BioWorld International Correspondent
LONDON - A molecule that increases sensitivity to insulin, and therefore could provide a therapeutic target for the treatment of Type II diabetes, has been identified by an international team of researchers. Mutations in the gene encoding this protein, which is called SHIP2, could be responsible for the development of Type II diabetes, the researchers suggest.
Stephane Schurmans, a molecular biologist at IRIBHN, or the Institute of Interdisciplinary Research, in Gosselies, Belgium, together with colleagues in Belgium and France and from the Amgen Institute/Ontario Cancer Institute at the University of Toronto in Canada, made their discovery by generating mice that lacked the gene for SHIP2. Their findings are reported in the Jan. 4, 2000, Nature in a paper titled, "The lipid phosphatase SHIP2 controls insulin sensitivity."
Schurmans told BioWorld International, "We have demonstrated for the first time that SHIP2 is a critical negative regulator of insulin signaling in vivo. This finding may have potential implications for the treatment and/or the diagnosis of Type II diabetes."
The team already has started to sequence the gene encoding SHIP2 in a large population of people in Belgium with Type II diabetes. "As well as screening patients for the presence of mutations in the gene, we have recently developed a high-throughput screening test that could be used to identify molecules interacting with SHIP2," he said. "If they exist, these molecules will, of course, represent good candidates for therapeutic targets for the treatment of this type of diabetes."
SHIP2 is the shorthand name for Type-II SH2-domain-containing inositol 5-phosphatase, which belongs to the inositol polyphosphate 5-phosphatase family.
Schurmans and colleagues first developed and studied mice that lacked only one allele of the gene encoding SHIP2. These mice apparently were normal. They gained weight normally and had a normal life expectancy.
From these animals, the researchers obtained mice that lacked both copies of the gene in question. These mice, called SHIP2 -/-, all died within three days of birth. Histological examination of their main organs showed no particular abnormalities, but tests carried out on live neonates showed that their blood glucose concentrations were significantly lower than those of wild-type mice or those of mice that lacked only one copy of the SHIP2 gene. Further investigations showed that the hypoglycemia was not caused by increased production of insulin, but by increased sensitivity to insulin.
The researchers went on to study the liver physiology of the SHIP2 -/- neonates. In normal animals at birth, gluconeogenesis takes place in the liver, releasing glucose into the blood to maintain a "normal" level.
Schurmans' group found, however, that levels of a key enzyme in this process, called phosphoenolpyruvate carboxy-kinase, were very low or nonexistent in the livers of SHIP2 -/- mice, compared to those of wild-type animals. Further experiments demonstrated that liver cells in SHIP2 -/- animals had higher than normal sensitivity to insulin.
The team went on to examine whether adult SHIP2 +/- (heterozygous) mice could metabolize glucose in the blood more rapidly than adult SHIP2 +/+ (wild-type) mice. In Nature, they wrote that there was a "significantly more profound hypoglycemia" in SHIP2 +/- mice both 30 minutes and 60 minutes after the animals were injected with insulin, than in wild-type mice.
Additional studies were designed to examine the effect of physiological levels of insulin on muscles isolated from wild-type animals and SHIP2 +/- mice. The researchers found that this resulted in "significantly higher glycogen synthesis in SHIP2 +/- muscles" than occurred in muscles from wild-type mice. These data, the team wrote, "indicate that insulin sensitivity is significantly increased in skeletal muscles from heterozygous mice expressing a reduced amount of SHIP2 protein."
These data on SHIP2, the researchers concluded, identify this protein as "a critical and essential negative regulator of insulin signaling and insulin sensitivity in vivo. Thus, SHIP2 is a potential therapeutic target for the treatment of Type II diabetes, and a candidate gene that predisposes to the same disease."