Transplantation of PC1/3-Expressing α-cells Improves Glucose Handling and Cold Tolerance in Leptin-resistant Mice

Type 2 diabetes (T2D) is characterized by elevated blood glucose levels owing to insufficient secretion and/or activity of the glucose-lowering hormone insulin. Glucagon-like peptide-1 (GLP-1) has received much attention as a new treatment for diabetes because of its multiple blood glucose–lowering effects, including glucose-dependent enhancement of insulin secretion, inhibition of gastric emptying, and promotion of the survival and growth of insulin-producing β-cells. GLP-1, along with GLP-2 and oxyntomodulin, is produced in the intestinal L-cell via processing of proglucagon by prohormone convertase 1/3 (PC1/3), while in the pancreatic α-cell, coexpression of proglucagon and the alternate enzyme PC2 typically results in differential processing of proglucagon to yield glucagon. We used alginate-encapsulated α-cells as a model to evaluate continuous delivery of PC1/3- or PC2-derived proglucagon products. In high fat–fed and db/db mice, PC1/3-, but not PC2-expressing α-cells improved glucose handling and transiently lowered fasting glucose levels, suggesting that continuous delivery of PC1/3-derived proglucagon products via cell therapy may be useful for diabetes treatment. In addition, we show that long-term treatment with PC1/3-expressing, but not PC2-expressing, α-cells improved cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more PC1/3-derived α-cell products. Type 2 diabetes (T2D) is characterized by elevated blood glucose levels owing to insufficient secretion and/or activity of the glucose-lowering hormone insulin. Glucagon-like peptide-1 (GLP-1) has received much attention as a new treatment for diabetes because of its multiple blood glucose–lowering effects, including glucose-dependent enhancement of insulin secretion, inhibition of gastric emptying, and promotion of the survival and growth of insulin-producing β-cells. GLP-1, along with GLP-2 and oxyntomodulin, is produced in the intestinal L-cell via processing of proglucagon by prohormone convertase 1/3 (PC1/3), while in the pancreatic α-cell, coexpression of proglucagon and the alternate enzyme PC2 typically results in differential processing of proglucagon to yield glucagon. We used alginate-encapsulated α-cells as a model to evaluate continuous delivery of PC1/3- or PC2-derived proglucagon products. In high fat–fed and db/db mice, PC1/3-, but not PC2-expressing α-cells improved glucose handling and transiently lowered fasting glucose levels, suggesting that continuous delivery of PC1/3-derived proglucagon products via cell therapy may be useful for diabetes treatment. In addition, we show that long-term treatment with PC1/3-expressing, but not PC2-expressing, α-cells improved cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more PC1/3-derived α-cell products. IntroductionProglucagon, which is expressed in pancreatic α-cells, intestinal L-cells, and in specific neurons in the central nervous system, is differentially processed to yield numerous peptides belonging to the glucagon superfamily of hormones.1Kieffer TJ Habener JF The glucagon-like peptides.Endocr Rev. 1999; 20: 876-913Crossref PubMed Scopus (886) Google Scholar Although members of this superfamily share significant peptide sequence homology, they have diverse and sometimes opposing regulatory functions. In the pancreatic α-cells, prohormone convertase (PC2) is the predominant processing enzyme, with the result that the major bioactive proglucagon-derived peptide (PGDP) arising in these cells is glucagon,2Furuta M Zhou A Webb G Carroll R Ravazzola M Orci L et al.Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice.J Biol Chem. 2001; 276: 27197-27202Crossref PubMed Scopus (131) Google Scholar,3Rouille Y Bianchi M Irminger JC Halban PA Role of the prohormone convertase PC2 in the processing of proglucagon to glucagon.FEBS Lett. 1997; 413: 119-123Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar a glucose-raising hormone opposing insulin action. While glucagon activity is crucial for preventing hypoglycemia under normal conditions, hyperglucagonemia accompanies and may exacerbate type 2 diabetes (T2D).4Unger RH Letter: glucagon in pathogenesis of diabetes.Lancet. 1975; 1: 1036-1042Abstract PubMed Scopus (2) Google ScholarIn contrast to the α-cell, in the enteroendocrine L-cell and the brain, PC1/3 is the predominant processing enzyme acting on proglucagon, liberating glucagon-like peptide-1 (GLP-1), GLP-2, and oxyntomodulin.5Rouille Y Kantengwa S Irminger JC Halban PA Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1.J Biol Chem. 1997; 272: 32810-32816Crossref PubMed Scopus (81) Google Scholar,6Zhu X Zhou A Dey A Norrbom C Carroll R Zhang C et al.Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.Proc Natl Acad Sci USA. 2002; 99: 10293-10298Crossref PubMed Scopus (278) Google Scholar GLP-1 has garnered significant therapeutic interest for the treatment of diabetes because of its pleiotropic blood glucose–lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of β-cell proliferation and survival.1Kieffer TJ Habener JF The glucagon-like peptides.Endocr Rev. 1999; 20: 876-913Crossref PubMed Scopus (886) Google Scholar,7Drucker DJ The biology of incretin hormones.Cell Metab. 2006; 3: 153-165Abstract Full Text Full Text PDF PubMed Scopus (1670) Google Scholar GLP-2 and oxyntomodulin also tend to lower blood glucose levels by promoting satiety and inhibiting gastric emptying.8Wynne K Bloom SR The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control.Nat Clin Pract Endocrinol Metab. 2006; 2: 612-620Crossref PubMed Scopus (65) Google Scholar,9Meier JJ Nauck MA Pott A Heinze K Goetze O Bulut K et al.Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans.Gastroenterology. 2006; 130: 44-54Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Thus proglucagon, depending on whether it is processed by PC2 or PC1/3, gives rise to products that tend to have either glucose-raising or glucose-lowering effects.We have previously shown that expression of PC1/3 rather than PC2 in α-cells induces GLP-1 production and converts the α-cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels and promotes islet survival in rodent models of type 1 diabetes.10Wideman RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar,11Wideman RD Yu IL Webber TD Verchere CB Johnson JD Cheung AT et al.Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1).Proc Natl Acad Sci USA. 2006; 103: 13468-13473Crossref PubMed Scopus (86) Google Scholar Here we have examined the metabolic effects of transplanting encapsulated PC1/3-expressing α-cells in rodent models of T2D, and demonstrate that cell therapy with PC1/3-expressing α-cells improves glucose handling and improves cold thermogenesis in leptin-resistant mice.ResultsWe and others have previously reported that αTCΔPC2 cells express PC1/3, but no functional PC2, and produce GLP-1.10Wideman RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar,12Webb GC Dey A Wang J Stein J Milewski M Steiner DF Altered proglucagon processing in an alpha-cell line derived from prohormone convertase 2 null mouse islets.J Biol Chem. 2004; 279: 31068-31075Crossref PubMed Scopus (26) Google Scholar We found that compared to PC2-expressing αTC-1 cells, αTCΔPC2 cells secrete higher levels of immunoreactive GLP-2 (255.8 ± 20.6 ng/ml versus 129.2 ± 17.0 ng/ml; n = 2) and oxyntomodulin (50.0 ± 5.7 ng/ml versus 27.7 ± 1.5 ng/ml; P < 0.01; n = 4; data not shown). In this study, we used encapsulated αTCΔPC2 cells to assess the efficacy of cell therapy with PC1/3-expressing α-cells in mouse models of T2D. We transplanted 40 × 106 encapsulated cells to the intraperitoneal (IP) cavity of 16-week-old C57BL/6 mice that had been fed a 60% kcal from fat diet from 4 weeks of age. Cell transplantation had no effect on body weight (Figure 1a), and we could not detect any changes in not shown). αTCΔPC2 had lower blood glucose levels than (Figure ± versus ± P < ± versus ± P < glucose that αTCΔPC2 had glucose than as by a more of blood glucose levels (Figure P < and P < and an in (Figure P < insulin levels not glucose ± for cell versus ± for P = n = but cell to have higher insulin levels glucose ± versus ± for P = n = αTCΔPC2 cells improved in the high fat–fed model of glucose we that transplantation of but not αTC-1 cells the of diabetes in the db/db mouse model of T2D. We not detect any of cell on either body weight or not shown). Although αTCΔPC2 cell lowered fasting blood glucose levels ± versus ± 2 P < blood glucose levels not and of diabetes a (Figure In αTC-1 had elevated blood glucose levels compared to (Figure ± versus ± P < ± versus ± P < whether αTCΔPC2 cell body in db/db mice, we αTCΔPC2 found to have a but significant in the of body (Figure P < any in body not that a from the αTCΔPC2 cell fat and/or in these in db/db mice prohormone convertase 1/3 or PC2-expressing α-cell glucose a in mice αTCΔPC2 or αTC-1 cell or body by < < compared to n = of glucose levels, αTCΔPC2 cells improved glucose with mice lower blood glucose levels (Figure P < P < and and P < and a in compared to (Figure P < In 4 αTC-1 had no in glucose compared to (Figure blood glucose levels ± versus ± ± versus ± P < n = and no in (Figure has been reported a new in the PubMed Scopus Google Scholar db/db mice an and had glucose-stimulated insulin secretion in the glucose αTCΔPC2 cell lower fasting insulin levels ± versus ± for P < and a of insulin secretion in to glucose (Figure P < and P < the of αTCΔPC2 cells on glucose no for a of blood glucose levels the (Figure P < GLP-1 levels in a blood and GLP-1 the of in but one αTCΔPC2 had GLP-1 levels of ± = homeostasis in db/db mice prohormone convertase 1/3 or PC2-expressing α-cell glucose an 4 or transplantation of αTCΔPC2 or αTC-1 under the the the and for insulin expressed as compared to < < < compared to n = with in the db/db to have lower body in the and as as cold-induced compared to P in the The role of thermogenesis in PubMed Scopus Google Scholar assess whether α-cell products could body in this we in db/db mice that had received αTCΔPC2 or αTC-1 cell or αTCΔPC2 had a in to body in a 4 with higher body (Figure P < and P < and In αTC-1 had no in to body compared to (Figure thermogenesis in db/db mice prohormone convertase 1/3 or PC2-expressing α-cell therapy or continuous of a proglucagon-derived transplantation of cells or transplantation of αTC-1 cells or of a with glucagon-like peptide-1 (GLP-1), GLP-2, or oxyntomodulin 4 and body a = < < compared to the effects of αTCΔPC2 cell on body cell in db/db mice and in study, transplantation of αTCΔPC2 cells not diabetes in db/db mice, improved glucose with lower blood glucose levels and a in under the compared to db/db mice not shown). In this of mice, we an cold and found no and db/db mice, had an to body compared to (Figure by db/db αTCΔPC2 cell to body cold than db/db (Figure P < and P < they had lower body than the of the cold We changes in body a in a of mice, and found that of db/db mice had lower body than αTCΔPC2 to have higher body than db/db mice, the (Figure P < P = for and body in db/db mice prohormone convertase 1/3 α-cell for 2 4 and body in mice in and < < for db/db versus db/db αTCΔPC2 n = or n = GLP-1, glucagon-like that αTCΔPC2 cells improved body in db/db mice to that one or more of the PC1/3-derived proglucagon products have a role in body We that GLP-1 in of body mice with of the have cold a cold no in body and mice and to than mice (Figure We also GLP-2, or oxyntomodulin db/db mice, and cold thermogenesis We no in the cold of mice any of the peptides compared to mice (Figure mice and or db/db mice and for db/db mice had (Figure P < for versus and (Figure P < for and P < for αTCΔPC2 versus than the of these fat not and db/db Although of db/db mice had in the and lipid in the in the compared to we not to detect any the of db/db mice (Figure and data not shown). we could not detect any in 1 levels in the of versus db/db mice (Figure and in db/db mice prohormone convertase 1/3 α-cell and and as a of body and of and = 1 and of to expression is expressed as and is for and for < versus < versus n 4 this study, we to cell therapy to evaluate the of continuous delivery of either PC1/3- or PC2-derived α-cell products in mouse models of T2D. α-cells which express PC2, αTCΔPC2 cells derived from mice bioactive PC2 and the for glucagon but express high levels of RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar,12Webb GC Dey A Wang J Stein J Milewski M Steiner DF Altered proglucagon processing in an alpha-cell line derived from prohormone convertase 2 null mouse islets.J Biol Chem. 2004; 279: 31068-31075Crossref PubMed Scopus (26) Google Scholar We have previously shown that αTCΔPC2 cells glucose handling in normal mice, and effects that to be to the secretion of GLP-1 from the transplanted RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar Here we αTCΔPC2 cells and αTC-1 cells to evaluate continuous cell therapy with either PC1/3-expressing or PC2-expressing α-cells in transplanted cells from and has been used for long-term of transplanted islets in models of A JJ GC of islets in mice in of an J 2004; PubMed Scopus Google K S J et and survival of islets transplanted PubMed Scopus Google Scholar We used to evaluate long-term therapy with PC1/3- or PC2-expressing α-cells in mice the for or of the cavity of weeks and it has been previously that GLP-1 levels elevated in mice transplantation of encapsulated αTCΔPC2 RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar and in the glucagon levels elevated transplantation of encapsulated αTC-1 cells in db/db mice not shown). these data that the encapsulated cells functional the of high fat–fed mice and db/db mice, αTCΔPC2 cells improved glucose and fasting blood while treatment of db/db mice with αTC-1 cells glucose levels and glucose In high fat–fed mice, αTCΔPC2 cells insulin in to with the effect of S GC Habener JF glucagon-like peptide in the glucagon is a of insulin in the Clin PubMed Scopus Google Scholar in db/db mice αTCΔPC2 cells fasting insulin levels and glucose-stimulated insulin αTCΔPC2 cell to the of diabetes in db/db mice, and had on glucose by 1 We that elevated blood glucose levels in db/db mice have secretion from the α-cell in contrast to the α-cell, which secretion of glucagon in to glucose RH of endogenous glucagon in and the of blood glucose its Clin PubMed Scopus Google Scholar in that αTCΔPC2 cells to changes in glucose not shown). that not the of GLP-1 and PC1/3-derived proglucagon products from the cell In may of the G K et of GLP-1 and expression by to incretin effects in 2007; 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56: 2744-2752Crossref PubMed Scopus (53) Google Scholar on a and received a diet kcal from kcal from and kcal from 60% of which is or and of which is from for mice, which on diet from kcal from kcal from and 60% kcal from of and glucose and body weight to a glucose and blood on mice via the by delivery of glucose to mice an glucose for 2 glucose delivery and insulin an mouse insulin by a of and in the for and transplantation of encapsulated αTC-1 and αTCΔPC2 cells in and and as with a and for immunoreactive GLP-2 and to of × transplanted in for αTCΔPC2 and for cells in and a cell a in a of weight and acid and to a to the a and as in and to to mice and to the cavity as RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar mice received an of under of GLP-2, and oxyntomodulin from and in with peptide or and The to the cavity of db/db mice and body with a in the the of cell in the but to one of the as not to with the The with a the to from and mice with 2 cold body a to the in cold mice in for the of the 4 and body for the mouse that from body to a and from the a from the body a to The to body and typically of the The of as P A M body in mice and by 2004; 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Full Text PDF PubMed Scopus Google 4 The with and an The and with an and expression for as ± and a and the of shown in < < < IntroductionProglucagon, which is expressed in pancreatic α-cells, intestinal L-cells, and in specific neurons in the central nervous system, is differentially processed to yield numerous peptides belonging to the glucagon superfamily of hormones.1Kieffer TJ Habener JF The glucagon-like peptides.Endocr Rev. 1999; 20: 876-913Crossref PubMed Scopus (886) Google Scholar Although members of this superfamily share significant peptide sequence homology, they have diverse and sometimes opposing regulatory functions. In the pancreatic α-cells, prohormone convertase (PC2) is the predominant processing enzyme, with the result that the major bioactive proglucagon-derived peptide (PGDP) arising in these cells is glucagon,2Furuta M Zhou A Webb G Carroll R Ravazzola M Orci L et al.Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice.J Biol Chem. 2001; 276: 27197-27202Crossref PubMed Scopus (131) Google Scholar,3Rouille Y Bianchi M Irminger JC Halban PA Role of the prohormone convertase PC2 in the processing of proglucagon to glucagon.FEBS Lett. 1997; 413: 119-123Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar a glucose-raising hormone opposing insulin action. While glucagon activity is crucial for preventing hypoglycemia under normal conditions, hyperglucagonemia accompanies and may exacerbate type 2 diabetes (T2D).4Unger RH Letter: glucagon in pathogenesis of diabetes.Lancet. 1975; 1: 1036-1042Abstract PubMed Scopus (2) Google ScholarIn contrast to the α-cell, in the enteroendocrine L-cell and the brain, PC1/3 is the predominant processing enzyme acting on proglucagon, liberating glucagon-like peptide-1 (GLP-1), GLP-2, and oxyntomodulin.5Rouille Y Kantengwa S Irminger JC Halban PA Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1.J Biol Chem. 1997; 272: 32810-32816Crossref PubMed Scopus (81) Google Scholar,6Zhu X Zhou A Dey A Norrbom C Carroll R Zhang C et al.Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.Proc Natl Acad Sci USA. 2002; 99: 10293-10298Crossref PubMed Scopus (278) Google Scholar GLP-1 has garnered significant therapeutic interest for the treatment of diabetes because of its pleiotropic blood glucose–lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of β-cell proliferation and survival.1Kieffer TJ Habener JF The glucagon-like peptides.Endocr Rev. 1999; 20: 876-913Crossref PubMed Scopus (886) Google Scholar,7Drucker DJ The biology of incretin hormones.Cell Metab. 2006; 3: 153-165Abstract Full Text Full Text PDF PubMed Scopus (1670) Google Scholar GLP-2 and oxyntomodulin also tend to lower blood glucose levels by promoting satiety and inhibiting gastric emptying.8Wynne K Bloom SR The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control.Nat Clin Pract Endocrinol Metab. 2006; 2: 612-620Crossref PubMed Scopus (65) Google Scholar,9Meier JJ Nauck MA Pott A Heinze K Goetze O Bulut K et al.Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans.Gastroenterology. 2006; 130: 44-54Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Thus proglucagon, depending on whether it is processed by PC2 or PC1/3, gives rise to products that tend to have either glucose-raising or glucose-lowering effects.We have previously shown that expression of PC1/3 rather than PC2 in α-cells induces GLP-1 production and converts the α-cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels and promotes islet survival in rodent models of type 1 diabetes.10Wideman RD Covey SD Webb GC Drucker DJ Kieffer TJ A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice.Diabetes. 2007; 56: 2744-2752Crossref PubMed Scopus (53) Google Scholar,11Wideman RD Yu IL Webber TD Verchere CB Johnson JD Cheung AT et al.Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1).Proc Natl Acad Sci USA. 2006; 103: 13468-13473Crossref PubMed Scopus (86) Google Scholar Here we have examined the metabolic effects of transplanting encapsulated PC1/3-expressing α-cells in rodent models of T2D, and demonstrate that cell therapy with PC1/3-expressing α-cells improves glucose handling and improves cold thermogenesis in leptin-resistant

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