CNS Insulin Action Research Articles

Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.

Insulin can inhibit hepatic glucose production (HGP) by acting directly on the liver as well as indirectly through effects on adipose tissue, pancreas, and brain. While insulin's indirect effects are indisputable, their physiologic role in the suppression of HGP seen in response to increased insulin secretion is not clear. Likewise, the mechanisms by which insulin suppresses lipolysis and pancreatic α cell secretion under physiologic circumstances are also debated. In this study, insulin was infused into the hepatic portal vein to mimic increased insulin secretion, and insulin's indirect liver effects were blocked either individually or collectively. During physiologic hyperinsulinemia, plasma free fatty acid (FFA) and glucagon levels were clamped at basal values and brain insulin action was blocked, but insulin's direct effects on the liver were left intact. Insulin was equally effective at suppressing HGP when its indirect effects were absent as when they were present. In addition, the inhibition of lipolysis, as well as glucagon and insulin secretion, did not require CNS insulin action or decreased plasma FFA. This indicates that the rapid suppression of HGP is attributable to insulin's direct effect on the liver and that its indirect effects are redundant in the context of a physiologic increase in insulin secretion.

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of KATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7). Figure 1 Brain insulin regulation of hepatic glucose production and adipose tissue lipolysis. The insulin-signaling pathway in the arcuate hypothalamus involves the activation of PI3K and AKT and the subsequent inactivation of FoxO1. Also, the inhibition of AMPK and opening of KATP channels are linked to brain insulin’s peripheral metabolic effects. In addition …

Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

Ventromedial hypothalamus-specific Ptpn1 deletion exacerbates diet-induced obesity in female mice.

Protein-tyrosine phosphatase 1B (PTP1B) regulates food intake (FI) and energy expenditure (EE) by inhibiting leptin signaling in the hypothalamus. In peripheral tissues, PTP1B regulates insulin signaling, but its effects on CNS insulin action are largely unknown. Mice harboring a whole-brain deletion of the gene encoding PTP1B (Ptpn1) are lean, leptin-hypersensitive, and resistant to high fat diet-induced (HFD-induced) obesity. Arcuate proopiomelanocortin (POMC) neuron-specific deletion of Ptpn1 causes a similar, but much milder, phenotype, suggesting that PTP1B also acts in other neurons to regulate metabolism. Steroidogenic factor-1-expressing (SF-1-expressing) neurons in the ventromedial hypothalamus (VMH) play an important role in regulating body weight, FI, and EE. Surprisingly, Ptpn1 deletion in SF-1 neurons caused an age-dependent increase in adiposity in HFD-fed female mice. Although leptin sensitivity was increased and FI was reduced in these mice, they had impaired sympathetic output and decreased EE. Immunohistochemical analysis showed enhanced leptin and insulin signaling in VMH neurons from mice lacking PTP1B in SF-1 neurons. Thus, in the VMH, leptin negatively regulates FI, promoting weight loss, whereas insulin suppresses EE, leading to weight gain. Our results establish a novel role for PTP1B in regulating insulin action in the VMH and suggest that increased insulin responsiveness in SF-1 neurons can overcome leptin hypersensitivity and enhance adiposity.

P110alpha subunit of PI3K is a crucial component of brain insulin receptor signaling in regulating lumbar sympathetic nerve traffic

Increased regional sympathetic nerve activity (SNA) triggered by central nervous system (CNS) action of insulin has diverse physiological and pathophysiological implications. However, the molecular events underlying CNS action of insulin in mediating SNA elevation are poorly understood. Previously, we reported that pharmacological inhibition of phosphoinositide 3‐kinase (PI3K) selectively blocked the lumbar SNA response to intracerebroventricular (ICV) administration of insulin. Here, we tested the effect of genetic disruption of p110α catalytic subunit of PI3K on the sympathetic effect of CNS insulin. For this, we utilized a mouse model (p110αD933/WT) carrying a heterozygous mutation in p110α catalytic subunit of PI3K. We used multifiber sympathetic nerve recording to assess the SNA effects of insulin. In wild type mice, ICV administration of insulin (100 μU) caused a robust increase in lumbar SNA (259±37%, n=8). In contrast, ICV insulin failed to increase lumbar SNA in p110αD933/WTmice (−12±21%, n=5, P<0.05 vs. wild type mice). Our data demonstrate that p110α subunit of PI3K is an essential mediator of CNS insulin action to regulate lumbar sympathetic nerve traffic.

Insulin to treat Alzheimer’s disease: just follow your nose?

Evaluation of: Craft S, Baker LD, Montine TJ et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. doi:10.1001/archneurol.2011.233 (2011) (Epub ahead of print).Alzheimer’s disease (AD) is linked to CNS insulin resistance, decreased expression of insulin and insulin receptor genes, and lower cerebrospinal insulin levels. Against this background, impaired brain insulin signaling may account for some of the cognitive deficits associated with this disease. Using the intranasal method, which effectively bypasses the blood–brain barrier to deliver and target insulin directly from the nose to the brain, a series of acute clinical trials involving healthy humans and AD patients have shown that increased CNS insulin action enhances learning and memory processes. This article summarizes and evaluates data from a recently published clinical trial, in which 4 months of intranasal insulin administration (20 IU insulin/day) preserved not only general cognition but also reduced the loss of metabolic integrity of the brain in adults with mild-to-moderate AD.

Central insulin action regulates peripheral glucose and fat metabolism in mice

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.