What we think we know: The science behind the IPTN… and what we don’t know

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Insulin was discovered in the early 1920’s and we have learned much over the years about its roles in obesity and type 2 diabetes, including:

  • We know that food and metabolism are inextricably linked, and insulin is the main meal-dependent anabolic hormone and that insulin is essential for life.
  • We know that insulin levels are high in people who have gained weight and in early stage type 2 diabetes1, but this does not establish the causality relationship between insulin and obesity.
  • We know that specific insulin reduction prevents diet-induced weight gain and insulin resistance in animal models2,3.
  • We know that drugs that reduce insulin levels have been shown to cause weight loss in some clinical studies4,5.
  • We know that high doses of ‘long-acting insulin’ are sufficient to induce weight gain6.
  • We know that the insulin responses to nutrients are highly variable between individuals7.
  • We know that some people are able to lose weight and improve their metabolic homeostasis by adopting diets low in carbohydrates. In some people, this can alleviate the need for medications used to treat type 2 diabetes and ‘insulin resistance’, in our clinical experience.

There are still many unanswered questions:

  • The precise relationship between hyperinsulinemia and insulin resistance remains unclear.
  • It is not clear why some people exhibit different insulin responses to nutrients. Both genetic and non-genetic explanations should be considered.
  • It is not clear why some individuals respond to specific diets, while others fail with the same approach.

There is an urgent need for carefully designed pre-clinical and clinical studies to test these concepts in a individualized manner.

References:

  1. Nolan, C.J., Ruderman, N.B., Kahn, S.E., Pedersen, O. & Prentki, M. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes 64, 673-86 (2015).
  2. Mehran, A.E., Templeman, N.M., Brigidi, G.S., Lim, G.E., Chu, K.Y., Hu, X., Botezelli, J.D., Asadi, A., Hoffman, B.G., Kieffer, T.J., Bamji, S.X., Clee, S.M. & Johnson, J.D. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metabolism 16, 723-37 (2012).
  3. Templeman, N.M., Clee, S.M. & Johnson, J.D. Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity. Diabetologia (2015).
  4. Alemzadeh, R., Langley, G., Upchurch, L., Smith, P. & Slonim, A.E. Beneficial effect of diazoxide in obese hyperinsulinemic adults. J Clin Endocrinol Metab 83, 1911-5 (1998).
  5. Lustig, R.H., Rose, S.R., Burghen, G.A., Velasquez-Mieyer, P., Broome, D.C., Smith, K., Li, H., Hudson, M.M., Heideman, R.L. & Kun, L.E. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr 135, 162-8 (1999).
  6. Investigators, O.T., Gerstein, H.C., Bosch, J., Dagenais, G.R., Diaz, R., Jung, H., Maggioni, A.P., Pogue, J., Probstfield, J., Ramachandran, A., Riddle, M.C., Ryden, L.E. & Yusuf, S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367, 319-28 (2012).
  7. Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., Weinberger, A., Ben-Yacov, O., Lador, D., Avnit-Sagi, T., Lotan-Pompan, M., Suez, J., Mahdi, J.A., Matot, E., Malka, G., Kosower, N., Rein, M., Zilberman-Schapira, G., Dohnalova, L., Pevsner-Fischer, M., Bikovsky, R., Halpern, Z., Elinav, E. & Segal, E. Personalized Nutrition by Prediction of Glycemic Responses. Cell 163, 1079-94 (2015).

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