In This Issue of Diabetes

According to Lam et al. (p. 674), a novel population of highly proliferative hormone-negative islet cells may exist in human pancreata, and there is a hint that they might play an essential role in islet function and growth. Using a large collection of nondiabetic and type 1 diabetes human pancreas samples, the authors initially focused on the protein Ki67 as a marker of cell proliferation and reportedly found populations of proliferative islet cells. However, the population showed no signs of expressing insulin or that they were lymphocytes or endothelial cells. The question then was what were they. The authors report that pancreatic polypeptide, somatostatin, and ghrelin cells showed no real sign of proliferation. In contrast, glucagon-expressing α-cells were proliferative but only comprised about one-third of the total population of proliferative islet cells. The majority of the population was reportedly negative for any hormone expression. The focus then moved to the possibility that the proliferative cells might express markers of islet endocrine progenitors. After excluding one key progenitor (Ngn3), they found that most of the hormone-negative proliferative cells uniformly contained immunoreactivity for Sox9 (typically present in islet progenitors) and ARX (an α-cell marker). There were also various markers of islet endocrine cells and of various potential cellular functions. Author Jake A. Kushner told Diabetes: “Given previous work that reveals an age-dependent decline in β-cell proliferation, we were genuinely shocked to find these high-proliferative islet endocrine cells in adult pancreata. But, what does the presence of these cells mean? Honestly, we don’t know. The most obvious implication is that islets might retain some degree of plasticity into adulthood. These highly proliferative islet endocrine cells may play an unknown role in islet growth and/or regeneration. We’re eager to see where this research leads and hopeful that our findings could someday translate to help patients with diabetes.”

Lam et al. Highly proliferative α-cell-related islet endocrine cells in human pancreata. Diabetes 2018;67:674–686

A gain- and loss-of-function study in mice suggests that a specific portion of the mammalian genome that is supposedly noncoding may in fact be involved in regulating hepatic glucose and lipid metabolism. According to Wang et al. (p. 581), activating the long noncoding RNA suppressor of hepatic gluconeogenesis and lipogenesis/heterogeneous nuclear ribonucleoprotein A1 (lncSHGL/hnRNPAI) axis that they say they have identified might represent a potential strategy for the treatment of type 2 diabetes and also nonalcoholic fatty liver (steatosis). Using a series of experiments in mice with obesity and/or diabetes or neither and also human liver samples, the authors systematically explored the role of the specific region lncSHGL. They report that expression levels of lncSHGL in obese mice were reduced, which was equally true with the homologous human version called B4GALT1-AS1. Then, using a gain- and loss-of-function approach, they say that restoration of lncSHGL in obese diabetic mice improved hyperglycemia, insulin resistance, and steatosis. In contrast, normal mice that had lncSHGL inhibited had enhanced hyperglycemia and lipid deposition. They go on to demonstrate that overexpression of lncSHGL in the livers of obese mice resulted in increased Akt phosphorylation and reduced gluconeogenic and lipogenic gene expression. In contrast, inhibition of lncSHGL in normal mouse livers resulted in the opposite effect. Investigating potential mechanisms, they suggest that lncSHGL recruits hnRNPAI to enhance calmodulin mRNA translation. This results in an increase in the protein level of calmodulin, which then suppresses gluconeogenic and lipogenic pathways. Author Jichun Yang said: “The lncSHGL/hnRNPAI axis activates the Akt pathway to suppress hepatic gluconeogenesis. Importantly, it also represses the mTOR-SREBP1C pathway to inhibit hepatic lipid synthesis. Moreover, hepatic restoration of lncSHGL/hnRNPAI axis also prevents the lipid transfer from adipose to liver by improving global insulin resistance. Collectively, activating the hepatic lncSHGL pathway is a potential strategy for treating hyperglycemia and steatosis, particularly under severe insulin-resistant status.”

Wang et al. Long noncoding RNA lncSHGL recruits hnRNPAI to suppress hepatic gluconeogenesis and lipogenesis. Diabetes 2018;67:581–593

A series of mechanistic studies by Pan et al. (p. 717) reveal that the gene that encodes SLIT-ROBO ρGTPase-activating protein 2a (SRGAP2a) may act as “hub” gene in renal podocytes that controls proteinuria and estimated glomerular filtration rates in patients with diabetic nephropathy. As a result, the authors suggest that podocyte SRGAP2a might be a potential therapeutic target to modify proteinuria in diabetic nephropathy. They focused on podocytes from humans, mice, and zebrafish, initially identifying SRGAP2a as a significant gene that was likely involved in alterations in proteinuria and estimated glomerular filtration rates in samples from patients with diabetic nephropathy and db/db mice. Then, they used immunofluorescence staining and Western blot analysis to reveal that SRGAP2a is likely primarily located in podocytes. The question naturally followed whether they could up- or downregulate the gene to prove its involvement. They report that SRGAP2a is downregulated in patients with diabetic nephropathy and in db/db mice, at both the mRNA and protein level. Moving onto cell cultures, they report that SRGAP2a activity in cultured podocytes is reduced in the presence of tumor growth factor-β or high-glucose concentrations (i.e., mimicking hyperglycemia). They showed, with various mechanistic and functional experiments, that SRGAP2a suppresses the motility of podocytes through the inactivation of various other genes. After confirming the results with a recapitulation of the findings in zebrafish, they showed it was possible to mitigate podocyte injury and proteinuria in db/db mice by increasing SRGAP2a levels via an adenovirus-based method. Author Zhihong Liu commented: “SRGAP2a was initially identified in neuronal cell in which it plays a critical role in regulating synapse formation. The protective role of SRGAP2a against diabetic nephropathy development is mainly through inactivating small GTPases of Rho family and suppressing podocyte migration.”

Pan et al. Dissection of glomerular transcriptional profile in patients with diabetic nephropathy: SRGAP2a protects podocyte structure and function. Diabetes 2018;67:717–730

Disruption of endoplasmic reticulum/mitochondria coupling is likely to be closely associated with impaired muscle insulin resistance in mice and humans according to Tubbs et al. (p. 636). The authors also reveal that reinforcing mitochondria-associated endoplasmic reticulum membranes (MAMs) increases the action of insulin, at least in human myotubes. As a result, they suggest that somehow targeting MAMs could be a strategy to improve insulin sensitivity to restore glucose homeostasis in type 2 diabetes. In a series of experiments involving cells, mice, and humans, they systematically investigated the integrity of MAMs in skeletal muscle and its role in insulin sensitivity. Reportedly, there was a marked disruption in endoplasmic reticulum-mitochondria interactions in skeletal muscle of mice models of obesity and type 2 diabetes, which they say is likely to be an early event prior to insulin resistance. Then, using human myotubes, they found that induced insulin resistance resulted in reduced interactions between mitochondria and endoplasmic reticulum. In contrast, by experimentally increasing contact between mitochondria and endoplasmic reticulum in the myotubes, they could prevent induced alterations in insulin signaling/action. Furthermore, the experimental disruption of MAMs was reportedly sufficient to alter muscle insulin signaling both in vitro and in vivo. They also found an association between altered insulin signaling and interactions between endoplasmic reticulum and mitochondria in obese humans with and without diabetes compared with healthy lean control subjects. Author Jennifer Rieusset said: “Our findings support the role of endoplasmic reticulum-mitochondria contact sites in the control of insulin signaling in another insulin-sensitive tissue, the skeletal muscle, and point toward endoplasmic reticulum-mitochondria miscommunication as a hallmark of muscle insulin resistance in mice and humans. Now, the next challenge is to determine whether MAMs could be a new therapeutic target for metabolic diseases. For that, we need to elucidate the processes of physiological regulation of these interactions in order to develop pharmacological tools capable of stimulating or inhibiting endoplasmic reticulum-mitochondria communication.”

Tubbs et al. Disruption of mitochondria-associated endoplasmic reticulum membrane (MAM) integrity contributes to muscle insulin resistance in mice and humans. Diabetes 2018;67:636–650