The Brain-Centered Glucoregulatory System: 4 Important New Studies

In December 2013, a key paper published in the journal Nature described the brain-centered glucoregulatory system (BCGS), (covered here in December 2013).¹ According to the BCGS theory, dysfunction in the central or peripheral systems of glucose homeostasis can set up a cycle in which both systems suffer, with the development of diabetes an ultimate result.  

What’s new in the research since the BCGS paper came out?

Brain and Periphery Communication

The BCGS model posits that the brain and periphery communicate continuously about glucose homeostasis. Changes at the brain level can increase or decrease insulin sensitivity in the periphery.

In a recent study at UT Southwestern Medical Center, published online on July 10, 2014 in Cell Metabolism, researchers found evidence in animal models for a genetic mechanism that links the brain and periphery.²  Just one transcription factor, they found, could play a role in leptin and insulin resistance, ultimately regulating body weight and glucose homeostasis. The implication is that manipulating one gene in the brain could regulate hepatic glucose production. Key findings:

  - The transcription factor Xbp1s controls gene activation in proopiomelanocortin (POMC) hypothalamic neurons (direct targets of leptin and insulin)

  - Mice fed a high-fat diet over-express  Xbp1s, which protects against obesity and diabetes

   - Xbp1s deficiency in hypothalamic POMC neurons results in hyperleptinemia, severe leptin resistance, lower metabolic rate, and obesity

  - Constitutive expression of Xbp1s in POMC neurons improves hepatic insulin sensitivity and decreases endogenous glucose production

Hypothalamus

The hypothalamus is thought to be the critical site of central dysfunction in the development of diabetes-especially damage to the neurocircuits in the ventromedial nucleus (VMN) which contains glucose-sensing cells.

In a study published online on July 28, 2014 in the Proceedings of the National Academy of Sciences, researchers at Yale School of Medicine think they have discovered how the VMN senses blood glucose levels.³ They looked at the enzyme prolyl endopeptidase (PREP), thought to play a previously unknown role in the central control of glucose metabolism.  In the hypothalamus, PREP is largely expressed in the VMN.  When PREP levels were low, the researchers found, hypothalamic neurons were no longer sensitive to rising glucose levels.  This rendered them ineffective in regulating pancreatic insulin release, and diabetes ensued.  Key points:

  - PREP sensitizes VMN neurons to rising glucose levels; these neurons in turn communicate with the pancreas to induce insulin release.

  - PREP-deficient knockout mice developed glucose intolerance, reduced fasting insulin, and increased pancreatic glucagon release

  - Central infusion of a PREP inhibitor led to impaired glucose tolerance and lower insulin levels in wild-type mice.

Human Studies

While animal studies about the BCGS far outnumber human studies, the evidence has been trickling in for humans, also. Do the animal fidings translate to humans?

Scientists postulate that the central melanocortin system helps regulate glucose metabolism by regulating peripheral insulin sensitivity, independent of its effect on energy homeostasis. Animal studies seem to back this up, but does the theory hold in humans? A recent case study says no.⁴ The case study was published in the International Journal of Obesityin January 2014 by researchers at the University of California, San Francisco. It describes an adolescent, the eighth human case of complete POMC deficiency and the first with concomitant T1DM. Key points:

  - The patient was severely obese and had concomitant adrenocortiocotropic hormone deficiency

  - Sequencing of the POMC gene revealed a mutation that completely obfuscated normal POMC synthesis

  - Insulin requirements for this patient, however, were consistent with age and stage of puberty.  This suggested that, while the central melanocortin system seemed to affect adiposity, it did not affect peripheral insulin sensitivity in this individual.

Past studies in animals have suggested that central insulin plays a role in controlling peripheral insulin sensitivity.  Whether this theory holds true in humans remains an open question. German scientists  tested this theory by looking at how intranasal insulin administration affects the brain and whole-body insulin sensitivity.⁵  Findings suggested that central administration of insulin activated the hypothalamus and improved peripheral insulin sensitivity in lean men, but not in obese men. Key points:

  - Intranasal insulin and placebo were administered in random order in lean and obese men.

  - Lean men: Insulin sensitivity improved, but participants needed a higher glucose infusion rate to maintain glycemic control, compared to placebo

  - Obese men: No insulin sensitizing effect was found

  - Whole-body insulin sensitivity: Correlated with alterations in hypothalamic activity (measured by fMRI).

Conclusion

At times the research can resemble a scatter plot, with scientists looking at a variety of oddly named genes, transcription factors, enzymes, and inflammatory molecules.  But there seems to be some method to the madness, and it offers accumulating evidence about the prominent role of the hypothalamus in diabetes.  As scientists pursue the conundrum, their work sustains hope for better diabetes drugs in the future-and possibly drugs that could even induce remission.

References:

• Schwartz MW, Seeley RJ, Tschop MH, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013;503:59-66.
• Williams KW, Liu T, Kong X. Xbp1s in POMC neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab.  Published online on July 10, 2014.
• Kima JD, Chitoku T, D’Agostinoa,G, et al.  Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice. Proc Natl Acad Sci U S A.  Published online on July 28, 2014. doi: 10.1073/pnas.1406000111
• Aslan IR, Ranadive SA, Valle I, Kollipara S, Noble JA, Vaisse C. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes (Lond). 2014;38:148-51. doi: 10.1038/ijo.2013.53.
• Heni M, Wagner R, Kullmann S, et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes. 2014 Jul 15. pii: DB_140477. [Epub ahead of print]