Insulin resistance and impaired insulin secretion are considered the major pathogenetic factors resulting in hyperglycemia in type 2 diabetes. Although several mechanisms play a part in the development of hyperglycemia (1), excessive renal glucose reabsorption is now receiving much attention as a mechanism that contributes to the development of hyperglycemia (2). In euglycemic conditions, the kidney reabsorbs all of the filtered glucose primarily via the sodium–glucose cotransporter 2 (SGLT2), and secondarily via SGLT1. Glucose transporters GLUT2 and GLUT1 carry glucose across the basolateral membrane into the bloodstream. Glycosuria occurs when plasma glucose levels exceed the maximal reabsorptive capacity of the renal SGLTs. In hyperglycemic conditions, glomerular filtration of glucose is increased and glucose and sodium reabsorption via SGLT2 and SGLT1 is enhanced. Moreover, protein kinase C–activated translocation of GLUT2 to the apical membrane may contribute to increased reabsorption of glucose (Fig. 1A). The enhanced glucose reabsorption of diabetes has been the target of therapeutic intervention with the development of specific SGLT2 inhibitors that, with their novel mechanism of action, represent a new tool for the treatment of diabetes (3). Recent evidence shows that glucose reabsorption is under the control of the sympathetic nervous system (SNS) (4). However, there is still a lot to learn about the mechanisms by which the SNS may regulate renal handling of glucose in physiological or pathological conditions.
In this issue of Diabetes, Chhabra et al. (5) unexpectedly discover a brain-kidney connection that modulates glycosuria via sympathetic innervation. The authors show that mice with deficiency of hypothalamic arcuate nucleus proopiomelanocortin (ArcPOMC), despite exhibiting severe obesity and insulin resistance, display normal fasting glucose, an unexpected improved glucose clearance in an oral and intravenous glucose tolerance test, and increased glucose effectiveness. The authors explain this apparent paradox by demonstrating that ArcPOMC-deficient mice exhibit increased glycosuria when compared with wild-type controls at comparable blood glucose concentrations. The glycosuria of ArcPOMC-deficient mice was reversed by the central nervous system administration of the melanocortin receptor antagonist melanotan II, while central administration of the antagonist Agouti-related peptide (AgRP) to wild-type mice improved glucose tolerance and increased glycosuria. The authors speculate that the lack of hypothalamic melanocortin action reduced renal sympathetic tone and caused increased glycosuria. In support of this hypothesis, renal concentration of catecholamines was decreased in ArcPOMC-deficient mice and pretreatment with epinephrine restored glucose tolerance to the levels of wild-type mice. The glycosuria of ArcPOMC appears to be associated with the increased expression of renal glucose transporter 2 (rGLUT2) and not SGLT2. Thus, the authors propose that the lack of hypothalamic melanocortin tone inhibits the renal sympathetic tone, which in turn causes glycosuria via the suppression of GLUT2 expression (Fig. 1B).
These findings have important implications for our understanding of the role of the brain in modulating peripheral glucose metabolism. First, they establish that the hypothalamic melanocortin pathway modulates glucose homeostasis with mechanisms independent of insulin action. This is an important notion, although not necessarily a novel one, as previous studies have highlighted the role of central melanocortin action in the modulation of peripheral glucose metabolism independent of insulin action (6–8). However, the paradoxical improvement of glycemic control in ArcPOMC-deficient mice in the settings of obesity and insulin resistance suggests that obesity secondary to the mutation of the melanocortin pathway may have a unique metabolic profile in which impaired glucose tolerance is attenuated by virtue of a decreased sympathetic tone. Indeed, obese human subjects with melanocortin 4 receptor deficiency have decreased SNS tone (9). Second, the fact that central nervous system delivery of AgRP can elicit glycosuria and decrease glucose effectiveness in wild-type mice suggests that these mechanisms also may operate in physiological conditions. As the hypothalamic melanocortin pathway is physiologically stimulated by leptin when fat stores and nutrient availability are high and AgRP is increased when fat stores and nutrient availability are low (10), one could speculate that the activation of renal SNS in periods of adequate or high fat stores may prevent the loss of nutrients via glycosuria. Conversely, the suppression of renal SNS during starvation or fasting would result in a rather small amount of glycosuria because of the lower plasma glucose levels. Third, SGLT2 was not increased in the kidneys of ArcPOMC-deficient mice, indicating that the upregulation of this transporter found in diabetes did not take place in these mutant mice. In addition, GLUT2 was decreased in ArcPOMC-deficient mice, and its normal expression was restored by epinephrine treatment. In physiological conditions, GLUT2 is found at the basolateral membrane and is involved in the transport of glucose toward the bloodstream. However, in diabetes, GLUT2 can translocate to the apical membrane and contribute to the equilibration of the glucose concentration across the membrane (2). The expression profile of these glucose transporters suggests that hypothalamic POMC controls renal glucose handling with unknown mechanisms that will need to be elucidated. Finally, these studies indicate that the manipulation of the renal SNS may be a viable tool for improvement of hyperglycemia in diabetes.
Obese and diabetic rats exhibit higher renal SNS tone and overexpression of renal SGLT2 and GLUT2, and renal denervation (RDN) in these rats attenuates the overexpression of renal SGLT2 and GLUT2 and increases glycosuria (4). RDN has already been tested as potential treatment for diabetes. RDN has improved glycemia in a small group of drug-resistant hypertensive patients (11,12), but these results have not been confirmed in other studies (13). In the future, larger and better designed trials are required to establish the efficacy of RDN in improving glycemic control.
In summary, Chhabra et al. (5) present novel and intriguing data that support the notion that hypothalamic melanocortin tone controls renal handling of glucose via the SNS and can greatly improve glucose tolerance, with a mechanism independent of insulin action. These findings demonstrate a brain-kidney connection that may lead to the discovery of new targets for the treatment of diabetes.
See accompanying article, p. 660.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.