Exocrine cell dysfunction might be a major contributor of type 1 diabetes

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By mapping its genetic underpinnings, researchers at University of California San Diego School of Medicine have identified a predictive causal role for specific cell types in type 1 diabetes, a condition that affects more than 1.6 million Americans.

The findings are published in the May 19, 2021 online issue of Nature.

Type 1 diabetes is a complex autoimmune disease characterized by the impairment and loss of insulin-producing pancreatic beta cells and subsequent hyperglycemia (high blood sugar), which is damaging to the body and can cause other serious health problems, such as heart disease and vision loss.

Type 1 is less common than type 2 diabetes, but its prevalence is growing. The U.S. Centers for Disease Control and Prevention projects 5 million Americans will have type 1 diabetes by 2050. Currently, there is no cure, only disease management.

The mechanisms of type 1 diabetes, including how autoimmunity is triggered, are poorly understood. Because it has a strong genetic component, numerous genome-wide association studies (GWAS) have been conducted in recent years in which researchers compare whole genomes of persons with the same disease or condition, searching for differences in the genetic code that may be associated with that disease or condition.

In the case of type 1 diabetes, identified at-risk variants have largely been found in the non-coding regions of the genome. In the Nature study, senior author Kyle Gaulton, Ph.D., an assistant professor in the Department of Pediatrics at UC San Diego School of Medicine, and colleagues integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas.

Epigenomic mapping details how and when genes are turned on and off in cells, thus determining the production of proteins vital to specific cellular functions.

Specifically, researchers performed the largest-to-date GWAS of type 1 diabetes, analyzing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.

“By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally,” said Gaulton.

Pancreatic exocrine cells produce enzymes secreted into the small intestine, where they help digest food.

Co-author Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Pediatric Diabetes Research Center, said the findings represent a major leap in understanding the causes of type 1 diabetes. She described the work as “a landmark study.”

“The implication is that exocrine cell dysfunction might be a major contributor to disease. This study provides a genetic roadmap from which we can determine which exocrine genes may have a role in disease pathogenesis.”


Introduction: Clinical Features of DEP

Diabetes of the exocrine pancreas (DEP),refers to diabetes mellitus (DM) secondary to various exocrine pancreatic diseases such as pancreatitis, trauma/pancreatectomy, pancreatic neoplasia, etc. Due to confusion with type 2 diabetes mellitus (T2DM) (Petrov, 2017), it has been underestimated in clinical practice for a long time.

The incidence of DEP varies with geographical distribution and etiology (Ewald and Hardt, 2013; Pendharkar et al., 2017; Woodmansey et al., 2017; Bharmal et al., 2020a), with estimated true prevalence ranging from 1 to 9% of all diabetic patients (Hart et al., 2016). It has been noted that compared to other DM patients, the DEP patients present additional symptoms related to pancreatic disease, including decreased glucagon and somatostatin, pancreatic exocrine insufficiency (PEI), malabsorption of nutrients and micronutrients, severe and painful gastrointestinal symptoms, and nutritional deficiencies (Wynne et al., 2019).

These additional morbidities promote greater blood glucose fluctuations. Although there have been contradictory observations about glycemic control in DEP (Jethwa et al., 2006; Ewald et al., 2012), it is generally believed that serum glucose levels in DEP are difficult to control, with alternately occurrence of hypoglycemia and hyperglycemia, (also known as “brittle diabetes”) (Larsen et al., 1987; Larsen, 1993).

Currently, there is no uniformly recognized diagnostic criterion for DEP. Identification of the disease emphasizes the detection of exocrine pancreatic disorders and pathological changes of the exocrine pancreas different than the autoimmune mechanism which is the characteristic of type 1 diabetes mellitus (T1DM).

The current proposed diagnostic criteria include evidence of pancreatic exocrine disease such as functional insufficiency (identified with tests of the fecal elastase-1 or exocrine pancreatic function) and pathological changes of pancreatic imaging [computerized tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound], as well as potential alterations in incretin secretion and decreased levels of fat soluble vitamins (A,D,E, and K) in serum (Ewald and Bretzel, 2013; Wynne et al., 2019). In addition, certain novel biomarkers showed potential in discriminate DEP from other diabetes (Olesen et al., 2019; Bharmal et al., 2020b; Gold-Smith et al., 2020).

Similar to other DMs, the major goal of DEP treatments is to reduce hemoglobin A1c (HbA1c) levels for minimizing the macrovascular and microvascular complications risk, as well as delay the development of pancreatic cancer. Traditionally, physicians tend to choose similar drugs used to treat T2DM (Rickels et al., 2013), however recent knowledge about the potential differences from other diabetes suggested more careful treatment strategy. Lifestyle adjustment and dietary interventions are critical to improve nutrition status and overall health outcomes.

As for the anti-hyperglycemic medication, insulin therapy is preferred for most patients due to common insulin deficiency in DEP patients. In addition, insulin was suggested to benefits nutrition of patients. However, in considering of preserved peripheral insulin sensitivity, the dosing should be titrated, similar as in T1DM. Metformin was suggested to be used in patients with DEP due to chronic pancreatitis (CP), owe to reduced risk of pancreatic ductal adenocarcinoma (PDAC) (Gudipaty and Rickels, 2015; Wynne et al., 2019).

Due to potential differences in symptoms and etiology between DMs, personalized hyperglycemia solutions should pay special attention to drug indications and contraindications. For example, although being preferred selections for DM treatment in many situations, incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists have been suggested to be associated with increased pancreatitis risk (Buse et al., 2017; Abd El Aziz et al., 2020).

Although more thorough studies have suggested that incretin-based treatment did not increase pancreatitis risk (Wang et al., 2015, 2018; Abd El Aziz et al., 2020), it is still suggested to be used with vigilance (Buse et al., 2017; Abd El Aziz et al., 2020). Therefore, application of these drugs in DEP patients should be done with caution (Alves et al., 2012). Moreover, DM treatments in these patients should be applied in combination with pancreatic enzyme replacement therapy (PERT) for PEI and proper diet to maintain nutritional requirements and the absorption of fat-soluble vitamins (Duggan and Conlon, 2013; Lohr et al., 2017).

Etiology and Pathology of DEP

While CP was originally thought to be the most common cause of DEP, the greater numbers of patients with acute pancreatitis (AP) led to recent recognition that 80% of pancreatitis-related DEP is due to AP and 20% to CP (Petrov and Yadav, 2019). The pancreas is composed of both exocrine and endocrine structures. In addition, the endocrine part of the pancreas contains five different types of cells (α, β, δ, PP, and ε).

The endocrine hormones secreted include glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin (Da Silva Xavier, 2018; El Sayed and Mukherjee, 2019). Disorders of the exocrine compartment including AP and CP, pancreatic tumor, pancreatic trauma, cystic fibrosis, partial pancreatectomy, hemochromatosis, and pancreatic agenesis precede are characteristics of DEP, with the most common co-existing disorder being pancreatitis (Abu-Bakare et al., 1986; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003; Ewald et al., 2012; American Diabetes Association, 2019).

As a result of exocrine pancreatic disease, DEP is featured with pancreatic tissue damage compromising exocrine cells and cell subtypes within the islets of Langerhans (Walling and Freelove, 2017; Hammad et al., 2018; Pham and Forsmark, 2018). In this respect, DEP is significantly different from T1DM, in which autoimmune damage of β cells and secondary inflammation cause relatively limited damage to the exocrine compartment.

While much research indicates that extensive destruction of islet cells is the main reason of the development of DEP from CP (Ewald et al., 2012), β cell dysfunction without extensive destruction has also been observed in CP (Sasikala et al., 2012), but the contribution of other endocrine and exocrine cell types to the pathogenesis of DEP is unclear.

Besides cellular damage and dysfunction of pancreatic cells, other factors such as PEI and malnutrition, which are common in DEP, may promote DM pathology through mechanisms involving regulation of incretin secretion and perturbing intestine-pancreas crosstalk. These factors should be addressed in completing our understanding of DEP pathogenesis.

Since research studies specific for DEP are still rare, the understanding of DEP pathology often relies on the current knowledge about the characteristics and mechanisms underlying T1DM and T2DM pathology. It is often the differences in the extensities and combinations of these basic pathological changes that separate different DMs. In the next sections, we review different potential mechanisms involved in the development of DEP.

Exocrine Pancreas: Pancreatic Stellate Cells (PSCS)

Acinar cells and duct cells are the major components of exocrine pancreas. The pathogenetic changes of these cells may have influences on the structure and functions of endocrine islet as well. Activated PSCs play a central role in regulating extracellular matrix (ECM) protein synthesis and degradation (Omary et al., 2007; Apte et al., 2011) and was suggested to be correlated with occurrence and progression of CP and pancreatic cancer (Apte et al., 2015). PSCs also secrete various cytokines (Xue et al., 2018), which cause β cell dysfunction (Zang et al., 2015), leading to hyperglycemia, further aggravating the adverse effects of PSCs on β cells (Zechner et al., 2014; Zha et al., 2014).

PSCs-induced β cell dysfunction can be summarized as three components: (1) physical destruction of islets caused by a large number of ECM, such as collagen I and fibronectin, resulting in pancreatic fibrosis, which leads to islet dysfunction (Sasikala et al., 2012; Hart et al., 2016); (2) pathogenic factors such as inflammatory cytokines, oxidative stress and subsequent inflammatory response lead to islet dysfunction; (3) potential role of exosomes secreted by PSCs.

In addition, although the relevant experimental evidence is still insufficient, studies have found that PSCs have characteristics of stem/progenitor cells, suggesting that PSCs may have potential in pancreatic and islets regeneration and thus could play an important role in treatment of DEP in the future (Apte et al., 1998; Trim et al., 2000; Lardon et al., 2002; Joanette et al., 2004).

Insulin Resistance

In the past, insulin resistance was considered to be an unimportant contributor to DEP related to CP (Kumar et al., 2017). However, changes in insulin sensitivity have been documented in CP (Vlasakova et al., 2002), and DEP caused by total pancreatectomy (Yki-Jarvinen et al., 1986). One study of 30 patients with CP (4 normal glucose tolerant, 4 impaired glucose tolerant, 22 diabetic) found insulin resistance was present in 22 of the 30 patients and was more common in those with impaired glucose tolerance (IGT) (3 of 4) and diabetes (17 of 22) (Niebisz-Cieslak and Karnafel, 2010). A physiologic study of preoperative patients with pancreatic cancer also found higher insulin resistance compared to matched controls (Cersosimo et al., 1991).

Traditional T2DM risk factors for insulin resistance such as family history, obesity was also important in DM development in CP patients (Bellin et al., 2017). In fibrocalcific pancreatic diabetes (FCPD), although insulin secretion defects are considered major cause, the potential involvement of insulin resistance in pathogenesis has been more oftenly recognized (Dasgupta et al., 2015; Aiswarya et al., 2019). In AP, DEP was more frequently present in patients with higher disease severity of AP (Vujasinovic et al., 2014), and insulin resistance index was higher among these patients (Wu et al., 2011). In pancreatic cancer-associated diabetes, Galectin-3 and S100A9, which are related to DM development were reported to mediate insulin resistance (Liao et al., 2019).

Potential DEP Pathological Mechanisms Based on Pancreatic Exocrine Insufficiency (PEI)

Pancreatic diseases are often accompanied with PEI and malnutrition. In AP, prevalence of PEI during admission was 62 and 21–35% during follow up (Vujasinovic et al., 2014; Tu et al., 2017; Huang et al., 2019). After pancreatectomy, PEI was reported to develop in 36–76% of the patients with mean time to onset of 14–40 months (Lee et al., 2013; Beger et al., 2018; Hallac et al., 2019; Kusakabe et al., 2019). PEI facilitates pathology of DEP through malnutrition, regulation of incretin secretion, and crosstalk with intestinal flora.

Influence of PEI and Malnutrition

It is well known that CP patients are often with deficient nourishment due to malabsorption and increased metabolic activity (Shimosegawa, 2019). For example, CP patients often have decreased lean body mass and fat mass, which could lead to decreased functional capacity and further weight loss (Gilliland et al., 2017). The causes of CP nutritional deficiencies are multifaceted, including exocrine and/or endocrine dysfunction, severe abdominal pain, etc. leading to less food intake, often persistent alcohol consumption, and increased metabolic activity (O’Brien and Omer, 2019). The malnutrition severity was reported to be correlated with malabsorption and nutrients depletion, as well as increased metabolic activity (Rasmussen et al., 2013).

Pancreatic disease has differential effects on various nutrient components. In PEI, carbohydrate digestion is maintained, protein digestion is mildly impaired, while lipid digestion is most significantly impaired. Digestion of protein mainly depend on proteolytic activity in the stomach rarely damaged in CP. Lipids are mainly digested in the small intestine, and pancreatic lipase and coenzyme play a key role in this process. Due to the dysfunction of lipid digestion in CP patients, deficiency of fat-soluble vitamins A, D, E, and K are common.

In addition, insufficient secretion of pancreatic protease may cause vitamin B12 deficiency. Mineral intake and absorption are also affected in pancreatic disease (Papazachariou et al., 2000; Vujasinovic et al., 2019). Several markers change significantly in patients with PEI, including albumin, phosphorus, and fat-soluble vitamins (Alexandre-Heymann et al., 2019). Reductions of plasma amino acid levels have also been seen in CP, particularly sulfur containing amino acids and branched chain amino acids (Girish et al., 2011).

Changes of nutrient substrates may play a role in DM development. For example, various free fatty acids (FFA) have may cause various effects on different physiological processes, such as changing the formation and decomposition of adipose tissue, resulting in corresponding changes in endocrine and inflammatory responses. It may also cause changes in cell membrane composition. These effects of plasma FFA may eventually lead to insulin resistance (Sobczak et al., 2019). High levels of saturated FFA have been suggested to be correlated with impaired glucose tolerance in both T1DM and T2DM (Maulucci et al., 2016). Diacylglycerol signaling pathway regulates pancreatic β cells and insulin secretion (Kaneko and Ishikawa, 2015). Ceramide also plays a critical role in DM development (Galadari et al., 2013). The relation between nutritional substrates and diabetes has mostly been studied at level of vitamin deficiency. The correlation with disease risk and role in glycemic control of vitamin D in T2DM has been widely studied by many researchers including us (Wu et al., 2017; Munoz-Garach et al., 2019). In addition, mineral and amino acid levels appear to influence the risk of diabetes development. As a secondary disease of pancreas injury, in the study of DEP, attention needs to be paid to the role of malnutrition and deficiency of various substrates.

Incretin: Gut-Islet Hormone Interaction

Gut-islet interactions, mainly through incretin hormones has been widely studied. GLP-1 is mainly produced by L cells in the ileum and large intestine, while K cells are the main sources of GIP (Holst et al., 2009). During food intake, incretin hormones are released by these intestinal endocrine cells to facilitate insulin secretion response to glucose. Most of postprandial insulin secretion are induced by incretins. Then the rapid degradation of incretins by dipeptidyl peptidase IV (DPP-IV) ensures a transient response. Studies have shown a consistent correlation of the concentration of these peptide hormones with glycemia. In T2DM, GLP-1 secretion appears to be deficient while there appears to resistance to GIP (Nauck et al., 1993). Incretin-based pharmacotherapies (GLP-1 receptor agonists and DPP-IV inhibitors) have become popular choices in clinical treatment of diabetes. However, rather than the main cause leading to T2DM, the deficiency of incretin was more often considered as a results of deteriorating glucose homeostasis in T2DM (Knop et al., 2007b; Knop, 2010). Incretin-based pharmacotherapy has been suggested to be correlated with increased risk of AP in T2DM patients (Azoulay et al., 2016; Ueberberg et al., 2016; Tseng et al., 2017) although more recent and thorough studies have suggested that incretin-based treatment does not increase pancreatitis risk (Wang et al., 2015, 2018; Abd El Aziz et al., 2020). The GLP-1 receptor may activate PSCs, changes pancreatic gene, and enhances pancreatic mass, therefore inducing pancreatic injury (Koehler et al., 2009; Yang et al., 2013).

In normal conditions, the release of incretin hormones is mainly induced by fatty acids and other nutrients. Thus, deficiency in pancreatic exocrine function, which causes impaired fat digestion, may result in impaired incretin response, causing adverse effects on insulin release and blood glucose control. In addition, as discussed above, in settings of pancreatic disease and DEP, damage to δ cells and somatostatin may affect development of DM though influence on incretin hormone response. Some studies suggested that in DEP, patients are still sensitive to GLP-1, while GIP induced insulin secretion response is damaged, similar as in T2DM (Hedetoft et al., 2000; Knop et al., 2007a). However, in CP patients with normal glucose tolerance, the effect of intestinal incretin was preserved, while in patients with secondary DM, the effect of incretin was strongly reduced, indicating that incretin deficiency is the result of diabetes rather than pancreatitis (Knop et al., 2007b). In contrast, a different study in CP with or without diabetes found reduced GIP responses to a test meal in both groups, with no correlation with exocrine insufficiency (Gomez-Cerezo et al., 1996). Differing results between studies may reflect the meal tested; a study in CP found similar GIP response as controls to a mixed meal but a reduced response to a 100% fat meal (Ebert and Creutzfeldt, 1980).

Incretin functions in regulating survival, cell growth and differentiation of pancreatic cells which may play a role in β cell restoration and genesis (Tasyurek et al., 2014). For example, pueraria tuberosa tubers (PTY-2), which acts as an incretin receptor agonist, has been shown to inhibit β cell apoptosis therefore protects streptozocin (STZ)-induced diabetes (Srivastava et al., 2018). GLP-1 and gastrin signaling induce in vivo reprogramming of pancreatic exocrine cells into β cells (Sasaki et al., 2015). Considering the complicated effects of incretins on exocrine function deterioration and potential β cell protection, their roles in DEP pathogenesis, as well as the choice of incretin-based therapy in these patients need more careful studies.


More information: Joshua Chiou et al, Interpreting type 1 diabetes risk with genetics and single-cell epigenomics, Nature (2021). DOI: 10.1038/s41586-021-03552-w

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