The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.

CME: Can Slim People Have Type-2 Diabetes? Abstract. Most patients with type-2 diabetes mellitus are obese or overweight. In slim patients with suspected type 2 diabetes mellitus the possibility of other types of diabetes must be considered. In addition to type-1 diabetes in adulthood and genetic forms of diabetes (MODY, mitochondrial diabetes), it could also be diabetes due to a disease of the exocrine pancreas, a condition which is generally underdiagnosed.

Diabetes mellitus, a disease that affects nearly 536.6 million people worldwide, is characterized by the death or dysfunction of insulin-producing beta cells of the pancreas. The beta cells are found within the islets of Langerhans, which are composed of multiple hormone-producing endocrine cells including the alpha (glucagon), delta (somatostatin), PP (pancreatic polypeptide), and epsilon (ghrelin) cells. There is direct evidence that physical and paracrine interactions between the cells in the islet facilitate and support beta cell function. However, communication between endocrine and exocrine cells in the pancreas may also directly impact beta cell growth and function. Herein we review literature that contributes to the view that "crosstalk" between neighboring cells within the pancreas influences beta cell growth and function and the maintenance of beta cell health.

Diabetes secondary to pancreatic diseases (i.e., acute pancreatitis, chronic pancreatitis, and pancreatic cancer) is increasingly studied, but remains challenging to distinguish from type 2 diabetes (T2DM). We review the clinical significance and potential biomarkers that may help differentiate these types of diabetes.

Recent studies have identified several complications (including nonvascular) that occur more frequently in patients with diabetes secondary to acute and chronic pancreatitis than T2DM, and biomarkers to differentiate these types of diabetes. There have been advances that may enable the enrichment of a population of adults with new onset diabetes to potentially screen for occult pancreatic cancer, but efforts are needed to identify and validate promising diagnostic biomarkers.

High-quality studies are needed to more precisely understand the risk factors and natural course of diabetes secondary to pancreatic diseases. Mechanistic and interventional studies are awaited to provide insights that will distinguish diabetes secondary to pancreatic diseases and refine the management of hyperglycemia in this patient population.

Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.

Diabetes Mellitus (DM) is a chronic life-long progressive multisystem heterogeneous metabolic disorder with complex pathogenesis.

Hyperglycemia is not only one of the classical signs of DM, but it also serves as the pivotal prerequisite for the diagnosis of the disease. However, with the advancement in the field of analytical biochemistry, a number of alternative and specific biomarkers have been discovered which can be used for better diagnosis of the DM. In this review, we have discussed various aspects of DM and different biomarkers used in assessing glycemia.

A thorough literature survey was conducted to identify various studies that reported the use of conventional and non-conventional markers for the assessment of glycemia in DM patients.

The accurate detection and hence diagnosis of DM has become easy and more specific with the use of various biomarkers.

Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4-phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments has indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD-affected pancreas, because EMT was conceivably implicated in various fibrosis-associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA.

Type 3c diabetes mellitus (T3cDM) is a clinically relevant condition with a prevalence of 5-10% among all diabetic subjects in Western populations. Its prevalence and clinical importance have been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes, the endocrinopathy in T3cDM is very complex and complicated by additional present comorbidities such as maldigestion and concommitant qualitative malnutrition. The failure to correctly diagnose T3cDM leads to failure to implement an appropriate medical therapy of these patients. Physicians should screen for important and easily reversable pathological conditions such as exocrine insufficiency, lack of fat-soluble vitamins (especially vitamin D) and impairment of fat hydrolysis and incretin secretion which are found very commonly in T3cDM. Since most patients with T3cDM suffer from chronic pancreatitis, physicians must additionally be aware of the elevated risk of pancreatic cancer in this subset of patients.

The aim of this study was to evaluate the effectivity and safety of insulin therapy in patients with DM secondary to underlying chronic pancreatitis with initially inappropriate glycemic control.

Pancreatic DM patients treated with oral antidiabetics (OAD) or pre-mixed insulin (PMI) with HbA1c ≥7.0% were recruited. Intensive conservative insulin treatment (ICT) (Group A, n = 16) or PMI (Group B, n = 8) was introduced instead of OAD, or the initial PMI therapy was switched to ICT (Group C, n = 10). The changes in HbA1c, fasting plasma glucose, body weight and hypoglycemic events from baseline to 2 years were followed.

The patients in Group A and B had been treated with oral antidiabetics for 55 ± 68 months before switching to insulin therapy. The level of HbA1c had worsened from 8.3 ± 1.5% to 9.8 ± 1.7% during this period. The ICT had reduced HbA1c significantly from 9.7 ± 1.8% to 7.6 ± 1.4% after 12 weeks, in Group A, and five patients had HbA1c<7.0%. The introduction of PMI in Group B reduced HbA1c from 10.0 ± 1.4% to 9.0 ± 0.6% by 12 weeks. None of the patients had HbA1c<7.0%. By 12 weeks, the introduction of ICT in Group C had reduced the level of HbA1c from 8.8 ± 1.7% to 7.7 ± 1.2%. Two patients reached HbA1c<7.0%. There were two severe hypoglycemic episodes during the 2 years, one-one case in Group A and B.

Oral medication becomes insufficient early in pancreatic DM. Long-term improvement of glycemic control can be achieved through intensified insulin therapy and in selected cases through PMI with a low risk of hypoglycemia.