Neuronal regulation of glucagon secretion and gluconeogenesis

Abstract

Hypoglycemia almost never develops in healthy individuals, because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system, trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon, but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetes patients that receive insulin therapy. This leads to the risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques allow the characterization of glucose‐sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review discusses recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia and how they restore normoglycemia.

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia

“…Secretion of glucagon, which forms the first line of defence against hypoglycaemia, is controlled by multiple pancreatic-alpha-cell autonomous and non-autonomous mechanisms [ 2 ]. The role of central hypoglycaemia sensing in triggering glucagon secretion is well documented [ 3 ]. Neurons present in the brainstem, in particular in the dorsovagal complex, the parabrachial nucleus and the basolateral medulla, have been implicated in hypoglycaemia-induced glucagon secretion [ 4 ].…”

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

“…since this administration route resulted in significant higher levels of this SGA in plasma and hypothalamus in comparison to those of the oral treatment [ 32 ]. As such, we focused the present study in the connection between the hypothalamus and the liver since it has been reported that this axis modulates lipid metabolism in response to T 3 [ 19 ] and glucose homeostasis in response to leptin [ 100 , 101 ].…”

Pathophysiology and management of hypoglycemia in diabetes

“…116 In addition to these well-described counter-regulatory hormonal responses, the central nervous system (CNS) also plays a critical role in the response to hypoglycemia (Figure 1). Animal models have been instrumental in elucidating the different brain regions and neuronal circuits that contribute to an integrated response to falls in plasma glucose levels (several excellent reviews [117][118][119][120] ). Glucose-sensing neurons have been identified in the hindbrain, midbrain, as well as several regions within the hypothalamus, including the arcuate nucleus, the perifornical region of the lateral hypothalamus, as well as the ventromedial hypothalamus (VMH).…”