Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Impaired insulin action in the human brain: causes and metabolic consequences

Nature Reviews Endocrinology volume 11, pages 701–711 (2015)Cite this article

Subjects

Key Points

  • The human brain is an insulin-sensitive organ

  • Insulin in the human brain modulates food intake, body weight and peripheral metabolism

  • The human brain can become insulin resistant, a condition found in obesity as well as in people with visceral fat accumulation or specific genetic backgrounds

  • Overcoming brain insulin resistance could be a novel approach for the prevention and treatment of metabolic diseases such as type 2 diabetes mellitus

Abstract

Over the past few years, evidence has accumulated that the human brain is an insulin-sensitive organ. Insulin regulates activity in a limited number of specific brain areas that are important for memory, reward, eating behaviour and the regulation of whole-body metabolism. Accordingly, insulin in the brain modulates cognition, food intake and body weight as well as whole-body glucose, energy and lipid metabolism. However, brain imaging studies have revealed that not everybody responds equally to insulin and that a substantial number of people are brain insulin resistant. In this Review, we provide an overview of the effects of insulin in the brain in humans and the relevance of the effects for physiology. We present emerging evidence for insulin resistance of the human brain. Factors associated with brain insulin resistance such as obesity and increasing age, as well as possible pathogenic factors such as visceral fat, saturated fatty acids, alterations at the blood–brain barrier and certain genetic polymorphisms, are reviewed. In particular, the metabolic consequences of brain insulin resistance are discussed and possible future approaches to overcome brain insulin resistance and thereby prevent or treat obesity and type 2 diabetes mellitus are outlined.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Insulin-sensitive brain areas in humans.
Figure 2: Physiologic effects of insulin action in the brain.
Figure 3: Possible causes of brain insulin resistance.

Similar content being viewed by others

References

  1. Bernard, C. Leçons de physiologie expérimentale appliquées à la médecine. [French] (J. B. Baillière et fils, 1855).

  2. Havrankova, J., Roth, J. & Brownstein, M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272, 827–829 (1978).

    CAS  PubMed  Google Scholar 

  3. Hill, J. M., Lesniak, M. A., Pert, C. B. & Roth, J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 17, 1127–1138 (1986).

    CAS  PubMed  Google Scholar 

  4. Lesniak, M. A. et al. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology 123, 2089–2099 (1988).

    CAS  PubMed  Google Scholar 

  5. Hopkins, D. F. & Williams, G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet. Med. 14, 1044–1050 (1997).

    CAS  PubMed  Google Scholar 

  6. Hom, F. G., Goodner, C. J. & Berrie, M. A. A (3H)2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo: validation of the model and the absence of an insulin effect on brain. Diabetes 33, 141–152 (1984).

    CAS  PubMed  Google Scholar 

  7. Seaquist, E. R., Damberg, G. S., Tkac, I. & Gruetter, R. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 50, 2203–2209 (2001).

    CAS  PubMed  Google Scholar 

  8. Brüning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    PubMed  Google Scholar 

  9. Kleinridders, A., Ferris, H. A., Cai, W. & Kahn, C. R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63, 2232–2243 (2014).

    PubMed  PubMed Central  Google Scholar 

  10. Vogt, M. C. & Brüning, J. C. CNS insulin signaling in the control of energy homeostasis and glucose metabolism—from embryo to old age. Trends Endocrinol. Metab. 24, 76–84 (2013).

    CAS  PubMed  Google Scholar 

  11. Fernandez, A. M. & Torres-Alemán, I. The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 13, 225–239 (2012).

    CAS  PubMed  Google Scholar 

  12. Tschritter, O. et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc. Natl Acad. Sci. USA 103, 12103–12108 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Porubská, K. et al. Processing of food-relevant visual stimuli measured by magnetoencephalography and its modulation by insulin. Int. Congr. Ser. 1300, 516–519 (2007).

    Google Scholar 

  14. Benedict, L., Nelson, C. A., Schunk, E., Sullwold, K. & Seaquist, E. R. Effect of insulin on the brain activity obtained during visual and memory tasks in healthy human subjects. Neuroendocrinology 83, 20–26 (2006).

    CAS  PubMed  Google Scholar 

  15. Hallschmid, M. et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 53, 2202–2208 (2004).

    CAS  PubMed  Google Scholar 

  16. Anthony, K. et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes 55, 2986–2992 (2006).

    CAS  PubMed  Google Scholar 

  17. Bingham, E. M. et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51, 3384–3390 (2002).

    CAS  PubMed  Google Scholar 

  18. Rotte, M. et al. Insulin affects the neuronal response in the medial temporal lobe in humans. Neuroendocrinology 81, 49–55 (2005).

    CAS  PubMed  Google Scholar 

  19. Seaquist, E. R. et al. Insulin reduces the BOLD response but is without effect on the VEP during presentation of a visual task in humans. J. Cereb. Blood Flow Metab. 27, 154–160 (2007).

    CAS  PubMed  Google Scholar 

  20. Born, J. et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5, 514–516 (2002).

    CAS  PubMed  Google Scholar 

  21. Stingl, K. T. et al. Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects. Front. Syst. Neurosci. 4, 157 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kern, W., Born, J., Schreiber, H. & Fehm, H. L. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 48, 557–563 (1999).

    CAS  PubMed  Google Scholar 

  23. Guthoff, M. et al. The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects. PLoS ONE 6, e19482 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Renner, D. B. et al. Intranasal delivery of insulin via the olfactory nerve pathway. J. Pharm. Pharmacol. 64, 1709–1714 (2012).

    CAS  PubMed  Google Scholar 

  25. Heni, M. et al. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Diabetologia 55, 1773–1782 (2012).

    CAS  PubMed  Google Scholar 

  26. Spetter, M. & Hallschmid, M. Intranasal neuropeptide administration to target the human brain in health and disease. Mol. Pharm. 12, 2767–2780 (2015).

    CAS  PubMed  Google Scholar 

  27. Havrankova, J., Schmechel, D., Roth, J. & Brownstein, M. Identification of insulin in rat brain. Proc. Natl Acad. Sci. USA 75, 5737–5741 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Woods, S. C., Seeley, R. J., Baskin, D. G. & Schwartz, M. W. Insulin and the blood–brain barrier. Curr. Pharm. Des. 9, 795–800 (2003).

    CAS  PubMed  Google Scholar 

  29. Banks, W. A. The source of cerebral insulin. Eur. J. Pharmacol. 490, 5–12 (2004).

    CAS  PubMed  Google Scholar 

  30. Wallum, B. J. et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190–194 (1987).

    CAS  PubMed  Google Scholar 

  31. Kern, W. et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia 49, 2790–2792 (2006).

    CAS  PubMed  Google Scholar 

  32. Heni, M. et al. Evidence for altered transport of insulin across the blood–brain barrier in insulin-resistant humans. Acta Diabetol. 51, 679–681 (2014).

    CAS  PubMed  Google Scholar 

  33. Bromander, S. et al. Cerebrospinal fluid insulin during non-neurological surgery. J. Neural Transm. 117, 1167–1170 (2010).

    CAS  PubMed  Google Scholar 

  34. Pardridge, W. M., Eisenberg, J. & Yang, J. Human blood–brain barrier insulin receptor. J. Neurochem. 44, 1771–1778 (1985).

    CAS  PubMed  Google Scholar 

  35. Frölich, L. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J. Neural Transm. 105, 423–438 (1998).

    PubMed  Google Scholar 

  36. Sartorius, T. et al. The brain response to peripheral insulin declines with age: a contribution of the blood–brain barrier? PLoS ONE 10, e0126804 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. Craft, S. et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50, 164–168 (1998).

    CAS  PubMed  Google Scholar 

  38. Gray, S. M., Meijer, R. I. & Barrett, E. J. Insulin regulates brain function, but how does it get there? Diabetes 63, 3992–3997 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kullmann, S., Heni, M., Fritsche, A. & Preissl, H. Insulin action in the human brain: evidence from neuroimaging studies. J. Neuroendocrinol. 27, 419–423 (2015).

    CAS  PubMed  Google Scholar 

  40. Matsuda, M. et al. Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes 48, 1801–1806 (1999).

    CAS  PubMed  Google Scholar 

  41. Little, T. J. et al. Mapping glucose-mediated gut-to-brain signalling pathways in humans. Neuroimage 96, 1–11 (2014).

    CAS  PubMed  Google Scholar 

  42. Heni, M. et al. Differential effect of glucose ingestion on the neural processing of food stimuli in lean and overweight adults. Hum. Brain Mapp. 35, 918–928 (2014).

    PubMed  Google Scholar 

  43. Smeets, P. A., de Graaf, C., Stafleu, A., van Osch, M. J. & van der Grond, J. Functional MRI of human hypothalamic responses following glucose ingestion. Neuroimage 24, 363–368 (2005).

    PubMed  Google Scholar 

  44. Teeuwisse, W. M. et al. Short-term caloric restriction normalizes hypothalamic neuronal responsiveness to glucose ingestion in patients with type 2 diabetes. Diabetes 61, 3255–3259 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Page, K. A. et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 309, 63–70 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Vidarsdottir, S. et al. Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Diabetes 56, 2547–2550 (2007).

    CAS  PubMed  Google Scholar 

  47. Kullmann, S. et al. Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women. Neuroendocrinology 97, 176–182 (2013).

    CAS  PubMed  Google Scholar 

  48. Kullmann, S. et al. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 38, 1044–1050 (2015).

    CAS  PubMed  Google Scholar 

  49. Guthoff, M. et al. Insulin modulates food-related activity in the central nervous system. J. Clin. Endocrinol. Metab. 95, 748–755 (2010).

    CAS  PubMed  Google Scholar 

  50. Kroemer, N. B. et al. (Still) longing for food: insulin reactivity modulates response to food pictures. Hum. Brain Mapp. 34, 2367–2380 (2012).

    PubMed  PubMed Central  Google Scholar 

  51. Zhang, H. et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64, 1025–1034 (2015).

    CAS  PubMed  Google Scholar 

  52. Winocur, G., Moscovitch, M. & Bontempi, B. Memory formation and long-term retention in humans and animals: convergence towards a transformation account of hippocampal–neocortical interactions. Neuropsychologia 48, 2339–2356 (2010).

    PubMed  Google Scholar 

  53. Kern, W. et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 74, 270–280 (2001).

    CAS  PubMed  Google Scholar 

  54. Benedict, C. et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326–1334 (2004).

    CAS  PubMed  Google Scholar 

  55. Benedict, C. et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32, 239–243 (2007).

    CAS  PubMed  Google Scholar 

  56. Benedict, C., Kern, W., Schultes, B., Born, J. & Hallschmid, M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab. 93, 1339–1344 (2008).

    CAS  PubMed  Google Scholar 

  57. Ott, V., Benedict, C., Schultes, B., Born, J. & Hallschmid, M. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes. Metab. 14, 214–221 (2012).

    CAS  PubMed  Google Scholar 

  58. Novak, V. et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37, 751–759 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Craft, S., Cholerton, B. & Baker, L. D. Insulin and Alzheimer's disease: untangling the web. J. Alzheimers Dis. 33, S263–S275 (2013).

    PubMed  Google Scholar 

  60. Freiherr, J. et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 27, 505–514 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yarchoan, M. & Arnold, S. E. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253–2261 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. Wallner-Liebmann, S. et al. Insulin and hippocampus activation in response to images of high-calorie food in normal weight and obese adolescents. Obes. (Silver Spring) 18, 1552–1557 (2010).

    CAS  Google Scholar 

  63. Ketterer, C. et al. Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects. Int. J. Obes. (Lond.) 35, 1135–1138 (2011).

    CAS  Google Scholar 

  64. Brünner, Y. F., Benedict, C. & Freiherr, J. Intranasal insulin reduces olfactory sensitivity in normosmic humans. J. Clin. Endocrinol. Metab. 98, E1626–E1630 (2013).

    PubMed  Google Scholar 

  65. Flint, A. et al. Associations between postprandial insulin and blood glucose responses, appetite sensations and energy intake in normal weight and overweight individuals: a meta-analysis of test meal studies. Br. J. Nutr. 98, 17–25 (2007).

    CAS  PubMed  Google Scholar 

  66. Hallschmid, M., Higgs, S., Thienel, M., Ott, V. & Lehnert, H. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61, 782–789 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Jauch-Chara, K. et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 61, 2261–2268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Hallschmid, M. et al. Intranasal insulin reduces body fat in men but not in women. Diabetes 53, 3024–3029 (2004).

    CAS  PubMed  Google Scholar 

  69. Tschritter, O. et al. High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention. Diabetologia 55, 175–182 (2012).

    CAS  PubMed  Google Scholar 

  70. Pontiroli, A. E., Miele, L. & Morabito, A. Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diabetes Obes. Metab. 13, 1008–1019 (2011).

    CAS  PubMed  Google Scholar 

  71. Scherer, T. & Buettner, C. Yin and yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Rev. Endocr. Metab. Disord. 12, 235–243 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Benedict, C. et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 60, 114–118 (2011).

    CAS  PubMed  Google Scholar 

  73. Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Koch, L. et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Invest. 118, 2132–2147 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Coomans, C. P. et al. Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice. J. Lipid Res. 52, 1712–1722 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Iwen, K. A. et al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab. 99, E246–E251 (2014).

    CAS  PubMed  Google Scholar 

  77. Jensen, M. D., Caruso, M., Heiling, V. & Miles, J. M. Insulin regulation of lipolysis in nondiabetic and IDDM subjects. Diabetes 38, 1595–1601 (1989).

    CAS  PubMed  Google Scholar 

  78. Heni, M. et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 63, 4083–4088 (2014).

    CAS  PubMed  Google Scholar 

  79. Gancheva, S. et al. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 64, 1966–1975 (2015).

    CAS  PubMed  Google Scholar 

  80. Dash, S., Xiao, C., Morgantini, C., Koulajian, K. & Lewis, G. F. Intranasal insulin suppresses endogenous glucose production in humans compared to placebo, in the presence of similar venous insulin concentration. Diabetes 64, 766–774 (2015).

    CAS  PubMed  Google Scholar 

  81. Heni, M., Wagner, R., Kullmann, S., Preissl, H. & Fritsche, A. Response to Comment on Heni. et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 2014;63:4083–4088. Diabetes 64, e8–e9 (2015).

    CAS  PubMed  Google Scholar 

  82. Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).

    CAS  PubMed  Google Scholar 

  83. Macedo, M. P. et al. Risk of postprandial insulin resistance: the liver/vagus rapport. Rev. Endocr. Metab. Disord. 15, 67–77 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Filippi, B. M., Yang, C. S., Tang, C. & Lam, T. K. T. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab. 16, 500–510 (2012).

    CAS  PubMed  Google Scholar 

  85. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain–liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005).

    CAS  PubMed  Google Scholar 

  86. Könner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007).

    PubMed  Google Scholar 

  87. Coomans, C. P. et al. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice. Diabetes 60, 3132–3140 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ramnanan, C. J., Edgerton, D. S. & Cherrington, A. D. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metab. 15, 656–664 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Girard, J. Insulin's effect on the liver: 'direct or indirect?' continues to be the question. J. Clin. Invest. 116, 302–304 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kishore, P. et al. Activation of KATP channels suppresses glucose production in humans. J. Clin. Invest. 121, 4916–4920 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).

    CAS  PubMed  Google Scholar 

  92. Wallace, T. M., Levy, J. C. & Matthews, D. R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487–1495 (2004).

    PubMed  Google Scholar 

  93. Nolan, J. J. & Færch, K. Estimating insulin sensitivity and β cell function: perspectives from the modern pandemics of obesity and type 2 diabetes. Diabetologia 55, 2863–2867 (2012).

    CAS  PubMed  Google Scholar 

  94. Edgerton, D. S. & Cherrington, A. D. Is brain insulin action relevant to the control of plasma glucose in humans? Diabetes 64, 696–699 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ott, V. et al. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. Diabetes 64, 760–765 (2015).

    CAS  PubMed  Google Scholar 

  96. Scarlett, J. M. & Schwartz, M. W. Gut–brain mechanisms controlling glucose homeostasis. F1000Prime Rep. 7, 12 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. Stockhorst, U., de Fries, D., Steingrueber, H.-J. & Scherbaum, W. A. Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial. Diabetologia 54, 1502–1506 (2011).

    CAS  PubMed  Google Scholar 

  98. Benedict, C. et al. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism 54, 1356–1361 (2005).

    CAS  PubMed  Google Scholar 

  99. Bohringer, A., Schwabe, L., Richter, S. & Schachinger, H. Intranasal insulin attenuates the hypothalamic–pituitary–adrenal axis response to psychosocial stress. Psychoneuroendocrinology 33, 1394–1400 (2008).

    CAS  PubMed  Google Scholar 

  100. Hallschmid, M., Benedict, C., Schultes, B., Born, J. & Kern, W. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int. J. Obes. (Lond.) 32, 275–282 (2008).

    CAS  Google Scholar 

  101. Chong, A. C., Vogt, M. C., Hill, A. S., Brüning, J. C. & Zeltser, L. M. Central insulin signaling modulates hypothalamus–pituitary–adrenal axis responsiveness. Mol. Metab. 4, 83–92 (2015).

    CAS  PubMed  Google Scholar 

  102. Fekete, C. et al. Differential effects of central leptin, insulin, or glucose administration during fasting on the hypothalamic–pituitary–thyroid axis and feeding-related neurons in the arcuate nucleus. Endocrinology 147, 520–529 (2006).

    CAS  PubMed  Google Scholar 

  103. Ketterer, C. et al. Insulin sensitivity of the human brain. Diabetes Res. Clin. Pract. 93, S47–S51 (2011).

    CAS  PubMed  Google Scholar 

  104. Hallschmid, M. & Schultes, B. Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders? Diabetologia 52, 2264–2269 (2009).

    CAS  PubMed  Google Scholar 

  105. Kullmann, S. et al. The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum. Brain Mapp. 33, 1052–1061 (2012).

    PubMed  Google Scholar 

  106. Tuulari, J. J. et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes 62, 2747–2751 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tschritter, O. et al. Cerebrocortical β activity in overweight humans responds to insulin detemir. PLoS ONE 2, e1196 (2007).

    PubMed  PubMed Central  Google Scholar 

  108. Hirvonen, J. et al. Effects of insulin on brain glucose metabolism in impaired glucose tolerance. Diabetes 60, 443–447 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Tschritter, O. et al. Insulin effects on β and θ activity in the human brain are differentially affected by ageing. Diabetologia 52, 169–171 (2009).

    CAS  PubMed  Google Scholar 

  110. Sobngwi, E. et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 361, 1861–1865 (2003).

    PubMed  Google Scholar 

  111. Dabelea, D. et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49, 2208–2211 (2000).

    CAS  PubMed  Google Scholar 

  112. Gupta, A., Srinivasan, M., Thamadilok, S. & Patel, M. S. Hypothalamic alterations in fetuses of high fat diet-fed obese female rats. J. Endocrinol. 200, 293–300 (2009).

    CAS  PubMed  Google Scholar 

  113. Vogt, M. C. et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156, 495–509 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Linder, K. et al. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity. Diabetologia 57, 1192–1198 (2014).

    CAS  PubMed  Google Scholar 

  115. Tschritter, O. et al. The insulin effect on cerebrocortical θ activity is associated with serum concentrations of saturated nonesterified fatty acids. J. Clin. Endocrinol. Metab. 94, 4600–4607 (2009).

    CAS  PubMed  Google Scholar 

  116. Krogmann, A. et al. Inflammatory response of human coronary artery endothelial cells to saturated long-chain fatty acids. Microvasc. Res. 81, 52–59 (2011).

    CAS  PubMed  Google Scholar 

  117. Stefan, N., Wahl, H. G., Fritsche, A., Häring, H. & Stumvoll, M. Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans. Horm. Metab. Res. 33, 432–438 (2001).

    CAS  PubMed  Google Scholar 

  118. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997).

    CAS  PubMed  Google Scholar 

  119. Könner, A. C. & Brüning, J. C. Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol. Metab. 22, 16–23 (2011).

    PubMed  Google Scholar 

  120. Hennige, A. M. et al. Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity. Diabetologia 52, 2416–2424 (2009).

    CAS  PubMed  Google Scholar 

  121. Sartorius, T. et al. Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture. FASEB J. 26, 1799–1809 (2012).

    CAS  PubMed  Google Scholar 

  122. Staiger, H. et al. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes. Res. 11, 368–372 (2003).

    CAS  PubMed  Google Scholar 

  123. Könner, A. C. & Brüning, J. C. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 16, 144–152 (2012).

    PubMed  Google Scholar 

  124. Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350–1355 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Sartorius, T. et al. Leptin affects insulin action in astrocytes and impairs insulin-mediated physical activity. Cell. Physiol. Biochem. 30, 238–246 (2012).

    CAS  PubMed  Google Scholar 

  126. Argente-Arizón, P., Freire-Regatillo, A., Argente, J. & Chowen, J. A. Role of non-neuronal cells in body weight and appetite control. Front. Endocrinol. 6, 42 (2015).

    Google Scholar 

  127. Farooqi, I. S. et al. Leptin regulates striatal regions and human eating behavior. Science 317, (2007).

  128. Frank, S. et al. Leptin therapy in a congenital leptin-deficient patient leads to acute and long-term changes in homeostatic, reward, and food-related brain areas. J. Clin. Endocrinol. Metab. 96, E1283–E1287 (2011).

    CAS  PubMed  Google Scholar 

  129. Frank, S. et al. Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient. PLoS ONE 8, (2013).

  130. Schwartz, M. W. et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503, 59–66 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006).

    CAS  PubMed  Google Scholar 

  132. Tschritter, O. et al. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50, 2602–2603 (2007).

    CAS  PubMed  Google Scholar 

  133. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    CAS  PubMed  Google Scholar 

  135. Haupt, A. et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp. Clin. Endocrinol. Diabetes 117, 194–197 (2009).

    CAS  PubMed  Google Scholar 

  136. Heni, M. et al. Variation in the obesity risk gene FTO determines the postprandial cerebral processing of food stimuli in the prefrontal cortex. Mol. Metab. 3, 109–113 (2013).

    PubMed  PubMed Central  Google Scholar 

  137. Tschritter, O. et al. An obesity risk SNP (rs17782313) near the MC4R gene is associated with cerebrocortical insulin resistance in humans. J. Obes. 2011, 283153 (2011).

    PubMed  PubMed Central  Google Scholar 

  138. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    CAS  PubMed  Google Scholar 

  139. Ketterer, C. et al. Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action. Obesity (Silver Spring) 22, 925–931 (2014).

    CAS  Google Scholar 

  140. Di Marzo, V. & Matias, I. Endocannabinoid control of food intake and energy balance. Nat. Neurosci. 8, 585–589 (2005).

    CAS  PubMed  Google Scholar 

  141. Yeo, G. S. H. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112 (1998).

    CAS  PubMed  Google Scholar 

  142. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114 (1998).

    CAS  PubMed  Google Scholar 

  143. Reger, M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451–458 (2006).

    CAS  PubMed  Google Scholar 

  144. Jastreboff, A. M. et al. Neural correlates of stress- and food cue-induced food craving in obesity: association with insulin levels. Diabetes Care 36, 394–402 (2013).

    PubMed  PubMed Central  Google Scholar 

  145. de la Monte, S. M. & Tong, M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem. Pharmacol. 88, 548–559 (2014).

    CAS  PubMed  Google Scholar 

  146. Craft, S. Alzheimer disease: insulin resistance and AD—extending the translational path. Nat. Rev. Neurol. 8, 360–362 (2012).

    CAS  PubMed  Google Scholar 

  147. Hennige, A. M. et al. Tissue selectivity of insulin detemir action in vivo. Diabetologia 49, 1274–1282 (2006).

    CAS  PubMed  Google Scholar 

  148. Begg, D. P. et al. Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin. Diabetes 64, 2457–2466 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Hallschmid, M. et al. Euglycemic infusion of insulin detemir compared with human insulin appears to increase direct current brain potential response and reduces food intake while inducing similar systemic effects. Diabetes 59, 1101–1107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Frier, B. M., Russell-Jones, D. & Heise, T. A comparison of insulin detemir and neutral protamine Hagedorn (isophane) insulin in the treatment of diabetes: a systematic review. Diabetes Obes. Metab. 15, 978–986 (2013).

    CAS  PubMed  Google Scholar 

  151. Claxton, A. et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J. Alzheimers Dis. 44, 897–906 (2015).

    CAS  PubMed  Google Scholar 

  152. Łabuzek, K. et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep. 62, 956–965 (2010).

    PubMed  Google Scholar 

  153. Begg, D. P. et al. Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats. Endocrinology 154, 1047–1054 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Gallwitz, B. Anorexigenic effects of GLP-1 and its analogues. Handb. Exp. Pharmacol. 209, 185–207 (2012).

    CAS  Google Scholar 

  155. Ferrannini, E. & Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat. Rev. Endocrinol. 8, 495–502 (2012).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to colleagues whose important contributions they were unable to cite owing to space limitations. The authors are partly supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Centre for Diabetes Research (DZD e.V.: 01GI09) and the Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University, Partners in the German Centre for Diabetes Research (DZD), Otfried-Müller-Street 10, Tübingen, 72076, Germany

    Martin Heni, Andreas Fritsche & Hans-Ulrich Häring

  2. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Partners in the German Centre for Diabetes Research (DZD), Otfried-Müller-Street 10, Tübingen, 72076, Germany

    Stephanie Kullmann & Hubert Preissl

Authors
  1. Martin Heni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephanie Kullmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hubert Preissl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Fritsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans-Ulrich Häring
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors provided substantial contribution to discussion of the content and reviewed/edited the manuscript before submission. M.H. wrote the article.

Corresponding author

Correspondence to Martin Heni.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heni, M., Kullmann, S., Preissl, H. et al. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol 11, 701–711 (2015). https://doi.org/10.1038/nrendo.2015.173

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2015.173

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing