Mark Pine

Diabetic mice lacking pancreatic ß-cells that make insulin have been successfully treated with the hormone leptin alone. The leptin treatment, administered by implanted infusion pumps, normalized mice’s blood glucose levels and and other diabetic abnormalities. In addition, leptin lowered fatty acid blood levels, and it corrected abnormalities of lipid levels induced by insulin treatment that promote insulin resistance and atherosclerosis.

Leptin is the hormone secreted by fat cells that has stirred widespread interest because of its effect on the appetite centers of the brain to reduce appetite and regulate weight.

The report of the new research appeared yesterday in PNAS, the journal of the National Academy of Sciences. Medical scientists at the University of Texas, Duke, Albert Einstein College of Medicine, and the VA North Texas Health Care System demonstrated these remarkable effects of leptin using mice whose insulin-secreting cells had been chemically destroyed. They are now planning a clinical trial of combination insulin/leptin therapy in diabetic people. (Because insulin is a mandatory life-sustaining treatment for type I diabetes, clinical trials of leptin alone would not be permitted, at least initially.)

The new hormonal treatment appears to work because of the action of leptin to suppress glucagon, another metabolic hormone secreted by the pancreas. Insulin and glucagon have opposing effects on blood glucose. Insulin stimulates the cells of the body to take in the sugar from the blood as the main source of energy. This reduces glucose levels in the blood.

In contrast, glucagon increases blood glucose by promoting synthesis of the sugar in the liver and stimulating the breakdown into glucose of glycogen, the starch stored in the body’s cells. Thus, blood glucose levels are raised in the blood either by insufficient insulin or glucagon secretion. The researchers showed that that effect of leptin in controlling blood glucose could be mediated by its effect on glucagon, because they found that glucagon levels were suppressed 80% in leptin-treated animals in comparison to those treated with insulin and saline-treated controls.

Insulin also increases blood fatty acid levels, fat storage and abnormalities of fat metabolism that promote atherosclerotic disease of the cardiovascular system. In contrast, leptin treatment normalized these lipid abnormalities. The scientists determined that these effects of insulin did not happen in the absence of glucagon secretion, and leptin treatment may have prevented them from occurring due to its suppression of glucagon.

Glucose levels were controlled at least as well by leptin as by insulin in the diabetic mice. Glucose levels in the leptin mice averaged 88 mg/dl (a normal level in humans); in the insulin mice glucose averaged 160 mg/dl (a somewhat elevated level in humans). The variability of blood glucose on leptin was less than on insulin, perhaps showing that glucose control was superior in the leptin group. Both leptin and insulin prevented the most severe effects of type I diabetes: ketoacidosis, wasting and death. And both normalized glycocylated hemoglobin A1c levels, a clinical marker of glucose control.

Leptin also substantially decreased the food intake of the mice. Leptin-treated mice ate 72% less than untreated diabetic mice and 15% less than insulin-treated mice. But the scientists showed that weight loss in the leptin mice resulted from loss of body fat, but lean tissue was spared.

These findings raise great hope that a superior treatment of insulin-dependent diabetes may be developed. Nevertheless, demonstrating the effectiveness of a new therapy in animals is always far from proving it in humans.

The potential of this new hormonal treatment is that it could revolutionize and improve the therapy of the most severe form of diabetes. We should keep our fingers crossed.