Akio Koizumi

Overload of pancreatic beta cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to beta cell exhaustion and type 2 diabetes. Because beta cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills beta cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced beta cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress-associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 beta cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8-10 weeks. We conclude that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.

Overload of pancreatic β cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to β cell exhaustion and type 2 diabetes. Because β cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills β cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced β cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress–associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 β cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8–10 weeks. We conclude that ER overload in β cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.

Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by aberrant vascular development. We report here a genetic epidemiologic study in a county, A, in the Akita prefecture (population 1.2 million) located in northern Japan. Nine HHT patients who had been referred to tertiary-care hospitals were located in and near the study county. A total of 137 pedigree members were traced of which 81 were alive and 32 were affected by HHT. Complications associated with cerebral or pulmonary arteriovenous malformations were proven in six out of seven families. Linkage analysis in two large families revealed a weak yet suggestive linkage to the HHT1 locus (encoding endoglin; ENG). Three novel mutations were found in four families, all of which led to a frameshift: a G to C transversion at the splicing donor site of intron 3 (Inv3+1 G>C) in one family, one base pair insertion (A) at nucleotide 828 (exon 7) of the endoglin cDNA in two large families (c.828-829 ins A), and a four base pair deletion (AAAG) beginning with nucleotide 1120 (exon 8) of the endoglin cDNA (c.1120-1123 delAAAG) in one family. The insertion of A in exon 11 (c.1470-1471 insA) mutation found in one family has also been reported in a European family. No endoglin gene mutations were found in two families. The population prevalence of HHT in the county was estimated to be 1:8,000 approximately 1:5,000, roughly comparable with those reported in European and U.S. populations, which is contradictory to the traditional view that HHT is rare among Asians. We recommend that families with HHT be screened for gene mutations in order that high-risk individuals receive early diagnosis and treatment initiation that will substantially alter their clinical course and prognosis.