Fact-checked by Grok 2 weeks ago

Beta cell

Beta cells, also known as β-cells, are specialized endocrine cells located within the clusters of cells called the islets of Langerhans in the . They serve as the of insulin, a that is crucial for maintaining by promoting the uptake and utilization of glucose in peripheral tissues. In humans, beta cells constitute the majority of cells in the pancreatic islets, where they are intermixed with other endocrine cell types such as alpha and delta cells, differing from the more centralized arrangement observed in . The core function of beta cells involves sensing fluctuations in blood glucose levels and responding with precise insulin secretion to prevent hyperglycemia. This glucose-sensing mechanism begins with the uptake of glucose via glucose transporters (primarily GLUT2 in rodents and GLUT1 in humans) on the beta cell membrane, followed by phosphorylation by the enzyme glucokinase, which acts as a glucose sensor due to its high Km value matching physiological glucose concentrations. Subsequent metabolism in the mitochondria increases the ATP/ADP ratio, leading to closure of ATP-sensitive potassium channels, membrane depolarization, influx of calcium ions through voltage-gated channels, and ultimately the exocytosis of insulin-containing secretory granules. This tightly regulated process ensures that insulin release is proportional to nutrient availability, supporting metabolic balance during fed and fasted states. Beta cells are vital for overall metabolic health, but their dysfunction or destruction underlies major endocrine disorders, particularly diabetes mellitus. In , autoimmune attack leads to the near-complete loss of beta cells, resulting in absolute insulin deficiency. In , beta cells initially compensate for by increasing secretion, but progressive cellular stress, deposition, and cause a gradual decline in function and mass. Ongoing research focuses on beta cell regeneration and protection as potential therapeutic strategies to restore glucose control in these conditions.

Anatomy and Distribution

Location in the Pancreas

Beta cells are primarily located within the islets of Langerhans, which are spherical clusters of endocrine cells embedded throughout the exocrine tissue of the . These islets constitute approximately 1-2% of the total pancreatic and are richly vascularized to facilitate release into the bloodstream. In the human , there are approximately 1 million islets, each containing 1,000 to 3,000 cells, with beta cells comprising 50-70% of the total islet cell population. The density of islets is unevenly distributed, being higher in the and regions compared to the head, where the islet area proportion is about 1.06% in the head, 1.09% in the , and 1.47% in the . This regional variation reflects differences in developmental origins, with the deriving primarily from the dorsal pancreatic bud. The islets were first described in 1869 by , a medical student, who identified these distinct cellular clusters in the during his doctoral thesis. In the early 20th century, following the 1921 discovery of insulin, beta cells were confirmed as the insulin-producing population through histological staining techniques, such as Gomori's aldehyde fuchsin method developed in 1950, which specifically targeted insulin granules in these cells. Pancreatic islet architecture exhibits evolutionary conservation across mammals, with beta cells forming a central core in islets, while in humans they are more intermixed with other endocrine cells, and appear dispersed in such as and pigs. This organization supports coordinated endocrine function, despite interspecies variations in cell mixing.

Cellular Composition and Morphology

Beta cells are polygonal endocrine cells typically measuring 10-20 μm in diameter, characterized by a large central , extensive , prominent Golgi apparatus, and numerous secretory granules. The abundant rER and Golgi reflect their specialization for protein synthesis and processing, essential for production. These cells are primarily distributed within the of Langerhans. Electron microscopy of beta cells reveals dense-core secretory granules, approximately 200-350 nm in diameter, containing crystalline arrays of insulin hexamers arranged in rhomboidal lattices. The resting of these cells is approximately -70 mV, maintained by activity. cells are identified histologically using Latin such as endocrinocytus B or insulinocytus, and they stain positively with aldehyde fuchsin for their granules or via immunolabeling for insulin. Beta cells exhibit heterogeneity in size and granule density, influenced by factors such as age and metabolic state; for instance, size and increase under metabolic stress, while content varies with physiological conditions. This variability underscores their adaptive structural features, though detailed functional subtypes are addressed elsewhere.

of Hormones

Insulin Synthesis Pathway

The insulin synthesis pathway in pancreatic beta cells commences with the transcription of the INS gene, located on the short arm of in humans. This gene encodes preproinsulin mRNA, which is translated on ribosomes associated with the (rER) into a 110-amino-acid precursor protein known as preproinsulin. Upon entry into the rER lumen, the N-terminal 24-amino-acid is rapidly cleaved by signal peptidase, yielding proinsulin, an 86-amino-acid polypeptide comprising the B-chain, , and A-chain connected by dibasic residues. Proinsulin then folds, forming three disulfide bonds essential for its structure: two interchain bonds between the A and B chains, and one intrachain bond in the A chain. This folded proinsulin is transported via vesicles to the Golgi apparatus and subsequently to the trans-Golgi network (TGN). In the immature secretory granules budding from the TGN, proinsulin undergoes proteolytic processing mediated by the prohormone convertases PC1/3 (also known as PC3) and PC2, in concert with carboxypeptidase E. PC1/3 primarily cleaves the B-C junction, while PC2 targets the A-C junction and completes the B-C cleavage, excising the 31-amino-acid and generating mature insulin—a 51-amino-acid heterodimer with the 21-amino-acid A chain and 30-amino-acid B chain linked by the disulfide bridges. The excised remains associated with insulin during storage. This processing occurs progressively as granules mature, with endoproteolytic cleavages followed by exopeptidase removal of C-terminal basic residues (lysine-arginine pairs). Glucose metabolism in beta cells upregulates gene transcription through the activation and nuclear translocation of key transcription factors, including PDX1 (pancreatic and duodenal 1), which binds to enhancer elements in the INS promoter to enhance expression; other factors such as MafA and NeuroD1 cooperate in this glucose-responsive regulation. On average, each beta cell synthesizes approximately 10^8 insulin molecules daily to maintain steady-state levels and meet physiological demands. Mature insulin and are concentrated and packaged into secretory , where ions (Zn²⁺) are co-transported via the ZnT8 transporter, promoting the assembly of insulin into stable hexamers that crystallize for efficient storage; these hexamers, with two Zn²⁺ ions per hexamer, occupy a significant portion of the granule volume. is stored equimolar to insulin within these granules and is co-secreted upon , serving as a marker of endogenous insulin production.

Synthesis of Other Hormones

In addition to insulin, pancreatic beta cells synthesize and secrete several other hormones and peptides, most notably , also known as islet amyloid polypeptide (IAPP). is encoded by the IAPP gene located on 12q24.2 in humans and is produced as a 67-amino-acid precursor protein, proIAPP, which undergoes post-translational processing within the secretory granules of beta cells. This processing mirrors that of proinsulin, involving cleavage by prohormone convertases to yield the mature 37-amino-acid peptide, which is then packaged alongside insulin. Amylin is co-synthesized and stored with insulin in the same secretory granules of beta cells, typically at a molar ratio of approximately 1:100 relative to insulin, though this can vary between 1:10 and 1:100 depending on physiological conditions. Its synthesis is upregulated by glucose stimulation, similar to insulin, leading to co-release during nutrient-responsive secretion. As a byproduct of insulin biosynthesis, C-peptide is generated in equimolar amounts to insulin during the cleavage of proinsulin in beta cell granules, serving as a reliable for endogenous insulin production rather than functioning as a itself. In pathological contexts, such as , amylin can misfold and aggregate into fibrils, contributing to beta cell dysfunction through the formation of extracellular deposits, though the precise mechanisms of remain under investigation.

Mechanisms of Secretion

Glucose-Stimulated Insulin Secretion

Glucose-stimulated insulin secretion (GSIS) is the primary mechanism by which pancreatic beta cells respond to elevated blood glucose levels, enabling the regulation of systemic glucose homeostasis. In this process, glucose enters the beta cell primarily through facilitative glucose transporters. In rodents, glucose uptake occurs predominantly via GLUT2, a low-affinity, high-capacity transporter with a K_m around 17 mM, allowing equilibration of glucose across the plasma membrane. In human beta cells, however, GLUT1 predominates as the primary glucose transporter (Km ~6 mM), with GLUT2 expressed in a subpopulation of cells (~13% coexpress with GLUT1), enabling efficient uptake at physiological concentrations. Once inside the cell, glucose undergoes and subsequent mitochondrial oxidation, leading to increased production of ATP. This rise in the ATP/ ratio inhibits ATP-sensitive potassium (KATP) channels, which are hetero-octameric complexes composed of four Kir6.2 pore-forming subunits and four SUR1 regulatory subunits located on the plasma membrane. Closure of these channels reduces the outward potassium current, described by the simplified equation for KATP conductance: I_{K_{ATP}} = g_{K_{ATP}} \cdot (V_m - [E_K](/page/Equilibrium)) where I_{K_{ATP}} is the current, g_{K_{ATP}} is the channel conductance, V_m is the , and E_K is the equilibrium potential; inhibition decreases g_{K_{ATP}}, thereby limiting I_{K_{ATP}} and causing . activates voltage-gated calcium channels, primarily L-type, allowing influx of extracellular Ca²⁺ into the . This in intracellular Ca²⁺ concentration serves as the key trigger for insulin granule , where docked secretory granules fuse with the plasma to release insulin. GSIS exhibits a characteristic biphasic pattern: the first phase is rapid and transient, reflecting the release of a readily releasable pool of granules near the , while the second phase is sustained, involving recruitment and of additional granules from the reserve pool. The glucose threshold for initiating GSIS is approximately 5 mM, corresponding to glucose levels, with half-maximal secretion occurring around 8-10 mM and maximal rates achieved at 20-25 mM, ensuring insulin release is finely tuned to postprandial glucose excursions.

Regulation of Secretion

The regulation of beta cell secretion involves multiple modulatory mechanisms that fine-tune insulin release beyond the core glucose-stimulated insulin secretion (GSIS) pathway. Incretin hormones, primarily glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play a central role in amplifying GSIS. These gut-derived hormones are released in response to nutrient ingestion and bind to G protein-coupled receptors on beta cells, activating Gs protein signaling that elevates cyclic AMP (cAMP) levels. The subsequent activation of protein kinase A (PKA) enhances the sensitivity of the exocytotic machinery to calcium ions (Ca²⁺), thereby potentiating insulin granule release without directly altering glucose metabolism. This incretin effect accounts for up to 60% of the postprandial insulin response in healthy individuals, underscoring its physiological importance. Autocrine and paracrine signals within the microenvironment provide additional layers of control to prevent excessive insulin secretion. Secreted insulin acts in an autocrine manner by binding to insulin receptors on the same or neighboring cells, activating (PI3K) pathways that inhibit further insulin release and promote beta cell rest. This helps maintain secretory during prolonged stimulation. Paracrine inhibition is mediated by released from adjacent delta cells, which binds to somatostatin receptors (SSTRs) on beta cells, suppressing production and thereby dampening insulin secretion to coordinate hormone output. Delta cell-derived somatostatin exerts a inhibitory , facilitating synchronized responses to metabolic cues. Neural and hormonal inputs further modulate beta cell activity in response to systemic signals. Parasympathetic innervation via the stimulates insulin secretion through release, which activates muscarinic receptors on beta cells to increase intracellular Ca²⁺ and enhance . In contrast, sympathetic activation, such as during stress, inhibits insulin release; adrenaline binds to α₂-adrenergic receptors on beta cells, coupling to proteins that reduce levels and hyperpolarize the via K⁺ channel activation. Circulating free fatty acids also potentiate GSIS by activating the 40 (GPR40), which triggers signaling to amplify Ca²⁺ signaling and insulin granule fusion. This nutrient-sensing mechanism links lipid availability to secretory enhancement under fed conditions. Long-term feedback mechanisms protect beta cells from overactivation but can lead to adaptive changes. Chronic exposure to elevated glucose levels induces glucotoxicity, characterized by downregulation of insulin gene transcription and impaired secretory responsiveness through and stress pathways. This desensitization manifests as reduced GSIS efficiency, serving as a protective response to prevent exhaustion but contributing to progressive beta cell dysfunction if unresolved.

Physiological Functions

Role in Glucose Homeostasis

Beta cells play a central role in maintaining by secreting insulin in response to elevated blood glucose levels, thereby preventing and ensuring euglycemia. In the state, blood glucose is typically maintained between 4 and 6 mM, while postprandial levels are controlled to remain below 8 mM through timely insulin release. Insulin acts primarily by promoting glucose uptake into peripheral tissues such as and via translocation of the transporter to the cell membrane, facilitating the conversion of glucose to for storage. Additionally, insulin inhibits hepatic glucose output by suppressing and in the liver, thereby reducing endogenous glucose production during periods of nutrient excess. Following a meal, beta cells detect the rise in circulating glucose—primarily arterial levels augmented by signals from glucose sensors—and initiate insulin secretion to match the influx of nutrients. This postprandial response ensures rapid restoration of euglycemia by enhancing glucose disposal and curbing hepatic glucose release. In healthy adults, the total beta cell mass is approximately 1 g, enabling basal insulin secretion of 1-2 units per hour to sustain fasting glucose control, with surges up to 10 units during meals to handle the increased glucose load. Complementing insulin, beta cells co-secrete , a that further supports by slowing gastric emptying to moderate absorption and suppressing postprandial glucagon secretion from alpha cells, thus preventing inappropriate hepatic glucose mobilization. This coordinated action of insulin and fine-tunes the post-meal glycemic excursion, promoting efficient energy storage without excessive blood glucose fluctuations.

Interactions with Other Cell Types

Beta cells, constituting the majority of cells within , engage in intricate with neighboring endocrine cell types to fine-tune release and maintain glucose . Alpha cells secrete , which acts locally on beta cells to potentiate glucose-stimulated insulin secretion through of glucagon receptors and, to a lesser extent, GLP-1 receptors on beta cell surfaces. This paracrine stimulation is particularly evident during moderate , where intraislet glucagon enhances beta cell responsiveness without causing systemic effects. Delta cells release , a potent of insulin from beta cells, mediated by somatostatin receptors that reduce cAMP levels and calcium influx in beta cells. This inhibitory feedback helps prevent excessive insulin release and coordinates islet responses to nutrient fluctuations. Pancreatic polypeptide (PP) cells, though less abundant, contribute to islet communication by secreting PP, which exerts insulinostatic effects on beta cells and may support beta cell turnover under physiological conditions. Beyond endocrine neighbors, beta cells interact closely with the islet vasculature, which features a dense network of fenestrated capillaries that facilitate rapid delivery of insulin directly into the hepatic . Beta cells actively promote this vascular architecture by secreting (VEGF-A), which induces endothelial and to ensure efficient nutrient sensing and hormone export. In turn, endothelial cells provide reciprocal signals, such as and other angiogenic factors, that regulate beta cell mass, survival, and function, thereby linking vascular integrity to islet health. Extrapancreatic interactions extend beta cell influence through hormonal crosstalk with distant tissues, notably the gut. Enteroendocrine cells in the intestine release incretins like (GLP-1) and (GIP) in response to , which travel via the bloodstream to bind receptors on beta cells and amplify glucose-dependent insulin secretion while promoting beta cell and . Within the pancreatic microenvironment, immune cells also play a supportive role; regulatory T cells (Tregs) infiltrate islets and maintain to beta cells by suppressing autoreactive responses and fostering an milieu. Intra-islet coordination is further enabled by direct physical connections among beta cells via gap junctions composed primarily of connexin 36 (Cx36). These channels permit electrical coupling, allowing synchronized calcium oscillations and pulsatile insulin release across the beta cell network, which enhances the efficiency and uniformity of secretory responses to glucose stimuli. Disruption of Cx36-mediated coupling leads to desynchronized activity and impaired insulin dynamics, underscoring its essential role in collective beta cell behavior.

Pathological Conditions

Autoimmune Destruction in Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells in the pancreatic islets, leading to absolute insulin deficiency. This process is primarily mediated by autoreactive T cells, particularly CD8+ cytotoxic T cells, which infiltrate the islets and target specific beta cell antigens such as insulin, glutamic acid decarboxylase 65 (GAD65), and insulinoma-associated antigen-2 (IA-2). These T cells recognize peptide epitopes presented on the surface of beta cells via major histocompatibility complex class I molecules, triggering cytotoxic responses that release perforin and granzymes to induce beta cell apoptosis. By the time of clinical diagnosis, approximately 70-80% of the beta cell mass has been lost, resulting in hyperglycemia and the need for exogenous insulin therapy. Genetic predisposition plays a central role in T1D susceptibility, with strong associations to specific (HLA) alleles, notably HLA-DR3 and haplotypes. Individuals heterozygous for DR3/DR4 exhibit the highest risk, as these alleles influence and T cell activation against beta cell autoantigens. Environmental factors, including viral infections, are thought to trigger the autoimmune response in genetically susceptible individuals; enteroviruses such as B have been implicated through molecular , where viral proteins cross-react with beta cell antigens, initiating or accelerating insulitis. These triggers likely interact with genetic factors to break , leading to the expansion of autoreactive T cell clones. The progression of beta cell destruction involves insulitis, an inflammatory infiltrate composed predominantly of CD8+ and CD4+ T cells, along with macrophages and B cells, that surrounds and penetrates the islets. This chronic inflammation gradually erodes beta cell over months to years before . Recent studies have shown that dysfunction in remaining beta cells can occur independently of insulitis, contributing to early impairment in insulin secretion. Following and initiation of insulin therapy, many patients experience a "honeymoon phase," a transient period of partial remission where residual beta cells regain some , reducing insulin requirements; this phase typically lasts 3-12 months and reflects the survival of a subset of beta cells not yet fully destroyed. Epidemiologically, T1D most commonly onset in childhood or , with global incidence rising over recent decades at an average annual rate of 3-4%, attributed to environmental and factors influencing susceptible populations.

Dysfunction in Type 2 Diabetes

In (T2D), beta cell dysfunction arises primarily from metabolic overload, leading to progressive impairment in insulin secretion and eventual beta cell exhaustion. Chronic exposure to elevated glucose levels, known as glucotoxicity, and free fatty acids, termed , overtaxes beta cells, disrupting their ability to maintain . This exhaustion manifests as reduced insulin responsiveness to stimuli, contributing to that further exacerbates the cycle. , in particular, induces beta cell demise through prolonged exposure to excess lipids, which impairs insulin secretion and promotes in human and animal models. A key pathological feature in T2D is the accumulation of amyloid polypeptide (IAPP) deposits, which form toxic aggregates that impair beta cell function and viability. These , derived from misfolded IAPP co-secreted with insulin, lead to beta cell and , reducing beta cell mass by approximately 40-60% in affected individuals compared to non-diabetic controls. This mass loss correlates with disease duration and severity, underscoring IAPP's role in accelerating beta cell failure. Underlying these changes are multiple cellular mechanisms, including endoplasmic reticulum (ER) stress, oxidative damage, and dedifferentiation. ER stress arises from the high protein synthesis demand in beta cells, activating the unfolded protein response that, if unresolved, triggers apoptosis; oxidative damage from reactive oxygen species further compromises mitochondrial function and insulin granule integrity. Dedifferentiation involves the loss of key transcription factors like PDX1 and MAFA, causing beta cells to revert to a progenitor-like state with diminished insulin production, while chronic hypersecretion leads to degranulation and depleted insulin stores. These processes collectively drive beta cell failure. However, recent research has demonstrated that functional recovery of beta cells is possible in human T2D, suggesting that some aspects of dysfunction may be reversible. Risk factors such as and genetic predispositions amplify this dysfunction. promotes , increasing beta cell workload and , while variants in the TCF7L2 gene, the strongest genetic risk factor for T2D, impair beta cell proliferation and insulin secretion by disrupting Wnt signaling pathways. The disease typically progresses from peripheral to overt beta cell failure over 10-15 years, with early compensatory giving way to secretory deficits. Recent studies highlight beta cell heterogeneity as a contributor to variable dysfunction in T2D, with subpopulations exhibiting differential susceptibility to and impaired secretory . For instance, genetic analyses from 2022 onward reveal that heterogeneous enhancer states and transcriptomic profiles in beta cells influence their response to metabolic demands, leading to uneven progression of dysfunction across islets. This variability may explain differences in disease onset and response to therapies.

Neoplastic Disorders like Insulinoma

Insulinomas are rare pancreatic neuroendocrine tumors originating from beta cells, with an annual incidence of 1 to 4 cases per million individuals. These tumors cause endogenous , leading to recurrent due to excessive insulin secretion independent of blood glucose levels. Approximately 90% of insulinomas are benign, while the remaining 10% are malignant, with the latter often presenting more aggressive behavior and potential for . About 5-10% of insulinomas are associated with (MEN1) syndrome, an autosomal dominant disorder caused by germline mutations in the MEN1 . Pathologically, insulinomas arise from monoclonal proliferation of beta cells within the , resulting in well-differentiated neuroendocrine neoplasms that express insulin and chromogranin A. In cases linked to , biallelic inactivation of the MEN1 gene disrupts menin protein function, promoting uncontrolled beta cell growth and tumor formation. Clinically, patients typically present with , characterized by symptoms of (such as sweating, tremors, confusion, or seizures), documented low plasma glucose levels (usually below 50 mg/dL or 2.8 mmol/L), and prompt resolution of symptoms upon glucose administration. These neuroglycopenic and adrenergic symptoms often occur during fasting or postprandially, reflecting the tumor's autonomous insulin release. Diagnosis of insulinoma relies on biochemical confirmation during a supervised 72-hour fast, where is accompanied by inappropriately elevated insulin levels (>3 μU/mL) and (>0.6 ng/mL), distinguishing it from exogenous insulin administration. Imaging modalities, such as or CT/MRI, are used for localization, though small tumors (<1 cm) may require intraoperative ultrasonography for detection. Genetic testing for MEN1 mutations is recommended in younger patients or those with family history, as it influences for associated tumors. Beyond insulinomas, neoplastic-like hyperfunction of beta cells can manifest as , a rare condition involving diffuse beta cell and neogenesis, leading to persistent hyperinsulinemic in adults. Unlike typical , nesidioblastosis features dysplastic islets budding from pancreatic ducts without discrete masses, potentially progressing to insulinoma in some cases due to underlying genetic alterations. In adults, it is infrequently linked to genetic defects, such as mutations in genes (e.g., ABCC8 or KCNJ11), though environmental factors may also contribute to this non-neoplastic proliferation. Diagnosis often requires histopathological examination post-resection, as imaging may not distinguish it from insulinoma.

Therapeutic Interventions

Pharmacological Agents Targeting Beta Cells

represent a cornerstone class of pharmacological agents targeting beta cells in the management of (T2D). These drugs, such as glipizide, exert their primary effect by binding to the sulfonylurea receptor (SUR) subunit of ATP-sensitive (KATP) channels on pancreatic beta cells, leading to channel closure. This closure depolarizes the beta cell membrane, opening voltage-gated calcium channels and triggering calcium influx, which stimulates insulin independent of glucose levels. Glipizide, a second-generation , specifically promotes insulin release from beta cells while also reducing hepatic glucose output and enhancing peripheral insulin sensitivity. Widely used in T2D to improve glycemic control, carry a notable risk of as a , occurring due to excessive insulin even at low glucose concentrations, with rates higher than many other antidiabetic agents. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by , offer a glucose-dependent mechanism to enhance beta cell function. Approved by the U.S. in 2017 for T2D treatment, activates GLP-1 receptors on beta cells, potentiating glucose-stimulated insulin secretion (GSIS) by increasing cyclic AMP levels and amplifying the incretin effect. These agents also promote beta cell proliferation and survival, as evidenced by 's upregulation of PDX-1 expression, a key for beta cell maintenance. Cardiovascular outcome trials, including analyses up to 2020, have demonstrated that GLP-1 agonists like reduce major adverse cardiovascular events, such as and , in patients with T2D and established . Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin, indirectly support beta cell health by mitigating glucotoxicity through renal glucose excretion and blood glucose lowering. By reducing , dapagliflozin alleviates stress and oxidative damage in beta cells, preserving insulin secretion and preventing functional decline in models of T2D. This protective effect restores beta cell mass and function without directly interacting with beta cell receptors. Dipeptidyl peptidase-4 (DPP-4) inhibitors complement incretin-based therapies by prolonging the activity of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). These agents inhibit DPP-4 enzymatic degradation of incretins, elevating their plasma levels to enhance GSIS from beta cells in a glucose-dependent manner and suppress glucagon release from alpha cells. Among emerging agents, metformin acts as an AMP-activated protein kinase (AMPK) activator that improves beta cell sensitivity to glucose and protects against lipotoxicity and dysfunction. By activating AMPK in beta cells, metformin reduces reactive oxygen species production and enhances insulin secretion efficiency, contributing to sustained glycemic control in T2D. This mechanism positions metformin as a foundational therapy that indirectly bolsters beta cell resilience, though long-term use requires monitoring for potential gastrointestinal side effects.

Surgical and Other Treatments

Pancreas and transplantation represent established surgical interventions for restoring beta cell function in patients with (T1D), where autoimmune destruction leads to insulin deficiency. Whole transplantation, often performed simultaneously with in patients with end-stage renal disease, provides a complete replacement of the endocrine and exocrine , achieving insulin in approximately 80-90% of recipients at one year post-transplant. However, this procedure carries significant surgical risks, including vascular and , and requires lifelong to prevent allograft rejection. transplantation, a less invasive alternative, involves infusing donor-derived pancreatic into the for engraftment in the liver, thereby restoring endogenous insulin production. In June 2023, the FDA approved donislecel (Lantidra), an allogeneic islet product, for adults with T1D and severe unawareness who have had a transplant or are not eligible for it, improving access to this therapy. The protocol, introduced in 2000, marked a pivotal advancement by using a steroid-free immunosuppressive regimen with , , and , enabling insulin in 7 of 7 initial recipients for at least one year. Long-term outcomes have shown sustained insulin in approximately 30-50% of patients at five years, depending on the protocol and patient selection, though many require additional infusions due to progressive graft loss from immune-mediated attrition and nonimmune factors like deposition. Despite these improvements, challenges persist, including donor shortages, the need for multiple donors, and side effects such as and risk. Surgical management of , a rare beta cell causing hyperinsulinemic , primarily involves tumor resection to achieve cure. For benign insulinomas, which constitute over 90% of cases, enucleation—the surgical removal of the tumor while preserving surrounding pancreatic tissue—is the preferred approach for lesions smaller than 2 cm, offering a high success rate with minimal endocrine or exocrine insufficiency. This parenchyma-sparing technique is feasible laparoscopically or robotically, reducing recovery time and complications compared to more extensive resections. For larger or multifocal tumors, partial (e.g., distal or en bloc resection) may be necessary, particularly if is suspected. Surgical excision cures approximately 90% of benign insulinomas, with recurrence rates below 5% in long-term follow-up, though malignant cases require additional oncologic therapies. Preoperative localization via or intraoperative palpation ensures precise intervention, underscoring surgery's role as the definitive treatment. Bariatric surgery offers a metabolic intervention for (T2D), where beta cell dysfunction contributes to , by promoting substantial and alleviating glucotoxicity. Procedures such as Roux-en-Y gastric bypass or induce rapid glycemic improvements, often leading to diabetes remission in 60-80% of patients within two years, independent of alone. This benefit arises from enhanced beta cell function, including improved insulin secretion and sensitivity to glucose, as well as evidence of partial beta cell mass recovery through reduced stress and . Sustained post-surgery "rests" overworked beta cells, allowing functional regeneration, though long-term durability varies with adherence to changes. These outcomes highlight bariatric surgery's potential as a non-pharmacological strategy to preserve residual beta cell capacity in obese T2D patients. Device-based therapies and emerging bioengineered approaches aim to mimic or replace beta cell without invasive surgery. Closed-loop insulin delivery systems, commonly known as artificial pancreas devices, integrate continuous glucose monitoring with automated insulin pumps to replicate the beta cell's real-time glucose-responsive insulin secretion, reducing and improving time in target glycemic range by 10-15% compared to sensor-augmented pumps. These hybrid systems, approved for clinical use, adjust basal insulin dynamically but require user input for meals, advancing toward fully automated versions. In parallel, clinical trials of bioengineered islets—derived from cells and encapsulated to evade immune rejection—seek to provide beta cell replacement without . Early phase 1/2 studies, including 2025 data from trials like Vertex's VX-880 and VX-264, have demonstrated insulin production, glycemic control, and insulin independence in T1D patients for up to one year or more, with encapsulated versions aiming to avoid . These innovations complement transplantation by offering scalable, patient-specific solutions for beta cell restoration.

Research and Future Directions

Experimental Models and Techniques

Experimental models for studying beta cells encompass a range of and approaches that enable detailed investigation of their function, signaling, and responses to physiological and pathological conditions. In vitro systems provide controlled environments to dissect cellular mechanisms, while in vivo models recapitulate systemic interactions relevant to . These techniques, combined with advanced and methods, have significantly advanced understanding of beta cell . Isolated islets from and pancreata serve as primary models, preserving the multicellular architecture and intercellular communications essential for glucose-stimulated insulin (GSIS). These preparations allow direct assessment of beta cell responses to nutrients and hormones, though challenges include donor variability and limited availability for islets. To address , immortalized cell lines such as MIN6, derived from a , and INS-1, from a , are extensively used; both lines exhibit glucose and GSIS akin to primary beta cells, facilitating high-throughput studies of insulin and signaling pathways. Complementary techniques like with the ratiometric dye Fura-2 enable real-time monitoring of cytosolic Ca²⁺ dynamics, a critical trigger for insulin , revealing oscillatory patterns during glucose stimulation in isolated beta cells and islets. Similarly, patch-clamp measures voltage-gated ion currents, such as Ca²⁺ and K⁺ channels, in single beta cells, demonstrating their role in membrane depolarization and ; for instance, recordings from intact islets show larger Ca²⁺ currents compared to dissociated cells, highlighting the influence of islet context. In vivo models, particularly genetically modified mice, model beta cell in the context of . The non-obese diabetic (NOD) mouse spontaneously develops through autoimmune destruction of beta cells, mimicking human insulitis and providing insights into immune-beta cell interactions; it remains a cornerstone for preclinical testing of immunomodulatory therapies. For , the db/db mouse, harboring a , exhibits , , and beta cell secretory deficits due to impaired GSIS and endoplasmic reticulum stress, closely paralleling human metabolic dysfunction. offers precise manipulation of beta cell activity in these models; expression of channelrhodopsin-2 in beta cells allows light-induced , enhancing insulin secretion and glycemic control in insulin-deficient mice without off-target effects. Such approaches reveal functional hierarchies within beta cell populations during glucose challenges. Omics technologies, notably single-cell sequencing (scRNA-seq), uncover transcriptomic heterogeneity and developmental states in cells. Single-cell sequencing (scRNA-seq) studies have identified maturity markers such as urocortin 3 (Ucn3) and glucose-6-phosphatase catalytic subunit 2 (G6pc2), distinguishing immature from functional adult cells and elucidating regulatory pathways for maturation. Advanced imaging techniques like two-photon enable non-invasive visualization of secretion dynamics in intact islets; by tracking fluorescently labeled insulin granules, it demonstrates polarized toward the vasculature, ensuring efficient hormone delivery and underscoring the spatial organization of cell function .

Advances in Regeneration and Stem Cell Therapy

One major advance in beta cell regeneration involves the of induced pluripotent stem cells (iPSCs) into functional beta-like cells using protocols that activate key transcription factors such as PDX1 and NEUROG3. Seminal seven-stage protocols developed in 2014 enable the scalable of glucose-responsive beta cells from human pluripotent stem cells, mimicking embryonic pancreatic development through sequential activation of definitive endoderm, posterior foregut, pancreatic progenitor, and endocrine stages. These methods have been refined to yield up to 70-80% insulin-producing cells with robust glucose-stimulated insulin secretion, addressing the loss of beta cell mass in (T1D). Clinical translation of these iPSC-derived beta cells is exemplified by ' VX-880 (now zimislecel), an investigational allogeneic stem cell-derived cell infused intraportal in T1D patients with severe unawareness. Initiated in 2021, phase 1/2 trial data, published in 2025, demonstrate that 10 of 12 patients achieved insulin independence with sustained production and normalized hemoglobin A1c levels for at least one year post-infusion, indicating functional beta cell engraftment and glycemic control without exogenous insulin. Neogenesis approaches focus on stimulating new beta cell formation, including transdifferentiation from alpha cells using pharmacological agents. A 2015 study identified harmine, a DYRK1A inhibitor, as capable of inducing proliferation of adult beta cells and expanding beta cell mass in mice, improving glycemic control without toxicity. Combining harmine with GLP-1 receptor agonists like exendin-4 further enhances beta cell replication and promotes alpha-to-beta in islet xenografts in mice, increasing beta cell mass up to sevenfold. Recent studies have further elucidated the mechanism, showing that harmine promotes regeneration through cycling alpha cells serving as progenitors for new beta cells in treated pancreatic islets. By 2024, a phase 1 trial of oral harmine in healthy volunteers confirmed its safety and tolerability at doses supporting beta cell regeneration, paving the way for diabetes-specific studies. Beta cell protection strategies complement regeneration by delaying autoimmune destruction in T1D. , an anti-CD3 , was FDA-approved in November 2022 to delay clinical T1D onset in at-risk individuals aged 8 and older, preserving residual beta cell function for an average of two to three years as measured by sustained levels. In newly diagnosed patients, treatment similarly extends beta cell preservation, reducing insulin needs and stabilizing glycemic control. Despite these advances, challenges persist in achieving scalable, long-term beta regeneration. Key hurdles include inadequate vascularization of transplanted cell clusters, which limits and post-engraftment, and immune rejection in non-immunosuppressed hosts, necessitating encapsulation or gene-editing for hypoimmunogenicity. A 2022 review emphasizes that while preclinical models show promise, translating these to humans requires overcoming variability in cell maturity, off-target , and integration into architecture to ensure physiological function.

Understanding Heterogeneity and Development

Beta cells originate from pancreatic progenitors marked by the PDX1 during early embryonic development, around weeks 4-5 of gestation, when the pancreatic buds form from the foregut endoderm. These progenitors undergo endocrine specification primarily through transient expression of NEUROG3, a key driver of differentiation into endocrine cell types, with the initial wave occurring between weeks 8 and 10 of . This process leads to the formation of fetal beta cells capable of insulin production, though their functional maturity is limited at this stage. Following birth, beta cell mass expands severalfold into adulthood, primarily through replication rather than neogenesis, with islets increasing in size but not number. Replication rates are highest during infancy, gradually declining thereafter, and exhibit significant inter-individual variability. Human beta cells are functionally immature at birth, showing poor glucose-stimulated insulin secretion despite insulin content; full glucose responsiveness develops postnatally, achieving adult-like thresholds by approximately 2-3 years of age through metabolic adaptations like enhanced and mitochondrial function. Under chronic stressors such as , , or , mature beta cells can dedifferentiate, losing identity markers (e.g., PDX1, MAFA) and reacquiring progenitor-like states via mechanisms including stress and oxidative damage. Beta cell populations exhibit heterogeneity in maturity, function, and , with subpopulations organized topologically within islets—such as central "hub" beta cells in the core that display higher and coordinated responses to glucose, contrasted with peripheral "mantle" regions showing gradients in secretory capacity. Recent 2025 studies using advanced and modeling have further demonstrated that this drives modular beta cell network activity during glucose responses. Single-cell transcriptomic studies have revealed these functional gradients, highlighting diverse subpopulations with varying insulin profiles and responses. Emerging research in the 2020s has elucidated epigenetic mechanisms regulating beta cell maturity, including 27 (H3K27ac) marks at active enhancers that promote maturation-associated ; disruptions in these marks, as seen in growth-restricted models, impair functional development. This heterogeneity contributes to aging-related vulnerabilities, where age-associated epigenetic remodeling accelerates in susceptible individuals, linking diverse beta cell states to risk through reduced adaptive capacity and increased propensity.

References

  1. [1]
    Pancreas—Islets of Langerhans - SEER Training Modules
    Beta cells in the pancreatic islets secrete the hormone insulin in response to a high concentration of glucose in the blood.
  2. [2]
    The Pancreatic Beta Cell: Editorial - PMC - PubMed Central
    Mar 8, 2023 · Pancreatic beta cells play a critical role in maintaining glucose homeostasis by serving as the primary source of insulin.
  3. [3]
    Unique Arrangement of α- and β-Cells in Human Islets of Langerhans
    In most rodents, β-cells compose the core of the islets and the non–β-cells, including α-, δ-, and pancreatic polypeptide (PP)-cells, form the mantle region.
  4. [4]
    Glucose-sensing mechanisms in pancreatic β-cells - PMC
    Beta-cells of the pancreatic islets of Langerhans act as glucose sensors, adjusting insulin output to the prevailing blood glucose level.
  5. [5]
    Mechanisms of glucose sensing in the pancreatic β-cell
    Pancreatic β-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm with a subsequent ...
  6. [6]
    Pancreatic Disorders - MedlinePlus
    May 31, 2025 · In type 1 diabetes, the beta cells of the pancreas no longer make insulin because the body's immune system has attacked them. In type 2 diabetes ...
  7. [7]
    Pancreatic Beta Cell Identity in Humans and the Role of Type 2 ...
    May 23, 2017 · The key role of the beta cells is to produce and secrete insulin in a tightly regulated manner, to maintain circulating glucose concentrations ...
  8. [8]
    Pancreatic β-Cell Development and Regeneration - PMC
    The pancreatic β-cells are essential for regulating glucose homeostasis through the coordinated release of the insulin hormone.
  9. [9]
    The supply chain of human pancreatic β cell lines - PMC - NIH
    Sep 3, 2019 · Human β cells represent 1%–2% of the total pancreatic mass. Their study has been limited for years because of the scarcity of human donor ...
  10. [10]
    The Cells of the Islets of Langerhans - PMC - PubMed Central
    Mar 12, 2018 · In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
  11. [11]
    In Search of Unlimited Sources of Functional Human Pancreatic ...
    Beta cells represent only 1% of total pancreatic cells and are found dispersed in the pancreatic gland. During the past decades, many tools and approaches have ...
  12. [12]
    Pancreatic β-cell heterogeneity in adult human islets and stem cell ...
    Jun 3, 2023 · In contrast, the islets in humans have a lower proportion of β-cells, ranging from 55 to 70% and a higher percentage of α-cells, ranging ...
  13. [13]
    Regional variation of human pancreatic islets dimension and its ...
    The mean islet area proportion in the head, body and tail was 1.06 ± 0.1%, 1.09 ± 0.14% and 1.47 ± 0.15% respectively. The islet area proportion in the tail was ...
  14. [14]
    Physiology, Islets of Langerhans - StatPearls - NCBI Bookshelf
    ... islet through the central core of beta cells.[3]. Go to: Development. The pancreas derives from a dorsal and a ventral bud, both arising from the foregut ...
  15. [15]
    A Historical Perspective on the Identification of Cell Types in ...
    Before antibody-based staining methods, the most bona fide histochemical techniques for the identification of islet B cells were based on the detection of ...
  16. [16]
    Islet architecture: A comparative study - PMC - PubMed Central
    Jul 15, 2010 · In islets from mice and other rodents, the β-cells are located predominately in the central core with α- and δ-cells localized in the periphery ...
  17. [17]
    Pancreatic islet plasticity: interspecies comparison of islet ... - PubMed
    This particular species difference has raised concerns regarding the interpretation of data based on rodent studies to humans. On the other hand, further ...
  18. [18]
    INS gene: MedlinePlus Genetics
    Mar 1, 2013 · Genomic Location. The INS gene is found on chromosome 11. Related Health Topics. Genes and Gene Therapy · Genetic Disorders. MEDICAL ...
  19. [19]
    The making of insulin in health and disease - PMC - PubMed Central
    Sep 7, 2020 · Insulin biosynthesis begins with the translation of mRNA into preproinsulin, a polypeptide of 110 amino acids with an N-terminal signal peptide ...
  20. [20]
    Insulin Biosynthesis, Secretion, Structure, and Structure-Activity ...
    Feb 1, 2014 · Insulin is the biosynthetic product of a single-chain precursor, preproinsulin, whose proteolytic processing is coupled to trafficking between ...
  21. [21]
    Biosynthesis, structure, and folding of the insulin precursor protein
    Insulin synthesis in pancreatic beta cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and post-prandially, exert ...
  22. [22]
    Heterogeneous Expression of Proinsulin Processing Enzymes in ...
    The maturation of proinsulin into insulin occurs in the secretory granules and is mediated by the prohormone convertases (PC) 1/3, proprotein convertase 2 (PC2) ...
  23. [23]
    Biophysical insights into glucose-dependent transcriptional ...
    The pancreatic and duodenal homeobox 1 (PDX1) is a central regulator of glucose-dependent transcription of insulin in pancreatic β cells.
  24. [24]
    Regulation of the pdx1 gene promoter in pancreatic beta-cells
    The current study has established the fact that glucose, GLP-1, insulin, T(3), HB-EGF, and TNF-alpha all positively regulate the PDX1 gene promoter in ...<|separator|>
  25. [25]
    Insulin crystallization depends on zinc transporter ZnT8 expression ...
    These granules contain pro-insulin-zinc hexamers which are further processed into mature insulin and C-peptide by the prohormone convertases PC1/3 and PC2 (7).
  26. [26]
    Inside the Insulin Secretory Granule - PMC - NIH
    The insulin secretory granule (SG) in the pancreatic β-cell is essential for glucose homeostasis in the body. It is both the site of proinsulin conversion into ...
  27. [27]
    Identification and chromosomal localization of the human gene
    IAPP specific polyadenylated RNAs of 1.6 kb and 2.1 kb are present in human insulinoma RNA. The human IAPP gene is located on chromosome 12.
  28. [28]
    Processing of synthetic pro-islet amyloid polypeptide (proIAPP ...
    Human IAPP is synthesized as a 67-residue propeptide in islet beta-cells and colocalized with insulin in beta-cell granules. The mature 37-amino acid peptide is ...
  29. [29]
    Processing of pro-islet amyloid polypeptide in the constitutive and ...
    We used a pulse-chase approach to investigate the kinetics of processing and secretion of the IAPP precursor, proIAPP, in beta cells. By only 20 min after ...
  30. [30]
    Neuroendocrine hormone amylin in diabetes - PMC - PubMed Central
    The basal plasma concentrations of amylin in human in the 2-15 pmol/L range, with an insulin/amylin ratio of 10-100:1[30,31]. In healthy subjects, circulating ...
  31. [31]
    Cosecretion of amylin and insulin from isolated rat pancreas - PubMed
    The molar ratio of amylin amounts to 10% of that of insulin. The biological significance of amylin is still unknown, but a paracrine/endocrine role in glucose ...
  32. [32]
    Newly identified pancreatic protein islet amyloid polypeptide. What ...
    IAPP is stored with insulin in beta-cell secretory vesicles and is cosecreted with insulin in response to glucose and several secretagogues. IAPP has been ...
  33. [33]
    The role of somatostatin in GLP-1-induced inhibition of glucagon ...
    May 27, 2017 · The mechanism of action of GLP-1 analogues is to increase the glucose sensitivity of beta cells, thereby enhancing glucose-induced insulin ...
  34. [34]
    GLP-1 receptor signaling increases PCSK1 and β cell ... - JCI Insight
    Feb 8, 2021 · Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a β cell GLP-1R–dependent manner.
  35. [35]
    Biochemistry, C Peptide - StatPearls - NCBI Bookshelf
    Aug 1, 2023 · It is secreted from the beta cells of islets of Langerhans of the endocrine pancreas when proinsulin is cleaved into insulin and C-peptide. It ...Introduction · Fundamentals · Cellular Level · Testing
  36. [36]
    A Practical Review of C-Peptide Testing in Diabetes - PMC
    May 8, 2017 · C-peptide is a widely used measure of pancreatic beta cell function. It is produced in equimolar amounts to endogenous insulin but is excreted at a more ...
  37. [37]
    IAPP/amylin and β-cell failure: implication of the risk factors of type 2 ...
    In this review, we will discuss the possibility of IAPP, related intermediates, or islet amyloid to induce β-cell failure through a multifactorial process.
  38. [38]
    Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology
    The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined.
  39. [39]
    Glucose transporters in the 21st Century
    Glut2 has a uniquely high Km for glucose (∼17 mM), and it is expressed at a very high level in pancreatic β-cells and in the basolateral membranes of intestinal ...Glut1 · Glut2 · Gluts 6--8 And 10--14
  40. [40]
    Glucose Transporters Are Key Components of the Human Glucostat
    May 22, 2024 · In this study, we confirmed GLUT1 to be the predominantly expressed glucose transporter in both adult and fetal human β-cells.Introduction · Research Design and Methods · Results · Discussion
  41. [41]
    Diabetes, Insulin Secretion, and the Pancreatic Beta-Cell ...
    Dec 13, 2001 · Following its entry into the beta cell, glucose is phosphorylated by glucokinase. This rate-limiting enzymatic step constitutes a glucose sensor ...
  42. [42]
    Diabetes and Insulin Secretion: The ATP-Sensitive K + Channel (K ...
    Nov 1, 2005 · When KATP channels open, β-cells hyperpolarize and insulin secretion is suppressed. The prediction that KATP channel “overactivity” should cause ...
  43. [43]
    In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in ...
    Feb 1, 2006 · Biphasic insulin secretion is the normal response of β-cells to a rapid and sustained increase in glucose concentration (1,2). The first phase ...
  44. [44]
    Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice ...
    The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration.
  45. [45]
    The Role of G Protein–Coupled Receptors and Receptor Kinases in ...
    The increased cAMP level is then able to activate PKA, sensitizing the β cell to calcium-induced exocytosis. Phosphoproteomic analysis of GLP-1–activated β ...A. The Incretin Effect... · Iv. Orphan Receptors And... · D. Single Cell Rna...
  46. [46]
    β‐Cell glutamate signaling: Its role in incretin‐induced insulin ...
    The incretins GLP‐1 and GIP are known to potentiate insulin secretion through activation of Gs protein signaling followed by cAMP signaling pathways, which ...
  47. [47]
    An Update on the Effect of Incretin-Based Therapies on β-Cell ...
    Apr 25, 2016 · GLP-1 and GIP directly increase GSIS in healthy subjects after glucose infusion, and the insulinotropic effects of GLP-1 and GIP are similar ...Missing: Ca2+ | Show results with:Ca2+
  48. [48]
    Direct Autocrine Action of Insulin on β-Cells - PubMed Central - NIH
    In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell.
  49. [49]
    Insulin receptor trafficking steers insulin action - PMC - NIH
    Feb 23, 2016 · Among the various signaling cascades modulating beta cell function, autocrine activation of the insulin receptor regulates both insulin ...
  50. [50]
    Somatostatin Secreted by Islet δ-Cells Fulfills Multiple Roles as a ...
    Somatostatin (SST) from islet δ-cells inhibits insulin and glucagon secretion, and may facilitate cholinergic activation and nutrient-induced glucagon  ...
  51. [51]
    The somatostatin-secreting pancreatic δ-cell in health and disease
    Jan 1, 2019 · Somatostatin secreted from the δ-cell acts locally within the islets as a paracrine inhibitor of insulin and glucagon secretion.
  52. [52]
    Designing a bioelectronic treatment for Type 1 diabetes: targeted ...
    Jul 28, 2020 · Parasympathetic signals provided by the vagus nerve result in release of insulin from pancreatic β-cells. A large body of literature ...
  53. [53]
    The autonomic nervous system regulates pancreatic β-cell ...
    We conclude that β-cell proliferation is stimulated by parasympathetic and inhibited by sympathetic signals.
  54. [54]
    The Fatty Acid Receptor GPR40 Plays a Role in Insulin Secretion In ...
    Fatty acids do not initiate insulin release in the absence of glucose, but they potentiate glucose-induced insulin secretion (GSIS) upon acute exposure. Their ...
  55. [55]
    β-cell Failure as a Complication of Diabetes - PMC - NIH
    Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene ...
  56. [56]
    Glucolipotoxicity: Fuel Excess and β-Cell Dysfunction - PMC
    Nov 29, 2007 · In this view, failure to correct hyperglycemia and hyperlipidemia dooms the β-cell to a continual onslaught of glucotoxicity and lipotoxicity ...Missing: feedback | Show results with:feedback
  57. [57]
    Physiology, Glucose - StatPearls - NCBI Bookshelf - NIH
    Apr 30, 2024 · Normal fasting blood glucose levels typically range from 70 to 100 mg/dL (3.9 to 5.6 mmol/L).[21]. Random Blood Glucose Testing. This test is ...
  58. [58]
    Target for Glycemic Control: Concentrating on glucose - PMC - NIH
    In terms of fasting glucose, recommended goals are set within a 70–130 mg/dl (3.9–7.2 mmol/l) range for the American Diabetes Association (17) and at <110 mg/dl ...
  59. [59]
    Biochemistry, Insulin Metabolic Effects - StatPearls - NCBI Bookshelf
    Thus, by increasing GLUT-4's presence on the plasma membrane, insulin allows glucose to enter skeletal muscle cells for metabolism into glycogen.
  60. [60]
    Insulin regulation of gluconeogenesis - PMC - PubMed Central - NIH
    Here, we review some of the molecular mechanisms through which insulin modulates hepatic gluconeogenesis, thus controlling glucose production by the liver.
  61. [61]
    Mechanisms of Insulin Action and Insulin Resistance - PMC
    In liver, insulin activates glycogen synthesis, increases lipogenic gene expression, and decreases gluconeogenic gene expression. In white adipocyte tissue (WAT) ...
  62. [62]
    Central Nervous System Control of Glucose Homeostasis
    ... portal glucose gradient (termed the portal signal) is specific to the postprandial setting and produces a robust, insulin-independent increase in net ...
  63. [63]
    β-Cell Mass and Turnover in Humans: Effects of obesity and aging
    β-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably ...
  64. [64]
    Amylin as a Future Obesity Treatment - PMC - PubMed Central
    In addition, amylin acts as an inhibitory signal to delay gastric emptying and suppress the release of glucagon from α pancreatic cells. POMC, ...
  65. [65]
    Amylin-mediated control of glycemia, energy balance, and cognition
    It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved ...
  66. [66]
    Report Insulin Secretion Depends on Intra-islet Glucagon Signaling
    Oct 30, 2018 · We found that glucagon stimulates insulin secretion through both Gcgr and GLP-1R. Moreover, loss of either Gcgr or GLP-1R does not change insulin responses.
  67. [67]
    Pancreatic δ-cells influence the glycaemic set point - Nature
    Feb 1, 2024 · Somatostatin, produced by pancreatic δ-cells, has been known to inhibit insulin secretion since its discovery in the 1970s.
  68. [68]
    Pancreatic polypeptide revisited: Potential therapeutic effects in ...
    We do know that PP exerts insulinostatic actions and may positively affect pancreatic beta-cell turnover.
  69. [69]
    Role of VEGF-A in Vascularization of Pancreatic Islets - ScienceDirect
    We show that endocrine cells signal back to the adjacent endothelial cells to induce the formation of a dense network of fenestrated capillaries in islets.
  70. [70]
    VEGF-A and blood vessels: a beta cell perspective | Diabetologia
    Aug 14, 2019 · This review summarises our understanding of the role of vascular endothelial growth factor-A (VEGF-A) and endothelial cells in beta cell development, ...
  71. [71]
    Biology of Incretins: GLP-1 and GIP - Gastroenterology
    This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptidesBiology Of Incretins: Glp-1... · Proglucagon Gene Structure... · Glp-1 Secretion, Metabolism...Missing: crosstalk | Show results with:crosstalk
  72. [72]
    Interactions between islets and regulatory immune cells in health ...
    Sep 22, 2021 · An emerging concept is that certain populations of immune cells may have the capacity to both promote tolerance and support the restoration of beta cells.
  73. [73]
    Connexin 36, a key element in pancreatic beta cell function - PubMed
    They are excitable cells and most of them are electrically coupled through gap junction channels. Connexin 36 (Cx36) has been identified at junctional membranes ...
  74. [74]
    Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines ...
    Apr 1, 2007 · Cx36-mediated coupling reduces β-cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics.
  75. [75]
    Autoimmune CD8+ T cells in type 1 diabetes - PubMed Central - NIH
    Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by pancreatic β cell destruction and mediated primarily by autoreactive CD8+ T cells.
  76. [76]
    Antigen Targets of Type 1 Diabetes Autoimmunity - PMC
    Frequencies of CD8 T cells reactive with insulin B10–18, PPI15–24, IGRP265–273, GAD65114–123, ppIAPP5–13, and IA-2797–805 were found to be significantly ...Targets Of Cd4 T Cells · Targets Of Cd8 T Cells · Islet Epitopes And Thymic...<|separator|>
  77. [77]
    Type 1 Diabetes Risk Variants Reduce Beta Cell Function - PMC - NIH
    Jan 29, 2025 · By the time diagnosis is made, there is a 70–80% reduction in β cell mass, which translates to reductions in insulin production [5]. The ...
  78. [78]
    Definition of High-Risk Type 1 Diabetes HLA-DR and HLA-DQ ... - NIH
    Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are ...
  79. [79]
    Viruses as a potential environmental trigger of type 1 diabetes ...
    Group B coxsackieviruses are more commonly implicated in the development of T1DM. Its persistence in pancreatic cells can trigger autoimmunity in genetically ...
  80. [80]
    Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes - PMC
    This destruction takes place during an inflammatory phase, known as insulitis, in which various immune cells infiltrate the islets (Lecompte, 1958; Gepts, 1965; ...
  81. [81]
    Honeymoon phase in type 1 diabetes mellitus: A window of ... - NIH
    The honeymoon phase of T1DM seems to provide the best window of opportunity for using targeted therapies using various immunomodulatory agents.
  82. [82]
    Epidemiology of type 1 diabetes mellitus in children and adolescents
    Apr 25, 2024 · It has been reported that the incidence of T1DM has increased, and diabetes occurs at earlier ages especially in the past 2 decades. , Every ...
  83. [83]
    Increasing trend of childhood type 1 diabetes incidence
    The global incidence rate (IR) of T1D has been rising since the 1950s, with an average annual increase of 3–4% over the past three decades [5–7]. In 2022, the ...
  84. [84]
    Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress ...
    Nov 26, 2021 · In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development.Missing: exhaustion | Show results with:exhaustion
  85. [85]
    Islet β cell failure in type 2 diabetes - PMC - PubMed Central
    Chronic hyperglycemia can result in a browning reaction between ... Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes ...
  86. [86]
    Induction of IAPP amyloid deposition and associated diabetic ...
    Aug 1, 2017 · β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition ... Preservation of β-cell function in type 2 ...
  87. [87]
    β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are ...
    Collectively, our findings strongly support a role for islet amyloid formation in the loss of β cells that is involved in the pathogenesis of type 2 diabetes.Regular Article · Results · Islet Amyloid Deposition<|separator|>
  88. [88]
    Full article: Beta-cell failure in type 2 diabetes: mechanisms, markers ...
    Histological analysis in autopsy studies has confirmed that beta-cell mass can be reduced by up to 60% in people with T2D compared with healthy individuals with ...
  89. [89]
    Protective and Harmful ER Stress Responses in Pancreatic β-Cells
    Oct 22, 2021 · UPR Pathways Suppress Damaging Oxidative Stress. ER stress and oxidative stress exert overlapping and related effects on β-cell health and ...
  90. [90]
    Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell ...
    Nov 4, 2021 · Furthermore, oxidative stress leads to loss of β-cell maturity genes MAFA and PDX1, and to a concomitant increase in progenitor marker ...
  91. [91]
    Mechanisms of β-cell dedifferentiation in diabetes: recent findings ...
    This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress ...
  92. [92]
    β‐Cell failure in type 2 diabetes - PMC
    Jan 21, 2011 · We believe type 2 diabetes develops on the basis of normal but 'weak'β‐cells unable to cope with excessive functional demands imposed by overnutrition and ...
  93. [93]
    The Role of TCF7L2 in Type 2 Diabetes - PMC - PubMed Central
    TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies.
  94. [94]
    The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of ...
    The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity ...
  95. [95]
    Natural history of β-cell adaptation and failure in type 2 diabetes
    In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process ...
  96. [96]
    https://www.tandfonline.com/doi/full/10.1080/00325481.2020.1771047
  97. [97]
    Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
    Feb 19, 2024 · Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often ...
  98. [98]
    Diagnosis and management of insulinoma - PMC - NIH
    Insulinomas, the most common cause of hypoglycemia related to endogenous hyperinsulinism, occur in 1-4 people per million of the general population.
  99. [99]
    Insulinoma - StatPearls - NCBI Bookshelf
    Insulinomas are functional neuroendocrine neoplasms arising from the pancreatic islet cells. · Most insulinomas are benign and are managed by surgical resection.
  100. [100]
    Insulinoma - Endotext - NCBI Bookshelf - NIH
    Apr 4, 2023 · Fifty percent of MEN-1 patients harbor pancreatic NENs (panNENs) (13, 15, 16). 5–10% of insulinomas are associated with the MEN1 syndrome.
  101. [101]
    Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls
    Oct 13, 2021 · This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high- ...Diagnostic Features · Pannet · Diagnostic Pitfalls
  102. [102]
    Molecular genetic studies of pancreatic neuroendocrine tumors ...
    Aug 1, 2023 · MEN1 germline mutations are found in >90% of MEN1 patients and comprise whole or partial gene deletions, frameshift deletions or insertions, in- ...
  103. [103]
    Insulinoma: pathophysiology, localization and management - PMC
    Insulinoma is the most common neuroendocrine tumor of the pancreas with an annual incidence of four in every 1 million persons [1].
  104. [104]
    Pathologic pancreatic endocrine cell hyperplasia - PMC - NIH
    Increased neogenesis (morphologically as nesidioblastosis) appears to be the main mechanism responsible for β cell hyperplasia. The etiology of β cell ...
  105. [105]
    Nesidioblastosis in adults: a challenging cause of organic ... - PubMed
    A link between beta-cell hyperplasia and progression to insulinoma based on not yet known genetic causes can be suspected. MeSH terms. Adult; Diagnosis, ...Missing: defects | Show results with:defects<|separator|>
  106. [106]
    Hyperinsulinemic hypoglycemia due to adult nesidioblastosis ... - NIH
    Nov 28, 2006 · Several genetic abnormalities were identified as the causes of PHH in infancy. The most important mutations are in the β-cell sulfonylurea ...
  107. [107]
    Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS ...
    This condition is known as nesidioblastosis. It is also known by the term islet cell hyperplasia, ductuloinsular proliferation, islet cell adenomatosis, and ...
  108. [108]
    Sulfonylurea KATP Blockade in Type II Diabetes and ...
    Opening of the KATP hyperpolarizes the cell. Inhibition of KATP channels causes membrane depolarization and an influx of calcium via voltage-dependent calcium ...
  109. [109]
    Glipizide - StatPearls - NCBI Bookshelf - NIH
    Glipizide is a sulfonylurea. It promotes insulin release from the pancreatic beta cells and reduces glucose output from the liver. It also improves insulin ...
  110. [110]
    Sulfonylureas - StatPearls - NCBI Bookshelf - NIH
    [33] Therefore, hypoglycemia is the most common side effect and a major concern associated with sulfonylureas.[2] Hypoglycemia occurs when blood glucose ...
  111. [111]
    [PDF] 209637Orig1s000 - accessdata.fda.gov
    Feb 12, 2017 · The safety profile of semaglutide is generally consistent with other long-acting GLP-1 receptor agonists. The cardiovascular safety of.Missing: GSIS proliferation 2020
  112. [112]
    GLP-1 receptor signalling promotes β-cell glucose metabolism via ...
    Jun 1, 2017 · Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-cells in a glucose dependent manner.
  113. [113]
    (PDF) GLP-1 analogue semaglutide regulates pancreatic beta-cell ...
    Jul 4, 2025 · Semaglutide is investigated to show whether long-term beta cell survival regulation is achieved through the same downstream signalling pathways.Missing: GSIS | Show results with:GSIS
  114. [114]
    Semaglutide, a glucagon like peptide-1 receptor agonist with ... - NIH
    Jan 7, 2022 · Cardiovascular (CV) outcome trials established that it can reduce various CV risk factors in patients with established CV disorders. Semaglutide ...
  115. [115]
    SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure ...
    Dapagliflozin therapy restores insulin content in non-obese NDM mice through reduction of β-cell stress. To determine whether reducing blood glucose reverts ...
  116. [116]
    Dapagliflozin exerts positive effects on beta cells, decreases ...
    These data suggest that SGLT2 inhibitors have positive effects on beta cells and decrease plasma and pancreatic glucagon, independent of changes in ambient ...
  117. [117]
    Mechanism of Action of DPP-4 Inhibitors—New Insights - PMC
    In practice, DPP-4 inhibitors increase concentrations of both active incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (secreted by the ...
  118. [118]
    Role of AMP-activated protein kinase in mechanism of metformin ...
    Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat ...Missing: emerging | Show results with:emerging
  119. [119]
    Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a ...
    Jun 27, 2019 · We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and ...
  120. [120]
    Generation of functional human pancreatic β cells in vitro - PubMed
    Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro.Missing: seminal Rezania
  121. [121]
    Reversal of diabetes with insulin-producing cells derived ... - PubMed
    We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of ...Missing: seminal iPSC Pagliuca
  122. [122]
    PDX1, Neurogenin-3, and MAFA: critical transcription regulators for ...
    Nov 2, 2017 · PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the ...
  123. [123]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC8736331/
  124. [124]
    Vertex Presents Positive Data for Zimislecel in Type 1 Diabetes at ...
    Jun 20, 2025 · Results from the study continue to demonstrate the transformative potential of zimislecel with consistent and durable patient benefit –.Missing: 2021 | Show results with:2021
  125. [125]
    140-OR: Durable Glycemic Control and Elimination of Exogenous ...
    Jun 20, 2025 · Results: These results reflect 12 participants who received a full VX-880 dose as a single infusion and were followed for at least one year, as ...
  126. [126]
    A high-throughput chemical screen reveals that harmine ... - PubMed
    Mar 9, 2015 · We show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control.Missing: transdifferentiation alpha
  127. [127]
    Harmine and exendin-4 combination therapy safely expands human ...
    Jul 10, 2024 · We demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and ...<|separator|>
  128. [128]
    Mount Sinai and City of Hope Scientists First to Demonstrate a ...
    The Mount Sinai team recently completed a phase 1 clinical trial of harmine in healthy volunteers to test its safety and tolerability. At the same time ...
  129. [129]
    [PDF] 11/2022 FULL PRESCRIBING INFORMATION - accessdata.fda.gov
    Teplizumab-mzwv binds to CD3 (a cell surface antigen present on T lymphocytes) and delays the onset of Stage 3 type 1 diabetes in adults and pediatric patients ...Missing: preservation | Show results with:preservation
  130. [130]
    Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes
    Oct 18, 2023 · In 2022, teplizumab (an Fc receptor–nonbinding anti-CD3 monoclonal antibody) was approved by the Food and Drug Administration (FDA) to delay the ...
  131. [131]
    β cell regeneration and novel strategies for treatment of diabetes ...
    Jun 29, 2022 · This review discusses the mechanisms of β cell regeneration and their potential in the treatment of diabetes.Missing: Sakran vascularization
  132. [132]
    PDX1, Neurogenin-3, and MAFA: critical transcription regulators for ...
    Nov 2, 2017 · PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory ...
  133. [133]
    The window period of NEUROGENIN3 during human gestation - PMC
    The window for pancreatic endocrine differentiation via NEUROG3 action opens at 8 wpc and closes between 21 and 35 wpc.Missing: timeline | Show results with:timeline
  134. [134]
    Development of the Human Pancreas From Foregut to Endocrine ...
    Sep 17, 2013 · The increase in NEUROG3 expression and of NEUROG3-positive cells during late embryogenesis was closely timed to the appearance of fetal insulin ...
  135. [135]
    β-Cell Replication Is the Primary Mechanism Subserving the ...
    Jun 1, 2008 · RESULTS— We report that 1) β-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this ...
  136. [136]
    Postnatal β-cell maturation is associated with islet-specific ... - Nature
    Sep 2, 2015 · β-cell glucose responsiveness is achieved through tight coupling of insulin exocytosis with glycolysis and mitochondrial metabolism. These ...
  137. [137]
    Targeting β-cell dedifferentiation and transdifferentiation
    In this section, we discuss the various stresses and mechanisms that trigger dedifferentiation ... (B) Stress is a major contributor to β-cell dedifferentiation ...
  138. [138]
    Heterogeneity of human pancreatic β-cells - PMC - NIH
    Sep 6, 2019 · Human pancreatic β-cells are heterogeneous. This has been known for a long time and is based on various functional and morphological readouts.
  139. [139]
    Epigenetic Regulation of β Cell Identity and Dysfunction - Frontiers
    Histone H3 lysine 27 acetylation (H3K27ac), a mark associated with active enhancers, is decreased in both 2-week and 10-week intrauterine growth retardation ( ...Missing: 2020s | Show results with:2020s
  140. [140]
    Epigenetics in β-cell adaptation and type 2 diabetes - PMC - NIH
    Here, we highlight the current studies on the epigenetic regulation of β-cell adaptation (Figure 1) and epigenetic features of β-cells linked with T2D.Missing: 2020s | Show results with:2020s