These people are diabetics. Diabetic research is one of the best ways we can help them.
This is an assignment for Genomics 309, Davidson College
"A new hormone may be the link between obesity and type II diabetes," raves Bijal Trivedi, a news writer for Celera's Genomics News.<<http://www.celera.com/genomics/news/articles/01_01/Resisting_insulin.cfm)>> The newly discovered hormone, resistin, is now the center of attention for clinicians and scientists trying to explain why glucose is rejected by cells in people with diabetes mellitus II.
In order to understand how resistin works, it is first necessary to know the questions scientists were asking to establish the link between obesity and diabetes. For example, it was known before resistin's discovery that obesity was a high-risk factor for acquiring diabetes mellitus II and that increased fat content in fat tissue disrupted the function of insulin.<<http://www.cushings-help.com/resistin.htm>> One question that follows from these observations is, "Do fat cells secrete a substance that keeps insulin from stimulating glucose uptake?" Such a question is a logical one that follows from the fact that fat cells are involved in signaling pathways. Fat cells secrete leptin which interacts with neural circuitry to regulate appetite, fat storage, and fertility. (Campbell et al., 2001)
To explore the possibility that fat cells secrete a substance that causes cells to reject glucose, scientists took fat cells and exposed them to thiazolidinediones (TZD's), which are a new class of anti-diabetic drugs.(Claire et al., 2001) Because these drugs help insulin to function properly, these scientists hypothesized that exposure of fat cells to TZD's would lead to the downregulation of a protein secreted by fat cells to block the effects of insulin. A northern blot using total RNA from TZD-exposed fat cells and normal fat cells demonstrated a significant difference in transcription for a 592-nucleotide RNA. (Claire et al., 2001) The scientists then took this RNA and sequenced it. They then demonstrated that the protein product of this RNA, termed resistin (resistance to insulin), is found in higher than normal levels in obese, diet-induced obese, and diabetic mice. (Claire et al., 2001) When resistin was injected into normal mice, blood serum concentrations of glucose increased by nearly 50%, indicating that cells were rejecting glucose. Injection of a resistin-antibody into obese and diabetic mice overexpressing resistin led to a decrease in blood serum glucose concentration, indicating that cells had taken in glucose. Thus, when resistin is inactivated, glucose uptake becomes more efficient. (Claire et al., 2001)
These results indicate that resistin disrupts insulin-mediated glucose uptake. Such an observation is supported by the fact that when resistin was injected into normal mice, insulin levels stayed the same whereas the cells resistance to glucose increased.(Claire et al., 2001) Thus, resistin interferes with the cell's insulin-mediated response to glucose but the mechanism is uncertain. What is more certain is the link between obesity and diabetes mellitus II. Since obese mice secrete relatively high amounts of resistin, it is understandable that obesity would be a risk factor for acquiring diabetes mellitus II.
Although these findings elucidate a role for resistin in linking obesity with diabetes mellitus II, there are still more questions that must be answered. For example, if resistin is the true link between obesity and diabetes, then it should be possible to make a resistin-knockout mouse that became obese as a result of a high-fat diet. <<http://www.celera.com/genomics/news/articles/01_01/Resisting_insulin.cfm>> This mouse, however, should not become diabetic because cellular glucose uptake is not reduced by the presence of resistin. Resistin's mechanism of countering insulin must also be elucidated. If resistin binds to a receptor to mediate insulin resistance, as is currently hypothesized, (Claire et al., 2001) then immunoprecipitation experiments with resistin must be done to isolate this receptor. After sequencing this receptor's amino acid and cDNA sequence, we could construct knockout mice for this receptor to observe their glucose uptake in the presence of high amounts of resistin. We would expect to see a similar level of blood glucose concentration as that in normal mice.
Despite the unanswered questions, resistin is a plausible candidate for linking obesity with diabetes mellitus II. Fat tissue is the only known tissue to date that expresses resistin. (Claire et al., 2001) More fat tissue means more resistin, which can lead to increased resistance to insulin. The fact that injection of resistin into normal mice reduces cellular glucose uptake in spite of normal insulin levels lends heavy credence to the notion that this protein alone may be sufficient to induce a diabetic response when present in abundance.
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