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Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity


All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed (‘disallowed’) in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1–7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell–beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion.

Graphical abstract

Specialisations of beta cell metabolism

The beta cell is a glucose sensor par excellence, allowing small fluctuations in circulating levels of the sugar to be tuned to insulin output. Certain amino acids, including those that enhance mitochondrial metabolism (e.g. glutamine and leucine) [1], also stimulate insulin release, a response that may be particularly important during fetal development [2]. Fatty acids also stimulate insulin secretion under some circumstances, but can be inhibitory [3].

Beta cell metabolism of glucose is central to secretion, and these cells express critical ‘glucose sensors’, including the glucose transporter GLUT2 (Slc2a2) in rodents (GLUT1 [SLC2A1] and GLUT3 [SLC2A3] are also expressed in human beta cells) [4]. More crucially for flux control, the low affinity/high KM (Michaelis–Menten constant) glucose phosphorylating enzyme, glucokinase (Gck), ensures that circulating glucose concentrations are matched to metabolism, which, via changes in electrical activity mediated by ATP-sensitive K+ (KATP) channels and Ca2+ influx, leads to insulin secretion [5]. Thus, a ‘triggering’ pathway for secretion, largely driven by glucose-induced increases in the intracellular ATP/ADP ratio, plays a cardinal role in glucose-stimulated insulin secretion (GSIS). Additional ‘amplifying’ pathways ensure that glucose also enhances secretion independently of the above pathway [6]. These are less well understood, but enhanced production of mitochondrial metabolites, including glutamate, citrate and reducing equivalents (generated as a result of the activation of metabolic cycles dependent upon mitochondria), notably, NAD(P)H, are all implicated. Work by Kibbey and colleagues [7], also suggests that activated mitochondrial GTP synthesis is a part of this mechanism (Fig. 1).

Fig. 1

Signalling mechanisms and the role of disallowed genes in beta cell insulin secretion in response to glucose (GSIS). See the main text for further details. GTP is proposed to stimulate insulin release in the cytosol. Products of disallowed genes involved in insulin secretion are represented in red. Lack of lactate dehydrogenase (LDH) and monocarboxylate transporter-1 (MCT-1/SLC16A1) prevents the conversion and extracellular entry, respectively, of lactate and pyruvate which would otherwise prompt inappropriate insulin release. NEFA are activated to FA-CoA in the cytoplasm and can access the mitochondria through carnitine palmitoyltransferase I (CPT-1), where β-oxidation generates Ac-CoA that incorporates into the TCA cycle to potentially enhance insulin secretion. In the cytosol, a glycerolipid/NEFA cycle (GL/NEFA), fatty acids (FA) are esterified with glucose-derived glycerol-3-phosphate (Gro3P) to generate monoacylglycerol (MAG), which enhances insulin release. NEFA could potentially (grey dotted arrow) be released from the beta cell and agonise free fatty acid receptor 1 (FFAR1/GPR40). Low ACOT7 limits the FA-CoA hydrolysis that would result in a lower FA-CoA/NEFA ratio in the cytoplasm or mitochondria. This could affect β-oxidation, the GL/NEFA cycle and the activation of FFAR1 and thus prevent undesired secretory granule release. Examples of transcription factors contributing to gene disallowance are depicted in blue (RFX6, PAX6) and miRNAs are shown in red (miR-29a/b). Ac-CoA, Acyl-CoA; GK, Glucokinase; Pyr, pyruvate; SCS-GTP, succinyl-CoA synthetase; TCA, tricarboxylate cycle. This figure is available as part of a downloadable slideset

The existence of variants in genes associated with monogenic forms of diabetes (neonatal diabetes or MODY) [8] provides ample evidence for the importance of several of the key players listed above, including GCK, and the KATP channel subunit genes KCNJ11 and ABCC8. Genome-wide association studies for type 2 diabetes have now also identified ~240 loci and ~400 distinct association signals in the human genome that impact disease risk [9]. Strikingly, the vast majority affect insulin secretion rather than insulin action. Several laboratories, including our own, have provided possible mechanisms of action for some of the implicated genes, including TCF7L2, encoding the Wnt-regulated transcription factor [10], SLC30A8 encoding zinc transporter 8 (ZnT8, the secretory granule zinc transporter) [11], PAM, encoding peptidylglycine α-amidating monooxygenase [12] and STARD10, encoding an intracellular lipid transporter [13]. The reader is referred to the recent review by Krentz and Gloyn [14] for a more comprehensive survey. A deeper understanding of the roles of these genes, afforded by functional genomics approaches that combine human genetics with interventional (e.g. gene knockout) approaches in tractable systems including mice or CRISPR/Cas9-edited human beta cell lines [14], has provided unexpected insights into beta cell biology, such as the importance of lipid transfer for proinsulin processing [13]. These approaches also offer the exciting prospect of new, and potentially personalised, therapeutic options (‘precision medicine’).

In addition to the roles of genes that are usually highly expressed in beta cells, the relatively weak expression (‘disallowance’) in these cells of several ‘housekeeping’ genes—expressed at high levels in essentially all other cell types in the body, and including founder members of this list of disallowed genes, Ldha and Mct-1 (Slc16a1) [15] —is also a defining characteristic of mature beta cells (see below). Inactivation of the latter enzymes is consistent with an unusually high proportion (>85%) of glucose carbon, which is converted to CO2 and water via mitochondrial oxidation in these cells [16]. Overexpression of either gene impairs GSIS [17] and unmasks unwanted pathways, including pyruvate-induced secretion [18]. The latter process underlies a genetic trait, exercise-induced hyperinsulism, in carriers of activating variants of the human SLC16A1 (MCT-1) gene [19] (Fig. 1).

A further example of a beta cell ‘disallowed’ gene is Acot7, the product of which hydrolyses long-chain acyl-CoAs into NEFA and CoA (Fig. 1). Overexpression of acyl-CoA thioesterase 7 (ACOT7) in beta cell lines, and in primary beta cells in mice in vivo, blunts their insulin secretory response to glucose and fatty acids and results in impaired glucose tolerance [20]. In this case, disallowance appears to reflect ATP sparing for the otherwise futile synthesis and degradation of certain lipid groups [20].

Our laboratory [21] and others [22] have now identified more than 60 beta cell disallowed genes, implicating a range of other cellular processes required for normal insulin secretion and/or the preservation of beta cell mass. The roles and regulation of a subset of these is described in Table 1. The mechanisms involved in the suppression of these genes, and their relevance for beta cell function and failure in diabetes, is currently an area of active research. DNA methylation [23] and histone modifications [24] (Table 1) are well-established mechanisms underlying beta cell-specific gene disallowance. Of note, the transcription factor gene RFX6, variants of which were recently identified in man as being responsible for a form of MODY [25], was recently shown to be more weakly expressed in islets from individuals with type 2 diabetes than individuals without the disease [26]. Importantly, inactivation of Rfx6 in the beta cell in mice both during development and in adult stages leads to impaired function [27]. This reflects impaired expression both of beta cell signature genes and of disallowed genes (below), the regulator regions of which are directly bound by regulatory factor X6 (RFX6). Similarly, another transcription factor important for beta cell development, paired box 6 (PAX6), also plays a pivotal role in maintaining cellular identity and the suppression of disallowed gene expression in adult mice [28, 29]. Like RFX6, PAX6 appears to be able to act ‘bimodally’ to either activate or repress gene expression depending on genomic context.

Table 1 Selected islet and beta cell disallowed genes describing putative roles, mechanisms of repression and evidence of increased expression in type 2 diabetes

MicroRNAs (miRNAs) are also important contributors to beta cell gene disallowance (Table 1). miRNAs are non-coding RNAs that silence gene expression to fine-tune biological pathways and reinforce cellular identity [30]. Beta cell-specific deletion of DICER, an enzyme essential for miRNA biogenesis, relieved the suppression of several disallowed genes in mice, namely, Fcgrt, Igfbp4, Maf, Oat, Pdgfra and Slc16a1 [31]. Whether the more recently identified disallowed genes highlighted in Pullen et al. [21] are also regulated by miRNAs remains to be investigated. Little is known about the identity of the miRNAs targeting these genes in beta cells, though miR-29a/b and miR-34a have been demonstrated to target Slc16a1 [32], and Pdgfra [33], respectively. It is conceivable that a complex network of miRNA-disallowed gene interactions contributes to reinforce beta cell identity by ensuring gene disallowance. Whether other non-coding RNA species (long non-coding RNAs, circular RNAs, etc.) are also involved remains to be explored.

Mitochondria and insulin secretion

Weak expression in beta cells of Ldha and Mct-1/Slc16a1 emphasises the likely importance of oxidative metabolism of glucose carbons for the normal stimulation of insulin release. Similarly, low expression of Acot7 underlines the importance of mitochondrial fatty acid metabolism for efficient ATP utilisation. Thus, mitochondrial ATP synthesis in response to elevated glucose or other nutrients is essential to both the triggering and amplifying pathways of insulin exocytosis [34]. There is strong evidence linking the loss or dysfunction of GSIS in beta cells of diabetic models with altered mitochondrial function, where nutrient storage and usage, as well as mitochondrial dynamics and morphology, are affected [35]. A further striking example is provided by hyperglycaemic ‘βV59M’ mice, expressing an activated form of the KATP channel subunit Kir6.2 [36], where an increase is observed in pyruvate dehydrogenase (PDH) kinase expression (expected to lower PDH activity and hence pyruvate entry into the cycle), as well as lowered levels of several citrate cycle genes.

Several mtDNA (mitochondrial DNA) variations in human populations have been implicated in increased or decreased risk of type 2 diabetes while, in animal models, alterations in beta cell mtDNA led to reduced insulin secretion, hyperglycaemia and beta cell loss [34]. In humans, maternally inherited diabetes and deafness (MIDD) is often linked to an mtDNA A3243G point mutation in the TRL-CAG1-7 (tRNALeu) gene, responsible for defective mitochondrial metabolism and impaired intracellular Ca2+ homeostasis [37].

mtDNA encodes most subunits of the electron transport chain, and inactivation of the mitochondrial transcription factor A (Tfam) specifically in mouse beta cells resulted not only in mtDNA depletion and deficient oxidative phosphorylation (OXPHOS) but also in impaired secretion and hyperglycaemia in vivo [38]. Moreover, mutations in the mitochondrial gene encoding frataxin, known for its iron–sulphur cluster activation and respiratory function in mitochondria, are associated with Friedreich’s ataxia (FRDA) [39], which involves mitochondrial iron overload, respiratory chain dysfunction, impaired OXPHOS and ATP production. Importantly, frataxin expression is upregulated by glucagon-like peptide (GLP-1) receptor agonists [40], an effect that may contribute to the glucose-lowering actions of these drugs.

The role of Ca2+ accumulation by mitochondria has long been a contested aspect of GSIS. Ca2+ uptake into these organelles in living beta cells was initially demonstrated in response to an increase in cytosolic Ca2+ through the use of a recombinant mitochondrially-targeted aequorin [41]. Although thought likely to lower mitochondrial membrane potential (Δψm), studies based on the discovery in the 1970s of Ca2+-sensitive intra-mitochondrial dehydrogenases in the citrate cycle [42] have suggested a positive role for Ca2+ as a stimulator of oxidative metabolism in this compartment. In line with the latter view, deletion of the mitochondrial Ca2+ uniporter (MCU) selectively in the beta cell of living mice [43] has revealed that Ca2+ uptake is essential for both phases of glucose-stimulated ATP synthesis and insulin secretion in vitro, as well as for the maintenance of normal beta cell mass. However, beta cell-selective Mcu null mice showed minor changes in insulin secretion in vivo, suggesting the existence of currently undefined compensatory mechanisms.

Beta cell mitochondria often exist as densely interconnected tubules that continually undergo interconversions with more granular forms via fission and fusion cycles that are under the control of specific regulatory proteins (Fig. 2). In most cell types, this dynamic process is influenced by nutrient supply as well as extra- or intracellular factors that are critical to cell survival. This is likely also to be the case in beta cells [44] and may be of particular relevance given the specialised roles of nutrient metabolism in these cells. Given that there is likely to be a close association between mitochondrial morphology and function, altered mitochondrial dynamics may well contribute to defective insulin secretion in diabetes. Indeed, several studies have demonstrated that mitochondrial morphology and function are altered in beta cells in diabetic animal models (e.g. the Zucker Diabetic Fatty rat) [42] and beta cell-derived lines [34].

Fig. 2

Putative roles for proteins controlling mitochondrial shape and dynamics in beta cells. See the text for further discussion. The outer mitochondrial membrane (OMM) GTPases MFN1 and MFN2 are responsible for the fusion of these membranes on two adjacent mitochondria, while optic atrophy 1 (OPA1), drives inner mitochondrial membrane (IMM) fusion. Heptad repeat domains 2 (HR2) are essential for the initial tethering between adjacent mitochondria, while hydrolysis of the GTPase domain is needed for fusion completion. The latter allows the transfer of mitochondrial membrane components, metabolites and normal mtDNA copies. Elongated mitochondria, with high secretory responsiveness, will undergo fission with the support of DRP1 and FIS1. Fragmentation is an essential process involved in isolating dysfunctional mitochondrial units or mutant mtDNA copies from the mitochondrial network. During mitochondrial division, organelles moderately malfunctioning or damaged (depolarised) due to oxidative stress will undergo autophagy, a process also referred to as mitophagy. Functional mitochondria will instead either remain fragmented (low secretory responsiveness) during high nutrient supply conditions or will fuse with neighbouring organelles when the cell is under high energy demand (starvation). Studies showed that deletion or silencing of Drp1 (Drp1/) or Mfn1 and Mfn2 (Mfn1/2/), affect insulin secretion and glucose homeostasis in mice. This figure is available as part of a downloadable slideset

Beta cells from patients with type 2 diabetes also display a marked change in mitochondrial function and morphology, including fragmentation and disruption of cristae morphology [45]. These changes are associated with reduced insulin secretion, a lower ATP/ADP ratio and impaired polarisation of the mitochondrial inner membrane (i.e. the generation of a Δψm to drive electron transport chain activity) [45]. However, mitochondrial volume density in beta cells from individuals with type 2 diabetes was significantly increased in comparison with healthy or type 1 diabetic donors [46].

Recent results from Ku and colleagues [47], and ourselves [48] demonstrate that the balance between mitochondrial fission and fusion (and hence the maintenance of an appropriately interlinked mitochondrial network) is critical for normal beta cell fuel sensing. Thus, deletion or silencing of one or more of these factors (e.g. Drp1, also known as Dnm1l) which controls mitochondrial fission) [47, 49] or the mitofusins Mfn1 and Mfn2 (which control fusion) [48] both exert profound effects on beta cell mass, insulin secretion and glucose homeostasis in mice. Similarly, deletion of the dynamin-related GTPase optic atrophy protein 1 (OPA1), responsible for fusion of the inner mitochondrial membrane, from beta cells, results in respiratory chain defects and impaired insulin secretion [50]. Of note, human syndromes such as multiple symmetrical lipomatosis (Madelung’s disease), caused by mutations in MFN2, appear chiefly to lower insulin sensitivity [51]. Therefore, ablation of both mitofusins may have a greater deleterious impact on beta cell function and survival rather than targeting and inactivating a single mitofusin gene. Interestingly, in studies from Shirihai and colleagues [52], promotion of a fragmented phenotype in cardiomyocyte-derived C2C12 cells resulted in a marked reduction in mitochondrial Ca2+ accumulation, hinting that similar changes may impair the uptake of these ions into mitochondria in beta cells, with consequences for glucose metabolism and insulin secretion. Nonetheless, the role and regulation of mitochondrial fission and fusion factors in the beta cell in diabetes mellitus remain to be fully elucidated.

A role for mitochondria in beta cell heterogeneity and intercellular connectivity?

As reviewed by Gutierrez et al. [53], data that first emerged in the 1980s indicated the existence within the islet of multiple beta cell subgroups with distinct metabolic properties. These early results were supported recently by a slew of new studies deploying single cell-omics, notably massive parallel RNA sequencing (RNA-seq) of islet cells from both mice and humans. This validation of the existence of intercellular heterogeneity has raised the possibility that distinct subgroups of beta cells may exert differing roles in the control of islet dynamics (note that the mechanisms though which individual islets are coordinated across the whole pancreas are not addressed here). Supporting this possibility, we have shown that intercellular connectivity is required in the islet for a full insulin secretory response to glucose and incretins [54]. The physical basis of the connections between cells that underlie this property are only partly understood; they include, but are not restricted to, the formation of Connexin 36- (Cx36/Gjd2) dependent gap junctions [55]. A subset of specialised beta cells, which are unusually highly connected (termed ‘hubs’ or ‘leaders’) [56] and are often the sites of initiation of Ca2+ waves, play a disproportionate role in the control of beta cell Ca2+ dynamics in the intact islet. Similar findings of functionally distinct (and potentially controlling) beta cell subpopulations have been described by others [57, 58]. Importantly, both glycolytic and mitochondrial metabolism appear to play exaggerated roles in hub/leader cells, as exemplified by RNA-seq analyses in the model zebrafish system (Fig. 3) [59]. Taken together, these data suggest that genetic variants or environmental insults (e.g. gluco/lipotoxicity or inflammation) may act through mitochondrial perturbations to impair beta cell network dynamics and hence insulin secretion (Fig. 4). Enhancing mitochondrial function in this critical subset of cells may thus provide a new therapeutic opportunity in some forms of diabetes.

Fig. 3

Single cell RNA-seq analysis of islets from the zebrafish (Danio rario) to identify putative hub/leader cells. Cluster analysis was performed based on the co-expression of high Gck, but low Ins1 levels in a subset corresponding to ~10% of all cells. (a) Heatmap showing the top 20 genes defining the putative hub cells. Hub and follower cells are defined as ‘1’ and ‘0’, respectively. (b) Statistically over-represented Gene Ontology (GO) Biological Process (BP) terms in genes upregulated in putative hub cells. FDR, false discovery rate. Adapted from [59] with permission from Springer Nature, ©2019. This figure is available as part of a downloadable slideset

Fig. 4

Beta cell network model depicting impairment of insulin secretion following external or genetic alterations to mitochondrial fusion protein expression. Leader (hub) beta cells (green) coordinate pulsatile insulin secretion and signal propagation across an islet through signalling routes such as the gap junction protein connexin 36. Diabetogenic insults or genetic deletion/lowered expression of proteins involved in the mitochondrial fusion process cause the mitochondrial network to rapidly fragment and no fusion occurs while these proteins are absent. This will also lead to progressive reduction in insulin secretion, loss of beta to beta cell interconnection, and development of type 2 diabetes, and may conceivably contribute to secretory insufficiency in type 1 diabetes [60] in some circumstances. For simplicity, non-beta cells are omitted from the islet diagram (left-hand panel). Red structures (no central nucleus) represent capillaries. This figure is available as part of a downloadable slideset

In summary, defective mitochondrial function is likely to have effects contributing to impaired insulin secretion in type 2 diabetes and, conceivably, in those cases of type 1 diabetes where detectable beta cell mass remains [60]. Importantly, altered mitochondrial function may affect both individual beta cells and the ensemble behaviour that coordinates pulsatile insulin secretion. Although not the subject of the present review, changes in mitochondrial function and structure may also modulate beta cell survival and, hence, mass in both disease settings, for example through the regulation of key pathways such as autophagy, apoptosis and cell senescence. Finally, altered mitochondrial metabolism and signal generation may play important roles in other islet endocrine (and critical non-endocrine) cells to influence the overall pancreatic output of endocrine hormones.


Δψm :

Mitochondrial membrane potential


Acyl-CoA thioesterase 7


Glucose-stimulated insulin secretion


ATP-sensitive K+ (channel)


Monocarboxylate transporter-1


Mitochondrial Ca2+ uniporter




Mitochondrial DNA


Oxidative phosphorylation


Paired box 6


Pyruvate dehydrogenase


Regulatory factor X6


RNA sequencing


  1. 1.

    Henquin JC, Dufrane D, Nenquin M (2006) Nutrient control of insulin secretion in isolated normal human islets. Diabetes 55(12):3470–3477.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Milner RD (1969) The secretion of insulin from foetal and postnatal rabbit pancreas in vitro in response to various substances. J Endocrinol 44(2):267–272.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A (2015) Pancreatic β-cell identity, glucose sensing and the control of insulin secretion. Biochem J 466:202–218

    Article  Google Scholar 

  4. 4.

    McCulloch LJ, van de Bunt M, Braun M, Frayn KN, Clark A, Gloyn AL (2011) GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus. Mol Genet Metab 104(4):648–653.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Rorsman P, Ashcroft FM (2018) Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiol Rev 98(1):117–214.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49(11):1751–1760.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Kibbey RG, Pongratz RL, Romanelli AJ, Wollheim CB, Cline GW, Shulman GI (2007) Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab 5(4):253–264.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Barbetti F, D’Annunzio G (2018) Genetic causes and treatment of neonatal diabetes and early childhood diabetes. Best Pract Res Clin Endocrinol Metab 32(4):575–591.

    Article  PubMed  Google Scholar 

  9. 9.

    Mahajan A, Taliun D, Thurner M et al (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet 50(11):1505–1513.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Mitchell RK, Mondragon A, Chen L et al (2014) Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass. Hum Mol Genet 24:1390–1399

    Article  Google Scholar 

  11. 11.

    Dwivedi OP, Lehtovirta M, Hastoy B et al (2019) Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet 51(11):1596–1606.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Thomsen SK, Raimondo A, Hastoy B et al (2018) Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells. Nat Genet 50(8):1122–1131.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Carrat GR, Hu M, Nguyen-Tu MS et al (2017) Decreased STARD10 expression is associated with defective insulin secretion in humans and mice. Am J Hum Genet 100(2):238–256.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Krentz NAJ, Gloyn AL (2020) Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol 16(4):202–212.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Sekine N, Cirulli V, Regazzi R et al (1994) Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic β-cell. Potential role in nutrient sensing. J Biol Chem 269(7):4895–4902

    CAS  PubMed  Google Scholar 

  16. 16.

    Schuit F, De Vos A, Farfari S et al (1997) Metabolic fate of glucose in purified islet cells. Glucose- regulated anaplerosis in beta cells. J Biol Chem 272(30):18572–18579.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Ishihara H, Wang H, Drewes LR, Wollheim CB (1999) Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. J Clin Invest 104:1621–1629

    CAS  Article  Google Scholar 

  18. 18.

    Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA (2012) Overexpression of monocarboxylate transporter-1 (Slc16a1) in the pancreatic β-cells leads to relative hyperinsulinism during exercise. Diabetes 61(7):1719–1725.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Otonkoski T, Jiao H, Kaminen-Ahola N et al (2007) Physical exercise-induced hyperinsulinemic hypoglycemia caused by failure of monocarboxylate transporter 1 silencing in pancreatic beta cells. Am J Hum Genet 81(3):467–474.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Martinez-Sanchez A, Pullen TJ, Chabosseau P et al (2016) Disallowance of Acot7 in β-cells is required for normal glucose tolerance and insulin secretion. Diabetes 65(5):1268–1282.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Pullen TJ, Huising MO, Rutter GA (2017) Analysis of purified pancreatic islet beta and alpha cell transcriptomes reveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a novel disallowed gene. Front Genet 8:41.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lemaire K, Thorrez L, Schuit F (2016) Disallowed and allowed gene expression: two faces of mature islet beta cells. Annu Rev Nutr 36(1):45–71.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Dhawan S, Tschen SI, Zeng C et al (2015) DNA methylation directs functional maturation of pancreatic beta cells. J Clin Invest 125(7):2851–2860.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    van Arensbergen J, Garcia-Hurtado J, Maestro MA et al (2013) Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells. Genes Dev 27(1):52–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Patel KA, Kettunen J, Laakso M et al (2017) Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nat Commun 8(1):888–00895.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Solimena M, Schulte AM, Marselli L et al (2018) Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. Diabetologia 61(3):641–657.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Piccand J, Strasser P, Hodson DJ et al (2014) Rfx6 maintains the functional identity of adult pancreatic β-cells. Cell Rep 9(6):2219–2232.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Mitchell RK, Nguyen-Tu MS, Chabosseau P et al (2017) The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis, and Ca2+ dynamics in adult mice. J Biol Chem 292(21):8892–8906.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Swisa A, Avrahami D, Eden N et al (2017) PAX6 maintains β cell identity by repressing genes of alternative islet cell types. J Clin Invest 127(1):230–243.

    Article  PubMed  Google Scholar 

  30. 30.

    Ebert MS, Sharp PA (2012) Roles for microRNAs in conferring robustness to biological processes. Cell 149(3):515–524.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Martinez-Sanchez A, Nguyen-Tu MS, Rutter GA (2015) DICER inactivation identifies pancreatic β-cell “disallowed” genes targeted by microRNAs. Mol Endocrinol 29(7):1067–1079.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Pullen TJ, da Silva Xavier G, Kelsey G, Rutter GA (2011) miR-29a and miR-29b contribute to pancreatic β-cell specific silencing of Monocarboxylate Transporter 1 (Mct1/slc16a1). Mol Cell Biol 31(15):3182–3194.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Tugay K, Guay C, Marques AC et al (2016) Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets. Diabetologia 59(1):161–169.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Supale S, Li N, Brun T, Maechler P (2012) Mitochondrial dysfunction in pancreatic β cells. Trends Endocrinol Metab 23(9):477–487.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Mulder H, Ling C (2009) Mitochondrial dysfunction in pancreatic beta-cells in type 2 diabetes. Mol Cell Endocrinol 297(1-2):34–40.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Haythorne E, Rohm M, van de Bunt M et al (2019) Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic beta-cells. Nat Commun 10(1):2474–10189.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    van den Ouweland JM, Lemkes HH, Ruitenbeek W et al (1992) Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1(5):368–371.

    Article  PubMed  Google Scholar 

  38. 38.

    Silva JP, Kohler M, Graff C et al (2000) Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat Genet 26(3):336–340.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Cnop M, Igoillo-Esteve M, Rai M et al (2012) Central role and mechanisms of β-cell dysfunction and death in friedreich ataxia-associated diabetes. Ann Neurol 72(6):971–982.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Igoillo-Esteve M, Oliveira AF, Cosentino C et al (2020) Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight 5:134221

    Article  Google Scholar 

  41. 41.

    Rutter GA, Theler J-M, Murta M, Wollheim CB, Pozzan T, Rizzuto R (1993) Stimulated Ca2+ influx raises mitochondrial free Ca2+ to supramicromolar levels in a pancreatic β-cell line: possible role in glucose and agonist-induced insulin secretion. J Biol Chem 268(30):22385–22390

    CAS  PubMed  Google Scholar 

  42. 42.

    Denton RM, McCormack JG (1980) On the role of the calcium transport cycle in the heart and other mammalian mitochondria. FEBS Lett 119(1):1–8.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Georgiadou E, Haythorne E, Dickerson MT et al (2020) The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice. Diabetologia 63(7):1368–1381.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Dlaskova A, Spacek T, Santorova J et al (2010) 4Pi microscopy reveals an impaired three-dimensional mitochondrial network of pancreatic islet beta-cells, an experimental model of type-2 diabetes. Biochim Biophys Acta 1797(6-7):1327–1341.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Anello M, Lupi R, Spampinato D et al (2005) Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48(2):282–289.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Masini M, Martino L, Marselli L et al (2017) Ultrastructural alterations of pancreatic beta cells in human diabetes mellitus. Diabetes Metab Res Rev 33:10

    Article  Google Scholar 

  47. 47.

    Hennings TG, Chopra DG, DeLeon ER et al (2018) In vivo deletion of β-cell Drp1 impairs insulin secretion without affecting islet oxygen consumption. Endocrinology 159(9):3245–3256.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Georgiadou E, Rodriguez TA, Muralidharan C, et al (2020) Pancreatic beta cell selective deletion of mitofusins 1 and 2 (Mfn1 and Mfn2) disrupts mitochondrial architecture and abrogates glucose-stimulated insulin secretion in vivo. BioRxiv

  49. 49.

    Reinhardt F, Schultz J, Waterstradt R, Baltrusch S (2016) Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells. Biochem Biophys Res Commun 474(4):646–651.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Zhang Z, Wakabayashi N, Wakabayashi J et al (2011) The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol Biol Cell 22(13):2235–2245.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Rocha N, Bulger DA, Frontini A et al (2017) Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. Elife 6:e23813.

  52. 52.

    Kowaltowski AJ, Menezes-Filho SL, Assali EA et al (2019) Mitochondrial morphology regulates organellar Ca2+ uptake and changes cellular Ca2+ homeostasis. FASEB J 33(12):13176–13188.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Gutierrez GD, Gromada J, Sussel L (2017) Heterogeneity of the pancreatic beta cell. Front Genet 8:22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hodson DJ, Mitchell RK, Bellomo EA et al (2013) Lipotoxicity disrupts incretin-regulated human β cell connectivity. J Clin Invest 123(10):4182–4194.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Head WS, Orseth ML, Nunemaker CS, Satin LS, Piston DW, Benninger RK (2012) Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61(7):1700–1707.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Johnston NR, Mitchell RK, Haythorne E et al (2016) Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab 24(3):389–401.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Stozer A, Gosak M, Dolensek J et al (2013) Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput Biol 9(2):e1002923.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Westacott MJ, Ludin NWF, Benninger RKP (2017) Spatially organized β-cell subpopulations control electrical dynamics across islets of Langerhans. Biophys J 113(5):1093–1108.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Salem V, Silva LS, Suba S et al (2019) Leader beta cells coordinate Ca2+ dynamics across pancreatic islets in vivo. Nat Metab 1(6):615–629.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Keenan HA, Sun JK, Levine J et al (2010) Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 59(11):2846–2853.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Marselli L, Thorne J, Dahiya S et al (2010) Gene expression profiles of beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS ONE 5(7):e11499.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Fadista J, Vikman P, Laakso EO et al (2014) Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci U S A 111(38):13924–13929.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Jacovetti C, Matkovich SJ, Rodriguez-Trejo A, Guay C, Regazzi R (2015) Postnatal beta-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning. Nat Commun 6(1):8084.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors’ relationships and activities

GAR has received funding from Sun Pharmaceuticals and Les Laboratories Servier. EG, AMS and TJP have no relationships or activities that might bias, or be perceived to bias, their work.


Work in GAR’s laboratory is supported by a Wellcome Trust Investigator Award (WT212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1, MR/R022259/1) and Experimental Challenge Grant (DIVA, MR/L02036X/1), MRC (MR/N00275X/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) grants. A.M-S. was supported by MRC New Investigator Research Grant (MR/P023223/1). GAR also receives funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY) to GAR.

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Correspondence to Guy A. Rutter.

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Rutter, G.A., Georgiadou, E., Martinez-Sanchez, A. et al. Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity. Diabetologia 63, 1990–1998 (2020).

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  • Beta cells
  • Disallowed genes
  • Insulin secretion
  • Interconnectivity
  • Mitochondria
  • Review
  • Type 2 diabetes