1Pax4 is one of the transcription factors that play an important role in the differentiation of islet -cells. We scanned the Pax4 gene in 200 unrelated Japanese type 2 diabetic patients and found a missense mutation (R121W) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects. The R121W mutation was located in the paired domain and was thought to affect its transcription activity through lack of DNA binding. Six of seven patients had family history of diabetes or impaired glucose tolerance, and four of seven had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. This is the first report of a Pax4 gene mutation that exhibits loss of function and seems to be associated with type 2 diabetes. This work provides significant implications for the Pax4 gene as one of the predisposing genes for type 2 diabetes in the Japanese.
Aims/Introduction: Islets in type 2 diabetes are characterized by deposition of islet amyloid polypeptide (IAPP) as well as β‐cell dysfunction. The unique amyloidogenic character of human (h)IAPP is associated with cytotoxicity. Autophagy is a ubiquitous system of cellular recycling that contributes to cell survival. Thus, we examined whether autophagy could ameliorate hIAPP‐associated cytotoxicity.Materials and Methods: First, we used a COS‐1 cell model, lacking endogenous IAPP that might affect cytotoxicity related to exogenous hIAPP. Next, we used the mouse β‐cell line, MIN‐6 cells. Both cells were transfected with hIAPP or rat (r)IAPP expression constructs, or transfected with bicistronic vectors expressing green fluorescent protein (GFP) and either hIAPP or rIAPP for flow cytometry analysis. Cell viability and apoptosis markers were studied in relation to chemical or genetic modulation of autophagy.Results: The viability of cells expressing hIAPP was significantly decreased as compared with those expressing rIAPP and the cleavage of pro‐caspase‐3 was elevated in hIAPP‐transfected cells. The formation of autophagosomes and the conversion of microtubule‐associated protein light chain 3B I to II were elevated in hIAPP‐expressing cells. The viability of hIAPP‐expressing cells was increased after treatment with rapamycin, an inducer of autophagy, and decreased after treatment with 3‐methyladenine, an inhibitor of autophagy. In MIN‐6 cells, annexin positive cells were increased by 3‐methyladenine and decreased by rapamycin using flow cytometry. Knocking down of the autophagy protein 5 gene decreased hIAPP‐transfected cell viability.Conclusions: Autophagy is co‐localized with hIAPP expression and it plays a protective role in hIAPP‐associated apoptosis. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00065.x, 2010)
Decreased function of the melanocortin-4 receptor (MC4R) was reported to cause late-onset obesity and insulin resistance in rodents. Thus mutations in the MC4R gene drew strong attention as a possible cause of obesity and diabetes. We screened for mutations in the MC4R gene in extremely obese [body mass index (BMI) 35 kg\m#] Japanese with diabetes by direct sequencing. A heterozygous mutation (V103I) was detected in one case (2.0 %), however the frequency was not significantly different from that in non-obese (BMI 24 kg\m#) and non-diabetic subjects (2.7 %). No other mutations were detected. These results suggest that mutations including V103I in the MC4R gene are not a major cause of obesity or diabetes in Japanese.
Obesity is defined as a state of pathologically excessive adipose tissue mass, which is caused by an imbalance between energy intake and expenditure. Although it is obvious that obesity is strongly linked to genetic factors (Stunkard et al. 1986(Stunkard et al. a, 1986, attempts to identify major candidate genes have been unsuccessful so far.Leptin and its signalling in the melanocortin system in the brain play a central role in decreasing appetite, which regulates energy intake. The melanocortin-4 receptor (MC4R) is a seven transmembrane G-coupled receptor which is expressed in the hypothalamus, and mediates leptin's signalling to the melanocortin system. Decreased function of MC4R by gene targeting causes late-onset obesity with insulin resistance Correspondence : Kishio Nanjo,
Aims/Introduction: In order to clarify the enhanced β‐cell dysfunction in type 2 diabetic patients carrying the S20G mutation of the islet amyloid polypeptide gene (S20G‐patients), we first estimated the decline of insulin secretion in Japanese type 2 diabetic patients without the S20G mutation (non‐S20G‐T2D‐patients) by long‐term observation, and then compared it with that of the S20G‐patients.Materials and Methods: We followed 70 non‐S20G‐T2D‐patients (body mass index <30 kg/m2) for more than 10 years and six S20G‐patients for more than 5 years. We measured fasting C‐peptide (F‐CP) every 1–2 years and carried out a glucagon test at least once during the follow‐up period. F‐CP and a 5‐min value of C‐peptide after glucagon injection (5′‐CP) were used as the indices of insulin secretion. We excluded patients who had renal dysfunction and/or anti‐insulin antibodies in the insulin‐treated patients. The individual annual declines were calculated from the slopes of the regression lines between C‐peptide levels and duration (years after diagnosis).Results: The mean individual annual declines of both F‐CP and 5′‐CP were significantly greater in the S20G‐patients than the non‐S20G‐T2D‐patients (F‐CP; 0.047 ± 0.026 vs 0.011 ± 0.037 nmol/L/year, P = 0.025, 5′‐CP; 0.139 ± 0.055 vs 0.022 ± 0.012 nmol/L/year, P = 0.008).Conclusions: We established the annual decline of insulin secretion in the Japanese type 2 diabetic patients by the long‐term observation. The results show that the decline of insulin secretion is more rapid in the S20G‐patients than the non‐S20G‐T2D‐patients. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00102.x, 2011)
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