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Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.

AbstractBackground/Aims:CEL-MODY is a monogenic form of diabetes and exocrine pancreatic insufficiency due to mutations in the carboxyl-ester lipase (CEL) gene. We aimed to investigate endocrine and exocrine pancreatic function in CELknockout mice (CELKO). Methods:A knockout mouse model with global targeted deletion of CELwas investigated physiologically and histopathologically, and compared to littermate control CEL+/+ mice at 7 and 12 months on normal chow and high-fat diets (HFD), i.e. 42 and 60 fat by calories. Results:CELKO+/+ and –/– mice showed normal growth and development and normal glucose metabolism on a chow diet. Female CEL–/– mice on 60 HFD, on the other hand, had increased random blood glucose compared to littermate controls (p = 0.02), and this was accompanied by a reduction in glucose tolerance that did not reach statistical significance. In these mice there was also islet hyperplasia, however, α- and β-islet cells appeared morphologically normal and pancreatic exocrine function was also normal. Conclusion: Although we observed mild glucose intolerance in female mice with whole-body knockout of CEL, the full phenotype of human CEL-MODY was not reproduced, suggesting that the pathogenic mechanisms involved are more complex than a simple loss of CEL function.Copyright © 2010 S. Karger AG, Basel and IAP

Background/Aims:CEL-MODY is a monogenic form of diabetes and exocrine pancreatic insufficiency due to mutations in the carboxyl-ester lipase (CEL)gene. We aimed to investigate endocrine and exocrine pancreatic function in CELknockout mice (CELKO). Methods:A knockout mouse model with global targeted deletion of CELwas investigated physiologically and histopathologically, and compared to littermate control CEL+/+ mice at 7 and 12 months on normal chow and high-fat diets (HFD), i.e. 42 and 60% fat by calories. Results:CELKO+/+ and -/- mice showed normal growth and development and normal glucose metabolism on a chow diet. Female CEL-/- mice on 60% HFD, on the other hand, had increased random blood glucose compared to littermate controls (p = 0.02), and this was accompanied by a reduction in glucose tolerance that did not reach statistical significance. In these mice there was also islet hyperplasia, however, a- and β-islet cells appeared morphologically normal and pancreatic exocrine function was also normal. Conclusion:Although we observed mild glucose intolerance in female mice with whole-body knockout of CEL, thefull phenotype of human CEL-MODY was not reproduced, suggesting that the pathogenic mechanisms involved are more complex than a simple loss of CEL function.

Glucagon plays a critical counter-regulatory role to insulin to maintain optimal glucose homeostasis. Glucagon secretion from pancreatic α-cells is regulated by glycemia, neural input, and secretion from neighboring β-cells. Recently, we provided direct genetic evidence of a critical role for insulin signaling in the regulation of glucagon secretion in vivo. Pancreatic α-cell targeted disruption of insulin receptor expression in mice resulted in glucose intolerance, hyperglycemia and hyperglucagonemia coupled with an abnormal glucagon response to hypoglycemia. Furthermore, streptozotocin treated mice exhibited paradoxically increased plasma glucagon suggesting a dominant role for insulin in the regulation of glucagon secretion compared with glucose. In fact, normalization of hyperglycemia by phrolidzin treatment decreased plasma glucagon levels suggesting a stimulatory effect of glucose on glucagon secretion and also revealed the significance of insulin in hyperglycemic states. Together these studies provide novel insights into intra-islet regulatory pathways in the modulation of glucagon secretion and provide potential opportunities to develop therapeutic approaches for the correction of α-cell dysfunction in diabetes.

Failure of pancreatic β-cells is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes mellitus is induced by destruction of pancreatic β-cells which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress are produced during this process, which has been proposed to play an important role in mediating β-cell destruction. The JNK pathway is also activated by such cytokines and oxidative stress, and is involved in β-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease, and β-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Under diabetic conditions, chronic hyperglycemia gradually deteriorates β-cell function and aggravates insulin resistance. This process is called “glucose toxicity”. Under such conditions, oxidative stress is provoked and the JNK pathway is activated, which is likely involved in pancreatic β-cells dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are also involved in the progression of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in deterioration of pancreatic -cell function found in diabetes. Oxidative stress and/or activation of the JNK pathway suppress insulin gene expression, accompanied by reduction of PDX-1 DNA binding activity. Treatment with antioxidants and/or suppression of the JNK pathway protect -cells from some of the toxic effects of hyperglycemia. The JNK pathway is also involved in the progression of insulin resistance suppression of the JNK pathway in obese diabetic mice markedly improves insulin resistance and ameliorates glucose tolerance. The phosphorylation state of key molecules for insulin signaling is altered upon modification of the JNK pathway. Taken together, the JNK pathway plays a crucial role in progression of insulin resistance as well as -cell dysfunction found in diabetes and thus could be a potential therapeutic target for diabetes.

The possible involvement of the protein kinase C (PKC) pathway in transcriptional regulation of the human insulin-like growth factor-I (IGF-I) gene has been suggested. In this study, we sought to determine whether a PKC-dependent pathway is implicated in the transcriptional control, and if it is, how this occurs. Treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) caused an increase in the activity of the human IGF-I gene major promoter in HepG2 cells. A CCAAT/enhancer-binding protein (C/EBP) binding site located at +22 to +30 was bound by C/EBPβ in a TPA-dependent manner and was solely responsible for the TPA responsiveness. This increase in C/EBPβ activity occurs through transcriptional and posttranslational regulation, and the latter is mediated by activation of p90 ribosomal S6 kinase (RSK): co-expression of dominant negative RSK abolished the TPA-responsive and C/EBPβ-dependent transactivation. Also, TPA-responsive activation of GAL4-C/EBPβ chimera required the Ser residue known as the RSK target. In SK-N-MC cells, which display constitutive, high expression of IGF-I on use of the major promoter, a large amount of C/EBPβ binding was observed with the C/EBP site in the basal state. Treatment with PKC inhibitors substantially reduced the promoter activity and mRNA amounts of IGF-I, with the binding of C/EBPβ to the C/EBP site also being reduced. When the C/EBP site was disrupted, the basal promoter activity was reduced, but the reduction by the PKC inhibitor was no longer observed. These observations suggest that the increase of C/EBPβ binding to the C/EBP site, which is in part mediated via activation of RSK, can primarily explain the TPA responsiveness of the IGF-I gene promoter. The intrinsic PKC activity in SK-N-MC cells should play a major role in the constitutive, high expression of IGF-I and may therefore contribute in part to the maintenance of the tumor phenotype of the cells.