Susceptibility to Type II diabetes is genetically influenced, but also it is abetted by what the American Diabetes Association gingerly describes as a "Western lifestyle" on its website.

That lifestyle could be more accurately, if more unkindly, described as overeating and under exercising. At any rate, it is no longer limited to the West; earlier this year, the World Health Organization and International Diabetes Foundation launched a joint program to "raise awareness about diabetes and stimulate and support the adoption of effective measures for the management and prevention of the condition in low- and middle-income countries and communities." According to their figures, the worldwide number of diabetics is set to more than double by 2030 to 366 million, and much of that increase will occur in developing countries.

Now, researchers from the East - specifically, from Osaka University Graduate School of Medicine and Tokyo University Graduate School of Pharmaceutical Sciences - reported on findings that could turn into a new approach for treating Type II diabetes. Their findings are in the October 2004 issue of Nature Medicine, in a paper titled "Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide."

Diabetes is preceded by insulin resistance, a communications breakdown between the pancreas and its target organs that is not unlike a slow deafening. In response to blood glucose, pancreatic cells secrete insulin to direct liver, fat and muscle cells to process that glucose. As high blood glucose levels lead to chronic high levels of insulin, overloaded target organs increasingly ignore insulin's nagging suggestion to handle glucose. Glucose levels stay high, prompting the pancreatic islet cells to valiantly produce more insulin, which keeps being ignored by the target organs. Full-blown diabetes can be the end result of that spiral.

Junk Food Activates JNK Pathway

At the cellular level, one pathway that shows increased activity in insulin resistance and diabetes is the so-called JNK pathway. The pathway is inactive under normal conditions, but is activated by cellular stress.

"We previously reported that JNK activation leads to reduction of insulin biosynthesis in pancreatic beta-cells, and also found recently that JNK activation leads to increase of insulin resistance. Thus, we got the idea to examine whether suppression of the JNK pathway leads to amelioration of diabetes," said Hideaki Kaneto, researcher at the University of Osaka Medical School and first author of the study in this month's Nature Medicine, via email.

The researchers first constructed a peptide that had two jobs: It needed to be able to get into cells in the first place, and once there, it needed to inhibit the JNK pathway. The scientists linked a short protein sequencem, known as JNK-inhibiting peptide or JIP, to a carrier peptide that is used by HIV to infect mammalian cells.

The chimera, which also had been conjugated to a fluorescent marker for visualization, was injected daily into obese diabetic mice, which had a genetic makeup predisposed them toward diabetes. After two weeks of peptide injections, the researchers first investigated where the peptide had gone after injection. Both the pancreatic islet cells, which secrete insulin, and the liver, fat and muscles, which are the major target organs, took up the peptide.

The mice injected with the inhibitory peptide ate and weighed about the same as diabetic mice injected with a control peptide that had a scrambled amino acid sequence, but they were able to deal with glucose much better. Treated mice had lower baseline glucose levels, and when the animals were injected with glucose after a six-hour fast (the so-called glucose-tolerance test), treated mice metabolized the glucose better, suggesting their pancreatic cells were working more efficiently.

Since insulin resistance is characterized by an unhealthy cycle of ever-increasing levels of both glucose and insulin, the scientists also investigated whether treatment had an effect on insulin levels.

"Roughly speaking, the glucose-tolerance test indicates whether pancreatic beta-cells appropriately secrete insulin in response to glucose. In contrast, the insulin-tolerance test indicates how well insulin works in target tissues, such as liver, fat and muscle," Kaneto told BioWorld Today.

Improving Listening Skills Of Liver, Fat, Muscle

When mice were injected with insulin, those that had been previously treated with inhibitory peptide showed a stronger reduction in glucose levels, demonstrating that their target tissues were able to respond to insulin better.

Though their research showed effects on both insulin secretion and response, the timing of events Kaneto and his colleagues observed lead them to believe that the effects seen primarily were due to the peptide's influence on target organs, rather than pancreatic beta-cells. Insulin resistance in the liver, fat and muscle cells was reduced before the scientists could detect an increase in secreted insulin, suggesting a direct effect on target organs via the JNK pathway.

In a final experiment, instead of using genetically diabetic mice for their experiments, researchers gave normal mice a taste of the "Western lifestyle": they were fed a diet high in fat and sugar. Two months of that increased the animals' blood glucose levels and induced insulin resistance. But as with their genetically diabetic cousins, inhibiting the JNK pathway led to improvements in both glucose levels and insulin responsiveness.

Kaneto and his colleagues have "not decided yet" how to best try to apply the results in the clinic, but are planning to move in that direction.

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