Jarrad M. Scarlett

Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

Functional identification of a neurocircuit regulating blood glucose

Significance Hypoglycemia is an important and frequently encountered complication of diabetes treatment. Here, we identify a subset of neurons located in the ventromedial hypothalamic nucleus, activation of which is both necessary and sufficient to mediate adaptive counterregulatory responses to hypoglycemia that return low blood glucose levels into the normal range. These neurons receive ascending input from neurons in the lateral parabrachial nucleus and in turn control blood glucose levels via projections to the anterior bed nucleus of the stria terminalis. Together, this work identifies a previously unrecognized functional neurocircuit involved in glycemic control. Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMNSF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMNSF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMNSF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMNSF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMNSF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMNSF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMNSF1→aBNST neurocircuit.

Gut-brain mechanisms controlling glucose homeostasis.

Our current understanding of glucose homeostasis is centered on glucose-induced secretion of insulin from pancreatic islets and insulin action on glucose metabolism in peripheral tissues. In addition, however, recent evidence suggests that neurocircuits located within a brain-centered glucoregulatory system work cooperatively with pancreatic islets to promote glucose homeostasis. Among key observations is evidence that, in addition to insulin-dependent mechanisms, the brain has the capacity to potently lower blood glucose levels via mechanisms that are insulin-independent, some of which are activated by signals emanating from the gastrointestinal tract. This review highlights evidence supporting a key role for a “gut-brain-liver axis” in control of glucose homeostasis by the brain-centered glucoregulatory system and the implications of this regulatory system for diabetes pathogenesis and treatment.

How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes

Although the brain is clearly capable of affecting blood glucose levels, whether such effects are important in day-to-day blood glucose control remains a matter of controversy. In this Perspective, we update and expand on a previously described brain-centric model of glucose homeostasis (1), highlighting recent evidence of the brain’s capacity to influence the biologically defended level of circulating glucose in part through rapid and highly coordinated adjustments of both insulin sensitivity and insulin secretion. We also discuss the possibility that dysfunction of this brain-centric system contributes to the pathogenesis of type 2 diabetes by raising the defended level of glycemia. Finally, we discuss the implications of these concepts for the future of diabetes treatment. Traditionally, the interaction between pancreatic islets and insulin-sensitive tissues has been deemed sufficient to explain most aspects of glucose homeostasis. Whether the brain participates in the physiological control of circulating glucose levels therefore remains a matter of controversy, and the possibility that a dysfunctional central control system contributes to the pathogenesis of diabetes is only beginning to be explored. The overarching goal of this Perspective is to synthesize work from our laboratory and elsewhere that highlights recent progress and identifies emerging research and therapeutic opportunities in these areas. There is little question about the brain’s ability to influence key determinants of glucose homeostasis (e.g., rates of glucose production or utilization) in response to input from humoral signals, including glucose (2–4) and other nutrients (e.g., amino acids [5] or free fatty acids [6,7]), and nutritionally relevant hormones (e.g., insulin, leptin, ghrelin, and GLP-1 [8–10]). What remains uncertain is the extent to which such effects participate in day-to-day glucoregulation. Studies that use loss-of-function strategies (e.g., targeted gene deletion, receptor blockade, enzyme inhibitors, etc.) are perhaps most …

Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure

Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure.

Deletion of Protein Kinase C Lambda in POMC Neurons Predisposes to Diet-Induced Obesity

Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-λ in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons.

In Uncontrolled Diabetes, Hyperglucagonemia and Ketosis Result From Deficient Leptin Action in the Parabrachial Nucleus

Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCK neurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCK neurons drives activation of this LPBN→VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCK neurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis.