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Role of Leptin Deficiency in Type 1 Diabetes

A new study in rats shows that a lack of the hormone leptin triggers a cascade of neuroendocrine events that affects adipose tissue as well as the liver, resulting in hyperglycemia and ketoacidosis…. 

Leptin is a hormone made by fat cells which regulates the amount of fat stored in the body. It does this by adjusting both the sensation of hunger and adjusting energy expenditures. Studies suggest that there is an inverse relationship between leptin levels and insulin secretion. It has also been suggested that the association between plasma leptin and diabetes may be a result of an underlying leptin resistance due to obesity.

In leptin-deficient diabetic rats, systemic administration of leptin rapidly reversed ketoacidosis and normalized blood glucose levels by decreasing the delivery of glycerol and fatty acids to the liver. The effect of leptin occurred via decreased hypothalamic pituitary adrenal (HPA) axis activity. In other words, less ACTH was released from the pituitary gland, which results in less corticosterone (the equivalent of human cortisol) secretion from the adrenal gland and less corticosterone induced lipolysis of adipose tissue triglycerides. In addition, leptin reduces the availability of actyl-CoA, which activates pyruvate carboxylase, produced by hepatic fatty acid catabolism, which is responsible for the inhibition of conversion of pyruvate to glucose.

These findings indicate that either leptin or downstream targets of leptin may have therapeutic potential for the treatment of diabetes. In contrast with the rat models used in the study, patients who have well controlled type 1 diabetes do not consistently have low plasma leptin levels, presumably because insulin stimulates secretion of leptin from adipose tissue. Further clinical studies that involve changing insulin doses to achieve adequate decline in plasma leptin concentration are needed to determine whether leptin has the same physiological effects in humans with type 1 diabetes as those observed in rates.

Practice Pearls:

  • Leptin is a hormone made by fat cells which regulates the amount of fat stored in the body.
  • Studies suggest that there is an inverse relationship between leptin levels and insulin secretion.
  • Findings indicate that either leptin or downstream targets of leptin may have therapeutic potential for the treatment of diabetes.

Mittendorfer, Bettina and Klein, Samuel. Absence of leptin triggers type 1 diabetes. Nature Medicine. 2014. (20) 705-706.