Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells

Spijker, H. Siebe; Ravelli, R.B.G.; Mommaas-Kienhuis, A.M.; Apeldoorn, Aart van; Engelse, Marten A.; Zaldumbide, Arnaud; Bonner-Weir, Susan; Rabelink, Ton J.; Hoeben, Rob C.; Clevers, Hans; Mummery, Christine L.; Carlotti, Françoise; Koning, Eelco J.P. de

doi:10.2337/db12-1001

Cited by 125 publications

(134 citation statements)

References 32 publications

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“…201 Notably, previous studies show that repression of MafB is required for maintenance of β-cell identity, because de-repression of MafB in the absence of the β-cell-specific transcription factor Pdx1 triggers a β-to-α-cell reprogramming 199 and thereby contributes to β-cell failure in T2DM. 172,202,203 In line with these evidences, the current data of the with normal lipoprotein levels did not affect glucose tolerance, presumably due to the low islet miR-155-5p expression level in these mice. 131 Thus, the effect of miR-155-5p…”

Section: Mafb Mediates the Effects Of Mir-155-5p In Isletssupporting

confidence: 83%

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

et al. 2017

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A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon-like peptide 1 (GLP-1)–mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic β-cells, which improved glucose metabolism and the adaptation of β-cells to obesity-induced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes β-cell function through IL-6–induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in β-cells by hyperlipidemia-associated endotoxemia improves the adaptation of β-cells to insulin resistance and represents a protective mechanism in the islet stress response.

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Section: Mafb Mediates the Effects Of Mir-155-5p In Isletssupporting

confidence: 83%

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

et al. 2017

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“…vitro results in increased numbers of glucagon-positive cells due to conversion of b-cells to a-cells (49). We surmise that signals causing a-cell dedifferentiation or conversion of b-cells to a-cells act together with IL-6 cytokines to stimulate GLP-1 secretion from a-cells.…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

et al. 2014

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Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of a-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary a-cells and stimulated glucagon secretion. Pancreatic a-cell gp130 knockout (agp130KO) mice showed no differences in glycemic control, a-cell function, or a-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, agp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved a-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of a-cell gp130 receptor signaling has deleterious effects on a-cell function, promoting hyperglycemia. Antagonism of a-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.Islet inflammation (1,2) and pancreatic a-cell dysfunction (3-6) contribute to hyperglycemia in patients with type 2 diabetes. Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).Pancreatic a-cell dysfunction is detectable in the early stages of type 2 diabetes, where the inverse relationship between pulsatile insulin and glucagon secretion is lost (19). This dysregulation is associated with relative hyperglucagonemia, which contributes to the development of fasting hyperglycemia associated with frank type 2 diabetes (6). Indeed, inhibition of glucagon action by various means reduces hyperglycemia in rodent models of this disease (5,6).

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“…Moreover, mouse b-cells that genetically lack FOXO1 can dedifferentiate in vivo under conditions of metabolic stress and subsequently can convert (or transdifferentiate) into glucagonproducing a-cells, accompanied by hyperglucagonemia (8). In our ex vivo culture system, lineage tracing showed that mature human b-cells can lose their identity and convert into a-cells following dispersion and reaggregation (10).…”

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confidence: 98%

Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

et al. 2015

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Loss of pancreatic islet b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulincontaining b-cells can convert into glucagon-containing a-cells ex vivo. This loss of b-cell identity was characterized by the presence of b-cell transcription factors (Nkx6.1, Pdx1) in glucagon + cells. Here, we investigated whether the loss of b-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin + cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1 + but insulin 2 coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1 + glucagon + insulin 2 cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1 + glucagon + insulin 2 cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of b-cell identity occurs in T2DM and could contribute to the decrease of functional b-cell mass. Maintenance of b-cell identity is a potential novel strategy to preserve b-cell function in diabetes.Loss of pancreatic b-cell mass and b-cell dysfunction are central in the development of type 2 diabetes (T2DM) and, in combination with peripheral insulin resistance, lead to hyperglycemia (1). Whereas b-cells, on the one hand, fail to properly secrete insulin at a given glucose level, there is also a progressive decline in the number of b-cells (2,3). Loss of b-cell mass has been ascribed to increased apoptosis in T2DM (4). In patients with T2DM, b-cell mass can be up to 40-60% lower than in healthy control subjects (4-6). In addition, abnormal function of glucagon-producing a-cells leading to hyperglucagonemia is associated with T2DM (7). b-cell dedifferentiation and subsequent transition to other islet cell types were suggested as an alternative explanation for the loss of functional b-cell mass in mice (8,9). In this concept, b-cells lose insulin content and insulin secretory capacity followed by the production of other endocrine hormones such as glucagon (8). We recently showed (10) that loss of b-cell identity with the conversion of b-cells into glucagon-containing a-cells can occur in human pancreatic islets ex vivo.A number of transcription factors have been identified to be essential for the development and maintenance of functional b-cells (11,12). Recent reports (13,14) indicate that a selective loss of transcription factors MafA, Nkx6.1, and Pdx1 is associated with b-cell dysfunction and T2DM. Chronic hyperglycemia in rats is accompanied by the loss of b-cell transcription factors (15). Moreover, mouse b-cells that genetically lack FOXO1 can dedifferentiate in vivo under conditions of metabolic stress and subsequently can convert (or transdifferentiate) into glucagonproducing a-cells...

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Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells

Cited by 125 publications

References 32 publications

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

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