Yong Ki Min

Serum gamma-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors.

Aims  Although many studies have reported an association between serum γ‐glutamyltransferase (GGT) and cardiovascular risk factors, the mechanism of this relationship has not been clarified.

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

Abstract.Aims/hypothesis: Interferon-γ (IFNγ) and TNFα synergistically induce pancreatic beta-cell apoptosis. Apart from their direct effect, we studied the possible indirect immunological role of IFNγ/TNFα synergism on pancreatic beta-cell death by investigating MHC class II induction by cytokines. The effect of nicotinamide on the cytokine-induced MHC class II expression and pancreatic beta-cell death was also studied. Methods: Immunocytochemistry, flow cytometry and RNase protection assay were used to study MHC class II expression. Immunoblotting was done to study downstream signals of IFNγ. The effects of nicotinamide on islet-cell apoptosis and diabetes mellitus were examined using MTT assay and adoptive transfer model. Results: IFNγ alone induced MHC class II expression on a small number of insulinoma cells. TNFα alone did not induce MHC class II expression, but enhanced IFNγ-induced MHC class II expression. MHC class II expression by cytokine(s) was due to the induction of class II transactivator (CIITA). Nicotinamide reduced MHC class II expression by cytokine(s) but did not protect insulinoma-cell apoptosis by IFNγ and TNFα in combination or protect against the development of diabetes mellitus after adoptive transfer of diabetogenic lymphocytes. Conclusion/interpretation: IFNγ and TNFα synergistically induced MHC class II expression on insulinoma cells through the induction of CIITA; nicotinamide reduced the expression of cytokine-induced MHC class II expression on insulinoma cells through its effect on CIITA expression; and the preventive effect of nicotimamide on Type I (insulin-dependent) diabetes mellitus is probably due to its effect of MHC class II expression rather than that on islet cell apoptosis. [Diabetologia (2002) 45: 385–393]

Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma.

Parafibromin is a protein encoded by the HRPT2 oncosuppressor gene, and the expression is reported to be decreased or absent in parathyroid carcinomas.

Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion

Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A,{ a blocker of mitochondrial permeability transition pore}. Caspase inhibitors further inhibited MIN6N8 cell death. PK11195 induced dissipation of mitochondrial potential and cytochrome c translocation to cytoplasm. PK11195 induced an increase in cytoplasmic [Ca2 +], which was reversed by cyclosporin A. Rhod-2 staining showed decreased mitochondrial [Ca2 +] after PK11195 treatment. PK11195 potentiated glucose-induced insulin secretion probably due to the increased cytoplasmic [Ca2 +]. Calpain was activated following Ca2 + release, and calpain inhibitors attenuated death of insulinoma cells by PK11195. These results suggest that PK11195 induces mitochondrial potential loss, cytochrome c translocation, increased insulin secretion in conjunction with an increase in cytoplasmic [Ca2 +] and calpain activation, which collectively leads to apoptosis of insulinoma cells.

Pathologic changes and glucose homeostasis according to expression of human islet amyloid polypeptide in type 2 diabetic patients.

The amount of amyloid detectable in islets varies, and is not always correlated with degree of β-cell loss. It has been hypothesized that islet amyloid polypeptide (IAPP) aggregation causes β-cell dysfunction. In this study, we investigated the relationship between IAPP expression and glucose homeostasis in pancreatectomized patients. Human pancreatic head tissues were collected from 46 pancreatic tumor patients. We divided the diabetic cases into two groups, patients with higher IAPP–expressing islets (DM-H) and patients with lower IAPP–expressing islets (DM-L), and compared both groups to patients with normal glucose tolerance (NGT). Interestingly, oral glucose tolerance test analyses showed that DM-L patients had significantly higher glucose levels and lower C-peptide levels than DM-H patients. Furthermore, the DM-H group showed a relative β-cell volume similar to that of the NGT group, as well as a significantly higher relative β-cell volume than the DM-L group. The DM-L group was significantly higher than the DM-H group, not only in the rates of replication and apoptosis, but also in the nuclear C/EBP homologous protein and the ratio of oligomer to IAPP. Thus, IAPP expression may not be an indicator of cell death induction. IAPP, including oligomer, may be an important determinant in the fate of islet β-cells. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.