In the current issue of Acta Physiologica, Nielsen and co‐workers publish a paper entitled "Regulation of integrin alpha6 by lactogenic hormones in rat pancreatic beta‐cells: Implications for the physiological adaptation to pregnancy" in which the authors describe a novel pathway for increased beta‐cell replication in response to lactogenic hormones like prolactin and growth hormone, both key players in the enlargement of pancreatic beta‐cell mass during pregnancy.1 This pathway involves selective upregulation of the integrin subunit alpha6 and was also observed during pregnancy in vivo. Furthermore, the authors show that this process involves synergistic activation of STAT5 signalling by both laminin‐integrin interaction and hormonal stimulation. Integrins are transmembrane receptors composed of one alpha and one beta subunit, and are instrumental for cellular adhesion and interaction with the extracellular matrix (ECM).2 The beta‐subunit is involved in mediating intracellular signalling and specifically the beta1 subunit has been shown to activate a variety of protein kinases like focal adhesion kinase (FAK), extracellular‐regulated kinase (ERK) and protein kinase B (AKT), all involved in growth and cell survival. In the current study the authors confirm the high level expression of integrin beta1 in pancreatic islets, and demonstrate by immunohistochemical staining that the majority of integrin alpha6beta1 is localized in the beta‐cell core of the islets. Interestingly, alpha6beta1 represents an integrin receptor that specifically binds to laminins, complex heterotrimeric glycoproteins of the basal membrane that have been shown to promote beta‐cell proliferation and prolong beta‐cell survival.3 Thus, the paper by Nielsen and co‐workers highlights a new axis between lactogenic hormones and the integrin‐ECM interaction that is required for adaptational regulation of pancreatic beta‐cell mass, a process playing a key role during pregnancy. The current study was performed in rats and substantial differences exist between rodents and humans regarding the interaction between pancreatic beta‐cells and the ECM. Whereas in rodents the increase in beta‐cell mass in the maternal pancreas is due to beta‐cell replication,4 neogenesis of beta‐cells from progenitor cells is of major importance in humans. However, this process may also be dependent on ECM interactions and, as discussed by the authors, the formation of an ECM network may be crucial for beta‐cell generation and expansion throughout life. In this context, the authors put forward the intriguing hypothesis that expression of integrin alpha6beta1 is a prerequisite for postnatal replication competence of the beta‐cells. This hypothesis merits additional investigations in the future.

Malfunction of beta‐cell formation due to an increasing demand on insulin secretion, as observed during pregnancy, leads to hyperglycaemia, a setting termed "gestational diabetes mellitus (GDM)." As recommended by the WHO, the term GDM should only be used when hyperglycaemia is first detected during pregnancy. GDM can be considered as the most common medical complication of pregnancy, affecting up to 10% of pregnancies depending on the population study, generating both maternal and neonatal adverse outcomes. The latter is related to excessive foetal growth, but the long‐term risk of developing type 2 diabetes and cardiovascular disease in women is of specific concern. In addition, GDM is known to confer an additional risk for diabetes and obesity in the offspring.5 It is well known that a progressive state of insulin resistance develops during normal pregnancy, which becomes most prominent during the third trimester. This insulin resistance is related to a number of factors including increased levels of oestrogen, progesterone and cortisol. Furthermore, cytokines and hormones released from the placenta contribute to this process. In addition, maternal obesity, lack of exercise and a higher caloric intake augment the loss of insulin sensitivity and the state of glucose intolerance. The increasing demand on the maternal pancreas for secreting higher amounts of insulin can only be compensated by an increase in the maternal beta‐cell mass. The study by Nielsen and co‐workers shows a biphasic increase of integrin alpha6 expression during pregnancy, with a high expression in late pregnancy when proliferation has declined. The authors therefore conclude that this integrin does not per se stimulate proliferation of beta‐cells. It is suggested, that this adhesion molecule may play a permissive role in the function of the prolactin receptor in the adaptation of pancreatic beta‐cells to pregnancy. The functional significance of the laminin‐integrin alpha6beta1 interaction is demonstrated by disruption of this process through application of a disintegrin peptide. Mechanistically, integrin‐mediated regulation of beta‐cell growth needs future investigations. As suggested previously, one possibility is the role of integrins as scaffolds building up efficient growth factor signalilng complexes.6 In addition, integrins do have signalling capacity despite the lack of enzymatic activity. One example is FAK, a tyrosine kinase interacting with signalling molecules like Grb2 resulting in the activation of mitogen‐activated protein kinase (MAPK). Another candidate is the integrin‐linked kinase (ILK), which is activated by integrin beta1 ‐2, and ‐3. The final target of ILK is AKT, which is well known to be of key importance for beta‐cell replication and function.

Beyond GDM, pancreatic beta‐cell replacement is another topic where adhesion of the beta‐cell to elements of the basal membrane is of key importance. Beta‐cell replacement by islet transplantation has experienced substantial progress in recent years. This includes novel transplant sites and encapsulation approaches to protect the islets. In this context, the ECM plays an important role to mediate long‐term graft survival and function. Using a decellularization approach and quantitative mass spectometry, the human pancreatic ECM has recently been characterized.7 In that study, 120 ECM‐associated proteins were identified including 7 laminin proteins. Removal of this highly complex environment, as is the case in highly purified islets, leads to an integrin‐mediated form of apoptosis named anoikis (meaning "without a home"). Very recently, a pharmacological approach to pancreatic‐beta cell replacement has been reported based on the transdifferentiation of pancreatic‐alpha to ‐beta cells induced by GABergic signaling.8 This plasticity is remarkable, however, controversial data have been reported and it is presently unclear if this process may be of relevance in humans. Intriguingly, it is known that ECM proteins like laminin and fibronectin are involved in transdifferentiation processes, but the role of the pancreatic ECM in this process remains underexplored and should be addressed in future studies.

In conclusion, the paper by Nielsen and co‐workers sheds new light on the physiological mechanisms of pregnancy‐related adaptation of the pancreas and underpins the prominent role of interaction between the ECM and the pancreatic beta‐cell for survival and functional competence.

Nielsen及其同事在本期《生理学报》上发表了一篇题为“大鼠胰岛β细胞中乳激素对整联蛋白α6的调节：对生理适应妊娠的影响”的论文，作者描述了增加妊娠的新途径β细胞复制是对泌乳激素（如催乳激素和生长激素）的响应，这两个因素都是怀孕期间胰腺β细胞质量增加的关键因素。1该途径涉及整联蛋白亚基α6的选择性上调，并且在体内妊娠期间也观察到。此外，作者表明，该过程涉及层粘连蛋白-整合素相互作用和激素刺激对STAT5信号的协同激活。整联蛋白是由一个α和一个β亚基组成的跨膜受体，并且对于细胞粘附和与细胞外基质（ECM）的相互作用是重要的。2β亚基参与介导细胞内信号传导，特别是β1亚基已显示出激活多种蛋白激酶，如粘着斑激酶（FAK），细胞外调节激酶（ERK）和蛋白激酶B（AKT），均参与在生长和细胞存活中。在本研究中，作者确认了胰岛中整合素beta1的高水平表达，并通过免疫组织化学染色证明了大部分整合素alpha6beta1位于胰岛的β细胞核心。有趣的是，alpha6beta1代表一种整联蛋白受体，它与层粘连蛋白，基底膜的复杂异源三聚体糖蛋白特异性结合，已被证明能促进β细胞增殖并延长β细胞存活。3因此，尼尔森（Nielsen）及其同事的论文强调了促泌激素与整合素-ECM相互作用之间的新轴，这是胰腺β细胞量适应性调节所必需的，这一过程在怀孕期间起着关键作用。当前的研究是在大鼠中进行的，啮齿动物和人类之间在胰腺β细胞与ECM之间的相互作用方面存在实质性差异。而在啮齿动物中，母体胰腺中β细胞质量的增加是由于β细胞复制引起的，4祖细胞中β细胞的新生对人类至关重要。然而，这一过程也可能取决于ECM的相互作用，正如作者所讨论的那样，ECM网络的形成对于整个生命中β细胞的产生和扩展可能至关重要。在这种情况下，作者提出了一个有趣的假设，即整联蛋白alpha6beta1的表达是β细胞出生后复制能力的前提。该假设值得在将来进行其他研究。

如在怀孕期间所观察到的，由于对胰岛素分泌的需求增加而导致的β细胞形成功能异常会导致高血糖症，即所谓的“妊娠糖尿病（GDM）”。根据WHO的建议，术语GDM仅在怀孕期间首次发现高血糖时使用。GDM可被认为是最常见的妊娠医学并发症，根据人群研究的不同，其影响高达10％的怀孕，并产生母体和新生儿不良后果。后者与胎儿过度生长有关，但是女性罹患2型糖尿病和心血管疾病的长期风险尤其值得关注。另外，已知GDM给后代带来糖尿病和肥胖症的额外风险。5众所周知，正常妊娠期间胰岛素抵抗逐渐发展，在孕晚期尤为明显。这种胰岛素抵抗与许多因素有关，包括雌激素，孕酮和皮质醇水平升高。此外，从胎盘释放的细胞因子和激素也有助于该过程。此外，孕妇肥胖，缺乏运动和较高的热量摄入会增加胰岛素敏感性的丧失和葡萄糖不耐症的状态。对孕产妇胰腺分泌更多胰岛素的需求增加只能通过增加孕产妇β细胞质量来弥补。Nielsen及其同事的研究表明，怀孕期间整联蛋白alpha6表达呈双相增加，在妊娠晚期扩散减少的时候表现出高表达。因此，作者得出结论，这种整联蛋白本身并不刺激β细胞的增殖。有人认为，这种粘附分子可能在催乳素受体在胰腺β细胞适应妊娠的功能中发挥了重要作用。层粘连蛋白-整合素α6β1相互作用的功能重要性通过应用整合素肽破坏了这一过程得到了证明。从机理上讲，整合素介导的β细胞生长调控需要进一步研究。如前所述，一种可能性是整联蛋白作为构建有效生长因子信号复合物的支架的作用。因此，作者得出结论，这种整联蛋白本身并不刺激β细胞的增殖。有人认为，这种粘附分子可能在催乳素受体在胰腺β细胞适应妊娠的功能中发挥了重要作用。层粘连蛋白-整合素α6β1相互作用的功能重要性通过应用整合素肽破坏了这一过程得到了证明。从机理上讲，整合素介导的β细胞生长调控需要进一步研究。如前所述，一种可能性是整联蛋白作为构建有效生长因子信号复合物的支架的作用。因此，作者得出结论，这种整联蛋白本身并不刺激β细胞的增殖。有人认为，这种粘附分子可能在催乳素受体在胰腺β细胞适应妊娠的功能中发挥了重要作用。层粘连蛋白-整合素α6β1相互作用的功能重要性通过应用整合素肽破坏了这一过程得到了证明。从机制上讲，整合素介导的β细胞生长调控需要进一步研究。如前所述，一种可能性是整联蛋白作为构建有效生长因子信号复合物的支架的作用。层粘连蛋白-整合素α6β1相互作用的功能重要性通过应用整合素肽破坏了这一过程得到了证明。从机理上讲，整合素介导的β细胞生长调控需要进一步研究。如前所述，一种可能性是整联蛋白作为构建有效生长因子信号复合物的支架的作用。层粘连蛋白-整合素α6β1相互作用的功能重要性通过应用整合素肽破坏了这一过程得到了证明。从机理上讲，整合素介导的β细胞生长调控需要进一步研究。如前所述，一种可能性是整联蛋白作为构建有效生长因子信号复合物的支架的作用。6此外，尽管缺乏酶促活性，整联蛋白的确具有信号传导能力。一个例子是FAK，一种酪氨酸激酶，与信号分子如Grb2相互作用，导致丝裂原激活的蛋白激酶（MAPK）激活。另一个候选者是整合素连接的激酶（ILK），其被整合素beta1-2和-3激活。ILK的最终靶标是AKT，众所周知它对β细胞的复制和功能至关重要。

除GDM之外，胰腺β细胞替代是另一个主题，其中β细胞与基底膜元素的粘附至关重要。近年来，胰岛移植替代了β细胞。这包括新颖的移植位点和封装方法来保护胰岛。在这种情况下，ECM在介导移植物的长期存活和功能中起着重要作用。使用脱细胞方法和定量质谱法，最近已经表征了人胰腺ECM。7在该研究中，鉴定出120种与ECM相关的蛋白，包括7种层粘连蛋白。去除这种高度复杂的环境（就像高度纯化的胰岛一样），会导致整合素介导的凋亡形式，称为anoikis（意为“无家可归”）。最近，已经报道了一种基于GABergic信号转导的胰腺α向β细胞转分化的药理学方法，用于胰腺β细胞的替代。8这种可塑性非常显着，但是，据报道有争议的数据，目前尚不清楚该过程是否与人类有关。有趣的是，众所周知，层粘连蛋白和纤连蛋白等ECM蛋白参与转分化过程，但胰腺ECM在此过程中的作用仍未得到充分研究，应在以后的研究中加以探讨。

总之，尼尔森及其同事的论文为胰腺妊娠适应性适应的生理机制提供了新的思路，并强调了ECM和胰腺β细胞之间相互作用对生存和功能能力的突出作用。