In This Issue of Diabetes
By Max Bingham, PhD
GLP-1 Can Help Transform α-Cells Into β-Cells: Mice Studies and Mechanisms
β-Cells can be generated out of α-cells, and the key ingredient is glucagon-like peptide 1 (GLP-1), according to Lee et al. (p. 2601). More specifically, it seems that GLP-1 can induce fibroblast growth factor 21 (FGF21), which in turn results in the stimulation of various transcription factors and the transdifferentiation of α-cells to β-cells. Besides identifying a role for GLP-1 and the potential mechanisms involved, the study seems to underline that regeneration of β-cells is technically feasible (at least in mice), which means potential insulin recovery in diabetes. The study focuses mainly on mice designated RIP-CreER;R26-YFP and Glucagon-rtTA;Tet-O-Cre;R26-YFP. After ablation of pancreatic β-cells using streptozotocin, the mice were treated with recombinant adenovirus expressing GLP-1 (rAd-GLP-1) to identify newly generated β-cells. Using the RIP-CreER;R26-YFP mice, they found that new β-cells were generated more from non–β-cells and that α-cells increased in islets after treatment. They also found that αTC1 clone 9 (αTC1-9) cells also proliferated when treated with exendin-4. Using the Glucagon-rtTA;Tet-O-Cre;R26-YFP mice, they go on to show that a high proportion of β-cells originated from α-cells when treated with rAd-GLP-1. Turning to mechanisms, the authors detail a series of steps involving GLP-1 and FGF21 that result in increased levels of cells expressing both insulin and glucagon. Conversely, transfection with small interfering RNA and knockout of FGF21 in mice resulted in significantly lower expression of both glucagon and insulin—clear signs, they say, that α-cells can differentiate into β-cells when the conditions are right. Author Hee-Sook Jun told Diabetes: “Our mouse studies provide evidence that GLP-1 can enhance the conversion of α-cells to β-cells, implicating the possibility of intra-islet conversion by GLP-1 for regenerative goals, although the relevance of these findings to humans remains to be investigated. The strategy or drugs that can induce and maintain α- to β-cell conversion may be beneficial for β-cell regeneration therapy for glycemic control.”
Proliferation of α-cells is increased in rAd-GLP-1–treated mice and exendin-4–treated αTC1-9 cells. Streptozotocin-induced diabetic RIP-CreER;R26-YFP mice were treated with recombinant adenovirus expressing β-galactosidase (rAd-βgal) or rAd-GLP-1, and pancreatic sections were prepared and triple-stained with anti-glucagon (Gcg), anti-insulin (Ins), and anti-BrdU antibodies.
Insm1 Regulates β-Cell Mass With Implications for Diabetes Risk
Insm1 appears to regulate postnatal baseline β-cell mass expansion, according to Tao et al. (p. 2615). Indeed, insufficiency of Insm1 appears to result in decreased β-cell mass and impaired glucose tolerance. As a result, the authors suggest that decreased Insm1 expression is a potential risk factor for diabetes. They also explore mechanisms behind the effects suggesting that decreased Insm1 prolongs cell cycling partly through targeting the cyclin D1 gene (Ccnd1). The conclusions come from a series of experiments in mice where one allele of Insm1 was ablated to model the effects of having insufficient Insm1. β-Cell mass was then determined via immunofluorescence at various points up to 13 months. Additional experiments used mice with an obesity background and mice fed a high-fat diet. They found that mice with the ablation had decreased baseline β-cell mass and impaired glucose tolerance and that the high-fat diet or obesity background made glucose tolerance worse in comparison to controls. In addition, they also found that the effects of Insm1 on β-cell mass regulation only appeared in the postnatal period (newborn to 2 months old). Pancreatic islets from mice with the ablation and a β-cell line with Insm1 knockdown showed that cell cycling was prolonged in β-cells, and this was due to downregulation of the cell cycle gene Ccnd1. Downregulation of Insm1 expression decreased binding of Insm1 to Ccnd1, whereas downregulation of Ccnd1 resulted in increased cell cycling time and overexpression reduced cell cycle abnormalities in β-cells deficient of Insm1. Author Shiqi Jia commented: “The baseline β-cell mass established at postnatal period should be an additional factor for counting diabetes risks. Deficits that influence the β-cell growth at early postnatal period could affect the correct baseline β-cell mass establishment and the development of diabetes in adulthood.”
Legend: Immunostaining of insulin, Ki67, and BrdU in the pancreas of wild-type and Insm1+/lacZ mice at postnatal day 14. Red arrows indicate BrdU+Ki67- β-cells.
Genetic Determinants of Glycemia in Pregnancy
Genetic variants known to be associated with various measures of glycemia in the general population also influence glycemic traits in pregnancy. Specifically, according to Powe et al. (p. 2703), genetic variants that associate with fasting glucose, insulin secretion, and insulin sensitivity describe glycemia in pregnancy and gestational diabetes mellitus risk. The study suggests that genetic traits and their influence on glycemia in pregnancy are shared with glycemic effects seen outside of pregnancy, despite the fact that pregnancy results in profound physiologic changes in relation to glycemia. Clinically speaking, that means genetic traits that are currently being considered for the prevention and treatment of type 2 diabetes might also apply to hyperglycemia in pregnancy. The analysis is based on two cohorts of women, Genetics of Glucose regulation in Gestation and Growth (Gen3G) and Hyperglycemia and Adverse Pregnancy Outcome (HAPO), who underwent oral glucose tolerance tests at 24–32 weeks of gestation and genotyping from which various genetic risk scores (GRSs) were constructed by the authors. These were based on 150 genetic variants known to be associated with glycemic traits or type 2 diabetes in the general population. The authors go on to describe a series of associations between genetic and glycemic traits seen in the general population that also appear to hold true during pregnancy and gestational diabetes mellitus. In particular, they highlight a strong association between fasting glucose GRS and fasting glucose and insulin secretion and sensitivity GRSs with the same traits in the Gen3G cohort (insulin measurements were not available in the HAPO cohort). Type 2 diabetes, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity GRSs also associated with gestational diabetes mellitus risk. Author Camille E. Powe said: “Our work demonstrates that each of the major physiologic mechanisms that lead to hyperglycemia outside of pregnancy also contribute to gestational diabetes mellitus, including defects in both insulin secretion and insulin sensitivity. Future work will test whether we can use maternal genetics to understand heterogeneity in gestational diabetes mellitus and develop novel precision approaches to this disease.”
Induced Hyperglycemia Results in Sustained Negative Effects on Glucose Metabolism
Three days of experimental but mild hyperglycemia in healthy adults results in multiple effects on glucose metabolism, according to Shannon et al. (p. 2507). Notably, the effects of hyperglycemia did not differ that much between individuals with or without family history of type 2 diabetes, which means glucotoxicity per se seems to increase insulin resistance and hence the risk of type 2 diabetes in the future. The study examined 25 individuals with normal glucose tolerance and their reaction to 3 days of mild hyperglycemia (plasma glucose was raised to ∼45 mg/dL). Ten individuals had a family history of type 2 diabetes, whereas another 15 did not. Five individuals from the group without family history served as control subjects, receiving saline rather than glucose in the clamp procedures used in the experiments. They found that family history of type 2 diabetes largely made no difference in the effects of raised blood glucose levels, with evidence emerging in both groups that 3 days of hyperglycemia produces marked insulin resistance in various pathways involved in glucose disposal. Author Ralph A. DeFronzo said: “It appears that a genetic predisposition to develop type 2 diabetes, as incurred with a positive family history of the disease, does not influence susceptibility to the detrimental effects of hyperglycemia-induced glucotoxicity in individuals with normal glucose tolerance. As in patients with type 2 diabetes, the development of insulin resistance with glucotoxicity was characterized by impairment of skeletal muscle glycogen synthase and a reduced capacity for nonoxidative glucose disposal. The magnitude of these effects, and the fact that they occurred over a relatively short time, highlights the importance of using insulin-sensitizing agents early in the pathogenesis of type 2 diabetes. These findings demonstrate that hyperglycemia is a self-sustaining causative factor for insulin resistance in patients with type 2 diabetes and emphasizes the importance of good glycemic control.”
- © 2018 by the American Diabetes Association.
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