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Disease of the pancreas and glucose metabolism. Types type 1 type 2 gestational MODY 1 2 3 4 5 6 Complications See Template:Diabetes. Hyperglycemia Oxyhyperglycemia Hypoglycemia Whipple's triad. Insulin resistance Hyperinsulinism Congenital hyperinsulinism Rabson—Mendenhall syndrome.

Pancreatic beta cell function Insulinoma Insulitis. Categories : Diabetes Human cells Endocrine pancreas Peptide hormone secreting cells. Overnutrition, obesity, and physical inactivity are the major systemic causes of insulin resistance.

At the molecular level, insulin resistance is caused by alterations in insulin signaling and its effectors Obesity, a common precursor to T2D, especially in North America and Western Europe, increases lipid accumulation and alters the secretion of adipokines, proinflammatory cytokines, and free fatty acids FFAs FFAs and proinflammatory cytokines act on metabolic tissues such as the liver and muscle, altering the inflammatory response and lipid profiles Insulin resistance in the liver results in impaired glycogen synthesis glycogenesis , increased glucose production glycogenolysis and gluconeogenesis , and excessive lipogenesis, which contribute to the development of fatty liver and its associated health risks In addition, insulin resistance decreases glucose uptake in muscle and fails to suppress lipolysis and FFA release in adipocytes, contributing to the increase in plasma FFA levels A When blood glucose concentrations rise after a meal, β-cells secrete insulin, which activates peripheral tissues to take up glucose and maintain glucose homeostasis.

For example, this process acts by reducing hepatic glucose output and gluconeogenesis liver , inducing glycogen synthesis liver and muscle , and increasing glucose uptake muscle and adipocytes. B , C Metabolic stresses, such as excessive calorie intake, obesity, and physical inactivity, promote the development of insulin resistance, a condition in which peripheral tissues become less responsive to insulin.

In response, β-cells produce and secrete an abnormally large amount of insulin hyperinsulinemia. Sustained metabolic stress exacerbates ER and oxidative stress and mitochondrial dysfunction, which collectively contribute to β-cell failure and the loss of β-cell mass, leading to hyperglycemia. To compensate for insulin resistance, pancreatic β-cells release more insulin, leading to hyperinsulinemia Fig.

Paradoxically, hyperinsulinemia makes things worse by causing insulin receptor downregulation and activating a vicious cycle of gradually increasing compensatory insulin levels and decreased insulin signaling 2.

In fact, hyperinsulinemia is a hallmark of insulin resistance The inability of pancreatic β-cells to secrete enough insulin to overcome insulin resistance results in hyperglycemia 2.

The early stages of T2D are associated with hyperinsulinemia, but plasma insulin levels steadily drop as β-cell dysfunction progresses. This results in a relative lack of insulin and a reduction in β-cell mass in the advanced state of progression of the disease 24 Fig. Numerous hypotheses have been proposed to explain β-cell failure.

Among these hypotheses, the most frequently invoked and experimentally validated are endoplasmic reticulum ER stress, mitochondrial dysfunction, and oxidative stress Increased β-cell insulin production intensifies the burden on the ER, where protein synthesis and folding take place.

ER stress can be caused by the accumulation of misfolded proinsulin as a result of either excess proinsulin in the ER or ER alterations that decrease folding efficiency To alleviate ER stress, cells activate the unfolded protein response UPR , which increases the functional capacity of the ER by increasing enzymes and chaperones to facilitate protein folding while decreasing protein translation through activating eIF2 phosphorylation and mRNA degradation Notably, the UPR can exert both beneficial and detrimental effects on β-cell function, depending on the level of ER stress While mild to moderate ER stress can promote β-cell proliferation and insulin synthesis through UPR activation, sustained insulin demand due to insulin resistance can lead to excessive ER stress and terminal UPR activation 31 , This can result in β-cell dysfunction and apoptosis, contributing to the development of T2D.

The mechanism responsible for the switch from beneficial to harmful UPR effects is not yet understood. However, it has been shown that chronic hyperglycemia promotes the overexpression of IRE1α, a central component of the UPR, which degrades proinsulin mRNA and contributes to β-cell failure Defective UPR can also contribute to the reduction of β-cell differentiation markers, such as Pdx1, NKX6.

Moreover, under sustained glucolipotoxicity-induced ER stress, THADA expression is upregulated and can activate a proapoptotic complex involving DR5, FADD, and caspase-8, ultimately exacerbating ER stress-induced apoptosis In β-cells, unlike other mammalian cells, glycolytic flow is tightly linked to elevated mitochondrial oxidative phosphorylation activity, where almost all glucose carbons are oxidized to CO 2 Sustained glucose stimulation can augment glycolytic flux in β-cells, elevating reactive oxygen species ROS production Additionally, high FFA levels can increase ROS production in β-cells However, β-cells only express low levels of antioxidant enzymes, rendering them particularly vulnerable to ROS-induced damage Oxidative stress can lower insulin gene expression by impairing the DNA binding ability of PDX-1 41 and affect the expression or activity of MafA, which is involved in β-cell function and maturation β-cells take up glucose through the glucose transporter GLUT2 and carry out glycolysis via glucokinase to generate pyruvate.

Pyruvate is transported into the mitochondria, where it produces ATP through the TCA cycle via oxidative phosphorylation Thus, mitochondria are both the primary sites of ROS generation and a critical component of glucose metabolism and insulin secretion in β-cells As a result, mitochondrial malfunction impairs GSIS and causes β-cell dysfunction Chronic hyperglycemia increases rates of glycolysis, the TCA cycle, and pyruvate oxidation This metabolic stress raises the mitochondrial membrane potential over a critical threshold, resulting in electron transport chain blockage at complex III and ROS generation Although mitochondrial mass may expand to compensate for metabolic stress, higher mitochondrial density has been shown to enhance ROS generation Mitophagy is a cellular process that clears damaged mitochondria Mitophagy-related genes have been shown to increase in prediabetic islets but decrease substantially in diabetic islets Failure to remove dysfunctional mitochondria due to impaired mitophagy can lead to oxidative stress.

A recent genome-wide CRISPR screening has demonstrated that CALCOCO2, a T2D risk gene, plays a role in β-cell dysfunction CALCOCO2 promotes mitophagy activation, which helps β-cells tolerate metabolic stress Additionally, mutations in mitoribosomal proteins MRPs have been associated with diabetes, resulting in reduced oxidative phosphorylation capacity and ultimately leading to mitochondrial dysfunction It is crucial to underline the tightly intertwined nature of these three factors and their potential to exacerbate one another, contributing to β-cell failure.

Mitochondrial dysfunction is directly linked to oxidative stress and vice versa. The ER and mitochondria interact closely to form microdomains called mitochondria-associated membranes MAMs Miscommunication between these organelles can lead to mitochondrial dysfunction, ER stress, and altered calcium levels and ultimately affect β-cell function 52 , Chronic metabolic stress leads to dysfunction of β-cells and consequent loss of β-cell mass Fig.

Conventionally and mechanically, β-cell death by apoptosis was thought to account for these features in response to metabolic stress 2. Many studies have demonstrated that stressed β-cells are susceptible to apoptosis.

However, rates of β-cell apoptosis are insufficient to explain the extent of β-cell loss observed in T2D Moreover, it has been shown that a few weeks of a low-calorie diet can partially restore β-cell function, even years after a T2D diagnosis, without affecting β-cell proliferation.

This observation challenges the notion that β-cells are irreversibly lost and suggests that cell death alone cannot fully account for the loss of β-cells. As an alternative mechanism, experimental research and clinical data suggest that changes in β-cell fate could provide a plausible biological explanation for the decrease in β-cell mass Fig.

While apoptosis was previously thought to be the primary cause of β-cell mass loss in response to metabolic stress, recent evidence suggests that the fundamental cause is an alteration in β-cell identity due to dedifferentiation or transdifferentiation.

These processes involve the loss of mature β-cell characteristics and the acquisition of alternative cell fates, leading to a reduced capacity for insulin secretion and impaired glucose metabolism. Chronic hyperglycemia in pancreatectomized rats impairs β-cell differentiation, as indicated by reduced β-cell markers, such as Pdx1 and Nkx 6.

Lineage tracing of β-cells in diabetic animal models revealed that β-cells do not die but lose their ability to produce insulin 6 , 11 , 12 , 56 , 57 , 58 , They in fact revert to a progenitor-like cell via β-cell dedifferentiation, as evidenced by the reactivation of progenitor cell markers, such as Ngn3, Nanog, OCT4, and L-Myc, and the downregulation of β-cell differentiation markers 6 , 11 , 12 , 56 , 57 , 58 , In addition, lineage tracing studies have shown that some cells undergo transdifferentiation or redifferentiation to become α-like or mesenchymal cells Fig.

Moreover, aldehyde dehydrogenase 1A3 ALDH1A3 has been identified as a marker of β-cell dedifferentiation in β-cell-specific Foxo s knockout mice 60 , where its expression is activated in lineage-traced dedifferentiated β-cells.

These findings suggest that β-cell dedifferentiation is a protective mechanism against cell death in chronic hyperglycemia and that under certain circumstances, cells can redifferentiate into functioning β-cells 6 , 11 , 12 , 56 , 57 , 58 , To determine the role of β-cell dedifferentiation in the pathophysiology of human T2D, it is essential to validate experimental animal models in human patients.

Although the mouse is a useful genetic tool for studying diabetes, there are differences in the anatomy and physiology of human and rodent islets. Human islets have proportionally fewer β-cells and more α-cells than mouse islets, and β-cells are not clustered but intermingle with other endocrine islet cells Mouse and human islets differ significantly in their innervation patterns.

In mouse islets, both sympathetic and parasympathetic axons innervate endocrine cells, whereas in human islets, sympathetic axons primarily contact smooth muscle cells of the vasculature It has also been shown that human islets are capable of accumulating lipid droplets LDs , which are not found in mouse islets, even under hyperglycemic and hyperlipidemic conditions Considering these differences, it is crucial to investigate whether β-cell dedifferentiation occurs in human T2D to develop effective therapeutic interventions that can reverse this process and treat diabetes.

Since in vivo lineage tracing is not possible in humans, it can be difficult to evaluate the plasticity of human endocrine pancreatic cells. However, it is still possible to survey the range of cell states that result in β-cell dedifferentiation.

Consistent with this idea, reduced expression of Foxo1, Nkx6. Ngn3 was not detected in these samples; however, consistent with animal research, the number of ALDH1A3-positive cells dedifferentiated β-cells is elevated in human T2D pancreases 9.

This observation has been confirmed by different clinical samples in European, North American 9 , Chinese 8 , and Japanese 7 T2D populations Lineage tracing studies in mouse models further demonstrate that under hyperglycemic conditions, β-cells transdifferentiate into other islet cell types.

In addition to the β-cell-specific FoxO1 inactivation in β-cells described above, lineage tracing of Nkx2. β-cells lacking Pdx1 lose β-cell differentiation markers but acquire α-cell-like characteristics by expressing glucagon and the α-cell-restricted transcription factor Arx Additionally, Arx activation in β-cells leads to transdifferentiation into α- or PP cells In cases of severe β-cell depletion, other islet cells can undergo transdifferentiation into β-cells For instance, lineage tracing experiments of α-cells in β-cell-ablated mice show conversion of α- to β-cells, suggesting that α-cells can sense β-cell mass Additionally, in mouse models, ectopic expression of PAX4 69 or deletion of Arx 70 , 71 in α-cells causes transdifferentiation into β-cells.

In addition to transdifferentiating between endocrine cells, exocrine cells have been shown to convert into β-cells. For example, pancreatic acinar cells overexpressing Ngn3, Pdx1, and Mafa simultaneously transdifferentiate into functional β-cells, which can reduce hyperglycemia in streptozotocin STZ -treated mice The presence of multihormone-positive cells, such as INS and GCG, in pancreas sections of T2D patients supports the idea of islet cell transdifferentiation 9.

Moreover, human β-cells have been observed to spontaneously transform into α-cells or ductal cells during islet cell reaggregation or long-term in vitro culture 73 , 74 , but the relevance of these findings to T2D pathogenesis in humans remains unclear.

The occurrence of dedifferentiation and transdifferentiation in β-cells in response to chronic hyperglycemia suggests that islet cells have a high degree of plasticity.

This offers the potential for developing therapeutic interventions that target the restoration of functional β-cells. To pave the way for the development of treatment strategies, it is necessary to understand the repertoire of islet cell heterogeneity that presents in T2D patients Fig.

Single-cell RNA sequencing scRNA-Seq can be informative in this regard. Numerous scRNA-Seq studies have been performed to examine islet cell heterogeneity in nondiabetic or T2D islets in humans 75 , 76 , 77 , Segerstolpe et al. Although the five clusters are not exclusively associated with diabetes, the authors report that T2D β-cells exhibit notably lower levels of INS mRNA and reduced expression of FXYD2 Na,K-ATPase gamma subunit , along with increased levels of GPD2, which is a crucial component of the NADH mitochondrial shuttle.

Muraro et al. described a group of genes that identify distinct β-cell subtypes, including SRXN1, SQSTM1, and three ferritin subunits FTH1P3, FTH1, and FTL , which are involved in the ER and oxidative stress responses Baron et al.

reported evidence of β-cell heterogeneity resulting from differences in the expression of ER stress response genes, such as HERPUD1, HSPA5, and DDIT3 78 , as well as the β-cell differentiation markers UCN3 and MAFA. Additionally, Xin et al. identified distinct subpopulations of β-cells in islets from nondiabetic donors based on the combined expression patterns of UPR and INS The authors also discovered that β-cell maturation markers ISL1, PDX1, MAFA, MAFB, NEUROD1, NKX, and SIX3 and mitochondrial biogenesis genes TFB2M are differentially expressed in β-cell subgroups Moreover, scRNA-Seq studies have provided further evidence supporting the notion of β-cell dedifferentiation 80 , Wang and Avrahami show that the gene expression patterns of α- and β-cells in T2D islets are similar to those observed in juvenile donors, suggesting that cell dedifferentiation occurs during the progression of T2D 80 , scRNA-Seq is a powerful tool for comprehensively understanding the repertoire of islet cells in both normal and T2D states.

Identifying key master regulators of each cell type, including dedifferentiated β-cells, offers insight into potential therapeutic targets. Targeting key regulators of β-cell dedifferentiation, such as BACH2 and ALDH1A3, using small molecule inhibitors may hold promise as a potential strategy to reverse β-cell identity and treat T2D.

To analyze the transcriptome at the single-cell level, transcripts from each cell were barcoded and then pooled together for sequencing.

After sequencing the pooled transcripts, the total number of reads was divided by the number of cells, and each read was debarcoded to assign it to the specific cell from which it originated. As a result, the sequencing depth in scRNA-Seq is substantially lower than that in bulk RNA-Seq.

The average number of genes detected in each cell ranges from a few hundred to a few thousands. Low-abundance RNAs will thus be detected by random chance in certain cells but not others.

Additionally, the function of these differentially expressed genes has not been determined This work also highlights the fact that several key transcription factors, such as Mafa, are not consistently detectable in many β-cells, although the gene product of this mRNA is readily detected by immunohistochemistry in most β-cells 84 , To overcome this problem, we applied a systems biology approach, ARACNe Algorithm for the Reconstruction of Accurate Cellular Networks 86 , to build protein activity analyses derived from scRNA-Seq termed Single-cell Protein Activity Analyses from human islets of normal and diabetic donors and metaVIPER Virtual Inference of Protein-activity by Enriched Regulon analysis 87 , 88 to identify mater regulatory MR proteins controlling the formation of distinct cellular phenotypes that represent putative mechanistic determinants of aberrant, T2D-related transcriptional β-cell states Thus, metaVIPER provides accurate, quantitative activity assessment of the function of proteins whose mRNA is not detected in a given cell, allowing the classification of key lineage markers in individual cells that would be missed at the gene expression level.

Using this approach, we identified distinct cell types that reflect physiologic β- and α-cell states as well as aberrant cell states that are highly enriched in T2D patients.

It is worth highlighting that our unsupervised analysis conducted in human T2D islets corroborated previous experimental animal data indicating β-cell dedifferentiation.

Treatment strategies for β-cell failure can be categorized into two groups: increasing cell number or enhancing insulin secretion. The former has been pursued by transplantation of cadaver islets 90 or stem cell-derived β-cells 91 in patients requiring immune suppression for unrelated organ transplant primarily kidney.

Stimulation of β-cell proliferation 92 and inhibition of β-cell apoptosis have also been proposed, but there are no currently approved drugs to achieve this goal 8 , Drugs that promote insulin secretion have been used for decades but are plagued by secondary failures The discovery of dedifferentiation as a feature of β-cell failure raised the question of whether the process is reversible and, if so, whether it represents an actionable treatment target Human studies in which low-calorie diets improve glucose homeostasis in T2D patients corroborate the notion that β-cell failure can be reversible for a long time even after disease onset 94 , 95 , 96 , In T2D patients, a low-calorie diet can restore glucose control, and chronic adherence to this diet has lasting benefits on glycemia 94 , 95 , 96 , 97 , 98 , In addition, phlorizin treatment has been demonstrated to prevent hyperglycemia by restoring insulin mRNA expression and β-cell differentiation markers 55 , These observations in humans and rodents are consistent with the possibility that β-cell function can be restored.

Lineage tracing experiments with inducible Pdx1-cre or neurogenin3-cre also support this idea 10 , 11 , 12 , Furthermore, CRISPR-mediated functional studies in human islets show that the T2D transcriptional signature can be reversed by targeted inhibition of a key master regulator of dedifferentiation, BACH2 89 , which we also characterized as an ectopically activated gene in FoxO1 knockout β-cells The administration of a BACH inhibitor reduced hyperglycemia in diabetic mice and restored β-cell function Fig.

Because BACH inhibitors which target both BACH2 and the related isoform BACH1 are FDA-approved for the treatment of disorders such as multiple sclerosis , there is an immediate opportunity to investigate this pathway in human clinical trials Thus, this proof-of-concept study opens a new avenue for understanding the reversal of disease progression and expands prospects for developing novel therapeutics for restoring β-cell function and identity in T2D.

Multiple factors, including oxidative and ER stress and mitochondrial dysfunction, contribute to the development of β-cell failure and altered β-cell identity. Thus, converting endocrine progenitor-like cells dedifferentiated β-cells to differentiated β-cells is an appealing therapeutic approach since it is reminiscent of the differentiation of β-cells that naturally takes place during development.

Further research is needed to understand the similarities and differences between natural endocrine progenitors and dedifferentiated β-cells. Advances in technology and analytic tools for genome-wide studies at the single-cell level will assist in elucidating this point.

With a better understanding of the repertoire of islet cell heterogeneity in both normal and T2D subjects, we can identify disease-specific subpopulations and link them with genetic risk factors, paving the way for designing personalized precision-based treatments.

In addition, a thorough investigation of islet cell subtypes in large human populations can help identify whether specific β-cell subpopulations are more susceptible to metabolic stress and failure as the disease progresses.

This knowledge can lead to targeted therapies that aim to protect vulnerable populations from metabolic stressors and prevent the progression of the disease. Heald, A. et al.

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Ishida, E. Diabetes 66 , — Learn more about diabetes medication here. Although medications can help, changes in lifestyle can also be important steps a person can take to prevent or manage type 2 diabetes. Individuals can reduce their food intake if necessary and make sure to get regular exercise.

These factors help reduce the workload of beta cells and increase insulin sensitivity. Increased insulin sensitivity means the body can use insulin more effectively and better control blood sugar. For people with type 2 diabetes, following a balanced diet and getting regular exercise are important in managing the condition and preventing it from progressing.

Reaching or maintaining a moderate body weight through changes in diet and exercise may also lead to remission of type 2 diabetes and return of proper beta cell function. Beta cells are cells in the pancreas that produce and release the hormone insulin to regulate blood sugar levels.

In people with type 2 diabetes, continuously high blood sugar levels can put extra pressure on beta cells, as they have to work harder to produce enough insulin to control glucose levels.

In the early stages of type 2 diabetes, the loss of beta cell function may be reversible through weight loss and reduction of blood glucose levels. Certain medications can help control or prevent type 2 diabetes.

However, the most effective steps a person can take to prevent or manage the condition are reaching or maintaining a moderate body weight and getting regular exercise.

Find out here about the differences and…. A type 2 diabetes care plan outlines how a person can manage their condition. It includes blood sugar monitoring, insulin dosage, and more.

Type 1, type 2, and gestational diabetes all involve an imbalance of blood sugar, but the risk factors for each may vary. Having a family history of…. A study in mice suggests a potential mechanism that could explain why only some individuals with obesity develop type 2 diabetes.

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Medical News Today. Health Conditions Health Products Discover Tools Connect. Type 2 diabetes: Beta cells explained. Medically reviewed by Michelle L. Griffith, MD — By Beth Sissons on October 25, Explanation Beta cell survival At specific times Treatment Lifestyle factors Summary Beta cells are cells in the pancreas that produce and release insulin in response to blood glucose levels.

What are beta cells in type 2 diabetes? Can beta cells survive in people with type 2 diabetes? Beta cell changes at specific times. Beta cells and treatment. Lifestyle factors. Diabetes Type 2.