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  • Review Article
  • Published:

Targeting the CNS to treat type 2 diabetes

Nature Reviews Drug Discovery volume 8, pages 386–398 (2009)Cite this article

Key Points

  • Most drug discovery efforts aimed at type 2 diabetes target insulin action in peripheral tissues (muscle, fat and liver).

  • Recently, data have emerged that suggest the central nervous system (CNS) senses and integrates information from a host of neural, hormonal and nutrient signals. These signals are generated in response to the ingestion of food and regulate glucose output by the liver and glucose uptake by peripheral tissues.

  • CNS administration of insulin, leptin, glucagon-like peptide 1, glucose and long-chain fatty acids have all been shown to regulate liver glucose production, glucose uptake by skeletal muscle and/or insulin secretion.

  • AMP-activated protein kinase and mammalian target of rapamycin are important hypothalamic fuel sensors that regulate energy and possibly glucose homeostasis.

  • Before the CNS can be pharmacologically targeted for the treatment of diabetes, several obstacles must be overcome, including: differential peripheral and central actions on glucose and/or energy homeostasis; the blood–brain barrier limiting CNS exposure to circulating substances; and the fact that the key regions of the CNS that regulate homeostasis are deep in the midbrain and not easily studied in human subjects.

  • There are various strategies that have the potential to overcome these obstacles, including pharmacological developments that take advantage of the physical properties of the blood–brain barrier to allow specific delivery of drugs to the CNS, and targeting components of the fuel-sensing pathways downstream of hormones and nutrients that are specific to the CNS.

  • Given the overlap between the circuits that regulate energy and glucose homeostasis, it is reasonable to propose that part of the link between obesity and diabetes involves dysregulation of these common CNS circuits. Targeting these circuits presents new avenues for the development of more effective therapies that could produce both weight loss and improvements in glucose regulation.

Abstract

Research on the role of peripheral organs in the regulation of glucose homeostasis has led to the development of various monotherapies that aim to improve glucose uptake and insulin action in these organs for the treatment of type 2 diabetes. It is now clear that the central nervous system (CNS) also plays an important part in orchestrating appropriate glucose metabolism, with accumulating evidence linking dysregulated CNS circuits to the failure of normal glucoregulatory mechanisms. There is evidence that there is substantial overlap between the CNS circuits that regulate energy balance and those that regulate glucose levels, suggesting that their dysregulation could link obesity and diabetes. These findings present new targets for therapies that may be capable of both inducing weight loss and improving glucose regulation.

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Figure 1: Endocrine and neuroendocrine regulation of postprandial glucose homeostasis.
Figure 2: Central nervous system (CNS) regulation of glucose homeostasis.
Figure 3: Neuronal fuel sensing and regulation of energy and glucose homeostasis.
Figure 4: Potential integration of hypothalamic insulin and leptin signalling on mTOR and AMPK and how this might regulate glucose homeostasis.

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Acknowledgements

The authors acknowledge grant support from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DK075365 to D.A.S. and DK54080, DK54890 and DK56863 to R.J.S.) and the American Diabetes Association (support to S.O.).

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  1. Department of Psychiatry, Genome Research Institute, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, 45237, Ohio, USA

    Darleen A. Sandoval, Silvana Obici & Randy J. Seeley

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  1. Darleen A. Sandoval
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  2. Silvana Obici
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Correspondence to Randy J. Seeley.

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Randy J. Seeley is on the scientific advisory boards for eli Lilly and Company, ethicon endoSurgery, Johnson & Johnson and Zafgen, and has received research support from amylin and ethicon endoSurgery.

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Glossary

Postprandial

Relating to the time period immediately after a meal.

Incretin

A hormone that is secreted from the gut in response to a meal and stimulates insulin secretion.

Glucagon-like peptide 1

A hormone secreted from the L-cells of the distal intestine that acts as an incretin.

Exenatide

A long-acting glucagon-like peptide 1 analogue that is used to treat type 2 diabetes. Its known effects include stimulation of insulin secretion and modest weight loss.

Blood–brain barrier

An endothelial layer composed of tight junctions that limit the ability of substances to freely diffuse into the brain. The blood–brain barrier functions to protect the central nervous system from the blood.

Gluconeogenesis

The metabolic process that takes place in the kidneys, liver and gut, whereby glucose is made from non-glucose precursors such as glycerol, lactate and amino acids.

KATP channel

A potassium channel located on the cell membranes of many tissues, including the pancreas and the brain, that is opened or closed by changes in ATP levels.

AMP-activated protein kinase

(AMPK). A cellular fuel sensor that is activated in response to low ATP (energy) levels. Activation of AMPK stimulates the metabolic breakdown of fuel to generate ATP and restore the energy levels of the cell. When AMPK is activated in the central nervous system (CNS), it is a signal of low energy status in the whole organism and the CNS responds by stimulating food intake to restore energy needs.

Leptin

A hormone secreted by adipose tissue that is thought to serve as a signal of adiposity to the central nervous system.

Saturable transport system

A system to transport a molecule across the plasma membrane involving a specific transmembrane carrier, for which the rate of uptake decreases as the concentration of the molecule in the plasma increases.

Glycogenolysis

The process of breaking down stored glycogen to make glucose.

Mammalian target of rapamycin

(mTOR). A cellular fuel sensor that is activated in response to high ATP levels. Activation of mTOR serves to stimulate pathways that are involved in protein biosynthesis. When mTOR is activated in the central nervous system (CNS), the CNS responds to this signal of nutrient excess in the whole organism by inhibiting food intake.

Endoplasmic reticulum stress

Stress in the endoplasmic reticulum (where protein and sterol synthesis and protein folding take place) results when the influx of unfolded proteins exceeds the ability of the endoplasmic reticulum to fold the proteins.

Hyperinsulinaemic euglycaemic clamp

The gold standard for assessing insulin sensitivity. It involves a primed continuous infusion of insulin and a variable rate of infusion of exogenous glucose that is determined by the glucose level at that time point, with the goal of maintaining glucose at basal levels.

Glucose rate of appearance

The rate of glucose appearance in the plasma. Glucose enters the plasma primarily through the gastrointestinal tract and the liver. In the context of euglycaemic clamp conditions, glucose rate of appearance corresponds to liver glucose output.

Sulphonylurea receptor

The regulatory subunit of the KATP channel. This receptor is targeted clinically to increase insulin secretion in patients with type 2 diabetes.

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Sandoval, D., Obici, S. & Seeley, R. Targeting the CNS to treat type 2 diabetes. Nat Rev Drug Discov 8, 386–398 (2009). https://doi.org/10.1038/nrd2874

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