AGING AND THE PANCREAS

年龄增长与2型糖尿病发病率增加有关。在研究随着衰老发生的β细胞胰岛素分泌的年龄相关性下降的特征时，似乎在糖尿病状态下发生的胰岛素分泌异常是正常衰老过程的夸大，加上在胰岛素抵抗的情况下对胰岛素释放的需求增加。随着年龄的增长，胰岛素合成和胰岛素储存减少，β细胞复制能力下降，感知葡萄糖主要水平的蛋白质功能下降。我们发现，这些变化可以逆转GLP-1使用ALZET渗透泵植入颈部皮下连续给药5天啮齿动物。GLP-1输注动物中胰岛素mRNA增加3倍。老年大鼠的胰岛素mRNA含量比年轻大鼠低（低50%），但胰岛素mRNA含量增加了3倍。胰岛素分泌随年龄增长的异常也通过该治疗正常化（J.Clin.Invest. 99：2883- 2889，1999）。非常令人感兴趣的是，在用GLP-1长期治疗后，β细胞质量和胰岛质量增加，GLP-1是一种天然存在的肽，响应于食物从肠道产生和释放（Diabetes 49：741-748，2000;Endocrinology 141：2000）。GLP-1还引起内分泌细胞增殖。这将需要进一步的研究，以确定GLP-1激活胰岛特异性基因的机制，它对治疗胰腺炎和1型糖尿病也有意义。GLP-1主要影响的一个特定基因是IPF-1（胰岛-胰腺因子）。它是胰腺发育所必需的，在成人β细胞中，它调节胰岛素、葡萄糖转运蛋白2和葡萄糖激酶基因。我们最近报道了GLP-1在调节IPF-1的水平和转移到细胞核中起主要作用（Endocrinology 140：4904-4907，1999）。使用腺泡细胞系，AR 42 J细胞，我们已经表明，当用GLP-1处理时，细胞可以产生胰岛素，并且它们对葡萄糖产生应答（Diabetes 48：2358-2366，1999）。我们已经研究了参与GLP-1诱导的AR 42 J细胞分化的细胞内信号，并发现它依赖于MAP激酶通路的持续激活。我们还完成了在导管细胞系中的研究，以观察是否涉及相同的途径（提交给J of Mol Endocrinol），以及完成了在啮齿动物中的体内研究（Diabetes 49：741-748，2000）。我们正在继续研究GLP-1调节IPF-1的机制。我们研究的一个主要目标是分离胰腺的上皮干细胞（具有成为胰岛细胞、导管细胞和腺泡细胞的能力），并研究相关因素。

Aging is associated with an increased incidence of type 2diabetes mellitus. On studying the characteristics of the age-related decline in beta cell insulin secretion that occurs with aging, it appears that the abnormality in insulin secretion that occurs in the diabetic state is an exaggeration of normal aging processes, coupled with increasing demand for insulin release in the setting of insulin resistance. There is a decrease, with age, in insulin synthesis and storage of insulin, a decrease in the ability of the beta cells to replicate and a decline in the function of the proteins which sense the prevailing levels of glucose. We showed that these changes could be reversed with continuous administration of GLP-1 using an ALZET osmotic pump implanted subcutaneously in the neck for 5 days in rodents. Insulin mRNA was increased 3-fold in the GLP-1 infused animals. Old rats, which have a lower amount of mRNA (50% lower)for insulin than young rats, had a 3-fold increase in insulin mRNA. The abnormality in insulin secretion with aging was also normalized by this treatment (J. Clin. Invest. 99:2883-2889,1999). Of great interest is the fact that there was an increase in beta cell mass and islet mass after chronic treatment with GLP-1, a naturally occuring peptide produced and released from the gut in response to food (Diabetes 49:741-748, 2000;Endocrinology 141:2000). GLP-1 also caused endocrine cell proliferation. It will require further study to determine the mechanism by which GLP-1 activates islet specific genes and it has implications for treating pancreatitis and type 1 diabetes, also. One specific gene which GLP-1 largely influences is IPF-1 (Islet-pancreatic factor). It is necessary for pancreatic development and in adult beta-cells, it regulates the insulin, glucose transporter 2 and glucokinase genes. We recently reported the GLP-1 plays a major role in regulating levels and translocation to the nucleus of IPF-1 (Endocrinology140:4904-4907, 1999). Using an acinar cell line, AR42J cells, we have shown that the cells can become insulin-producing when treated with GLP-1, and they become responsive to glucose(Diabetes 48: 2358-2366, 1999). We have investigated the intracellular signals involved in the GLP-1-induced differentiation of AR42J cells and found that it is dependent on the continuous activation of the MAP kinase pathway. We also completed studies in duct cells lines to see if the same pathways are involved (submitted to J of Mol Endocrinol) as well as completed in vivo studies in rodents(Diabetes 49:741-748, 2000). We are continuing our studies on the mechanisms whereby GLP-1 regulates IPF-1. A major thrust of our research is to isolate the epithelial stem cells of the pancreas(which have the capacity to become islets cells, duct cells and acinar cells) and study the factors involved.