, PALB2, and ATM genes, which have been previously reported. Studies have shown that individuals with a family history of pancreatic cancer have a higher risk of developing pancreatic cancer. A number of susceptibility genes have been identified. BRCA2 and PALB2 are the most commonly mutated genes in hereditary pancreatic cancer. Mutations in the CFTR gene have a moderate risk of developing pancreatic cancer at a young age. ATM gene mutations are associated with familial pancreatic cancer susceptibility.
2. Diagnosis
At present, there are no widely accepted diagnostic criteria for pancreatic diabetes. According to the 2021 American Diabetes Association, the diagnosis can be made by patients who meet the following criteria: (1) meet the diagnostic criteria for diabetes, (2) have pancreatic secretory insufficiency, (3) have pathological changes in the pancreas on imaging, and (4) do not have autoimmune markers associated with type 1 diabetes.
3. Treatment and management
There are currently no systematic guidelines for the treatment of pancreatic diabetes, which makes it impossible to effectively manage pancreatic diabetes. In addition, pancreatic diabetes is often misdiagnosed as type 2 diabetes in clinical practice, which leads to unsatisfactory treatment effects and even leads to poor prognosis in some patients. There is an urgent need to improve clinicians' understanding of pancreatic diabetes to help them decide which regimen to use to control the patient's symptoms and prevent the disease from worsening. At present, the pathogenesis of pancreatic diabetes can be started to carry out basic control and treatment of this type of diabetes. For pancreatic diabetes, the rise of blood sugar should be strictly controlled, exocrine insufficiency should be solved, and complications should be prevented and reduced, and the management of diet and nutrition should also be emphasized.
3.1 Control blood sugar
Metformin and insulin are the most commonly used drugs for pancreatic diabetes, which is consistent with several recent expert recommendations. Experts recommend insulin as a first-line treatment for diabetic patients with secondary pancreatitis, as this addresses the primary deficiency of insulin deficiency. Insulin is effective in addressing hyperglycemia caused by insulin deficiency in patients with advanced diabetes secondary to chronic pancreatitis. However, the use of insulin in the treatment of pancreatic diabetes mellitus is associated with a risk of hypoglycemia, especially in patients with chronic pancreatitis who may have increased peripheral insulin sensitivity, and Wu et al. mentioned that the use of insulin in diabetic patients with chronic pancreatitis is associated with an increased risk of pancreatic cancer.
Metformin, as an insulin sensitizer, can reduce hepatic glucose output and improve peripheral insulin sensitivity, and is commonly used in the first-line treatment of most patients with type 2 diabetes. Yang et al.'s study mentions that the use of metformin not only reduces the amount of insulin needed to lower blood sugar per day, but also has the effect of protecting β cells, and the anti-tumor effect of metformin may reduce the risk of pancreatic cancer. In addition, Maida et al. showed that metformin could enhance the gene expression of GLP-1 and GIP receptors in the pancreas of mice, which could have a favorable effect on the insulin secretion of pancreatic islets. Metformin has also been reported to prolong survival in patients with diabetic and non-metastatic pancreatic cancer. The above theories and studies can provide strong support for metformin as a first-line drug for pancreatic diabetes. Other drugs for the treatment of type 2 diabetes, such as thiazolidinediones, α-glucosidase inhibitors, sulfonylureas and dipeptidyl peptidase-4 inhibitors, can also be used in the treatment of pancreatic diabetes, but they are generally not used as routine treatment considering their side effects. There are no definitive treatment guidelines, and the treatment of pancreatic diabetes mellitus can only be used on the basis of monitoring for adverse drug reactions.
3.2 Solve exocrine insufficiency
Patients with pancreatic diabetes mellitus often have digestive and absorption disorders due to exocrine insufficiency, which in turn leads to metabolic complications. Clinically, pancreatic exocrine disorders are often treated with pancreatic enzyme substitution. That is, pancreatic enzymes are given at the same time as eating, and their efficacy is continuously monitored. Pancreatic enzymes help improve the response to insulin in patients with pancreatic steatorrhea and may reverse the decline in GIP responsiveness. In addition, exocrine pancreatic insufficiency may lead to impaired absorption of fat-soluble vitamins (vitamins A, D, E, and K). Duggan et al.'s study mentioned that patients with chronic pancreatitis, especially those with advanced disease and steatorrhea, have a high probability of bone loss and even osteoporosis. Therefore, vitamin D supplementation should be taken in time to prevent metabolic bone diseases.
3.3 Daily nutrition and management
Lifestyle changes should be made as soon as you are diagnosed with diabetes. Dietary structure should be consciously adjusted in daily life, and a low glycemic index diet should be preferred and the intake of carbohydrate foods should be limited to reduce the frequency of hyperglycemia as much as possible and reduce the risk of diabetic complications. Sugar-sweetened beverages should also be avoided except in the case of hypoglycemia. Obese patients should also actively lose weight, exercise regularly, and quit smoking and drinking.
3.4 Prevent and reduce the occurrence of complications
Pancreatic diabetes, also known as "fragility diabetes", is caused by pancreatic inflammation leading to the destruction of pancreatic islets, and the loss of β cells (insulin), α cells (glucagon), δ cells (somatostatin) and PP cells (pancreatic polypeptides) makes it difficult to control blood sugar in patients with this type of diabetes, so pancreatic diabetes is more likely to develop hypoglycemia and hypoglycemia-related complications. Therefore, the prevention of frequent hypoglycemic events should be prioritized in dietary management. Factors that contribute to hypoglycemia include carbohydrate malabsorption and irregular diet, among others. In view of these problems, patients should be educated about hypoglycemia, and patients should also be monitored for blood glucose, and blood glucose levels, dietary intake, pancreatic enzyme replacement therapy use and exercise should be recorded in detail, so as to actively adjust the use of diet and drugs, so as to reduce the occurrence of hypoglycemia and its complications.
4. Outlook
At present, due to the lack of understanding of the pancreatic diabetic system, this type of diabetes is often misdiagnosed as type 2 diabetes. However, compared with type 2 diabetes, patients with pancreatic diabetes have more difficult blood sugar control, more frequent episodes of hypoglycemia, higher doses of insulin, more complex regimens, a higher risk of developing cancer, an earlier age of death, and a greater risk of death. Therefore, the timely and correct diagnosis of pancreatic diabetes has far-reaching implications, which can greatly improve the survival and quality of life of patients with this type of diabetes, and greatly reduce the disability and mortality rates. Unfortunately, the complete pathogenesis of pancreatic diabetes is still unclear, there is still a lack of relevant epidemiological data in China, there is no systematic and efficient drug safety assessment, and there is no widely recognized diagnosis, treatment and management guidelines, which undoubtedly brings great challenges to clinical work, brings great pain to patients with pancreatic diabetes, and brings huge economic losses to the society. It is expected that there will be more research in related directions in the future to solve the current clinical problems.
引证本文 Citation
Wang Hope, Jin Jingjing, Wang Ying, et al . Pathogenesis, diagnosis and treatment of pancreatic diabetes mellitus[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(5): 1068-1072
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