Jessica T.Y. Yue

Hypothalamic glucagon signaling inhibits hepatic glucose production

Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor–PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor–PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.

Oleanolic acid enhances insulin secretion in pancreatic β‐cells

We investigated the effect of oleanolic acid, a plant‐derived triterpenoid, on insulin secretion and content in pancreatic β‐cells and rat islets. Oleanolic acid significantly enhanced insulin secretion at basal and stimulatory glucose concentrations in INS‐1 832/13 cells and enhanced acute glucose‐stimulated insulin secretion in isolated rat islets. In the cell line the effects of oleanolic acid on insulin secretion were comparable to that of the sulfonylurea tolbutamide at basal glucose levels and with the incretin mimetic Exendin‐4 under glucose‐stimulated conditions, yet neither Ca2+ nor cAMP rose in response to oleanolic acid. Chronic treatment with oleanolic acid increased total cellular insulin protein and mRNA levels. These effects may contribute to the anti‐diabetic properties of this natural product.

Lipid Sensing and Insulin Resistance in the Brain

Lipid sensing and insulin signaling in the brain independently triggers a negative feedback system to lower glucose production and food intake. Here, we discuss the underlying molecular and neuronal mechanisms of lipid sensing and insulin signaling in the hypothalamus and how these mechanisms are affected in response to high-fat feeding. We propose that high-fat feeding concurrently disrupts hypothalamic insulin-signaling and lipid-sensing mechanisms and that experiments aimed to restore both insulin action and lipid sensing in the brain could effectively lower glucose production and food intake to restore metabolic homeostasis in type 2 diabetes and obesity.

Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with beta-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these adaptations may, in part, be related to reductions in inflammation and oxidative stress. We investigated circulating and tissue-specific markers of inflammation and oxidative stress and insulin-signaling pathways in a rodent model of T2DM, the Zucker diabetic fatty rat, with and without voluntary exercise. At 5 wk of age, Zucker diabetic fatty rats (n = 8-9/group) were divided into basal (B), voluntary exercise (E), and sedentary control (S) groups. B rats were euthanized at 6 wk of age, and S and E rats were euthanized 10 wk later. E rats ran approximately 5 km/day, which improved insulin sensitivity and maintained fed and fasted glucose levels and glucose tolerance. Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. Hepatic phosphoenolpyruvate carboxykinase levels and Ser(307)-phosphorylated insulin receptor substrate-1 were also reduced in E compared with S rats. In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

Glycine Normalizes Hepatic Triglyceride-Rich VLDL Secretion by Triggering the CNS in High-Fat Fed Rats

Rationale: Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesity and type 2 diabetes contributes to the dyslipidemia that leads to cardiovascular morbidity. The central nervous system (CNS), particularly the hypothalamus, regulates hepatic lipid metabolism. Although the underlying neurocircuitry remains elusive, glycine has been documented to enhance CNS N-methyl-D-aspartate (NMDA) receptor-mediated transmission. Objective: We tested the hypothesis that glycine regulates hepatic VLDL-TG secretion by potentiating NMDA receptor-mediated transmission in the CNS. Methods and Results: Using 10-hour fasted male Sprague-Dawley rats implanted with stereotaxic cannulae into an extrahypothalamic region termed the dorsal vagal complex (DVC) and vascular catheters to enable direct DVC infusion and blood sampling, respectively, the rate of hepatic VLDL-TG secretion was measured following tyloxapol (an inhibitor of lipoprotein lipase) injection. Direct DVC infusion of glycine lowered VLDL-TG secretion, whereas NMDA receptor blocker MK-801 fully negated glycines effect. NR1 subunit of NMDA receptor antagonist 7-chlorokynurenic acid, adenoviral injection of NR1 short hairpin RNA (shRNA), and hepatic vagotomy also nullified glycines effect. Finally, DVC glycine normalized the hypersecretion of VLDL-TG induced by high-fat feeding. Conclusions: Molecular and pharmacological inhibition of the NR1-containing NMDA receptors in the DVC negated the ability of glycine to inhibit hepatic secretion of VLDL-TG in vivo. Importantly, the hypersecretion of VLDL-TG from the liver induced by a model of high-fat feeding was restored by the hepatic lipid control of CNS glycine sensing. These findings collectively suggest that glycine or glycine analogues may have therapeutic benefits in lowering plasma lipid levels in diabetes and obesity by triggering the CNS.

Somatostatin Receptor Type 2 Antagonism Improves Glucagon and Corticosterone Counterregulatory Responses to Hypoglycemia in Streptozotocin-Induced Diabetic Rats

Diminished responsiveness to hypoglycemia contributes to defective counterregulation in diabetes. Pancreatic and/or circulating somatostatin are elevated in diabetes, which may inhibit counterregulatory hormone release during hypoglycemia. Thus, a selective somatostatin receptor type 2 antagonist (SSTR2a) should improve hormone counterregulation to hypoglycemia. Nondiabetic (N) and streptozotocin-induced diabetic (D) rats underwent 4-h infusion of saline or SSTR2a with insulin-induced hypoglycemia clamped at 2.5 ± 0.5 mmol/L. To evaluate the effect of the SSTR2a in the absence of hypoglycemia, rats underwent a 4-h infusion of saline (Ctrl:N, Ctrl:D) or SSTR2a (Ctrl:D+SSTR2a) only. The attenuated glucagon response to hypoglycemia in D (P < 0.0002) was fully restored by SSTR2a (P < 0.0001). Furthermore, the attenuated corticosterone response in D (P < 0.002) was also enhanced by SSTR2a (P < 0.05). In the absence of hypoglycemia, SSTR2a did not alter basal blood glucose levels. D exhibited 62% more pancreatic somatostatin than N after hypoglycemia. In N rats, SSTR2a did not augment the glucagon or corticosterone response to hypoglycemia. Thus, somatostatin may contribute to impaired glucagon responsiveness to hypoglycemia in diabetes. We demonstrate that SSTR2 antagonism enhances hypoglycemia-stimulated glucagon and corticosterone release in D but not in N rats. SSTR2 antagonism does not affect basal glycemia in D rats.

Insulin and glucagon signaling in the central nervous system

The prevalence of the obesity and diabetes epidemic has triggered tremendous research investigating the role of the central nervous system (CNS) in the regulation of food intake, body weight gain and glucose homeostasis. This invited review focuses on the role of two pancreatic hormones—insulin and glucagon—that trigger signaling pathways in the brain to regulate energy and glucose homeostasis. Unlike in the periphery, insulin and glucagon signaling in the CNS does not seem to have opposing metabolic effects, as both hormones exert a suppressive effect on food intake and weight gain. They signal through different pathways and alter different neuronal populations suggesting a complementary action of the two hormones in regulating feeding behavior. Similar to its systemic effect, insulin signaling in the brain lowers glucose production. However, the ability of glucagon signaling in the brain to regulate glucose production remains unknown. Future studies that aim to dissect insulin and glucagon signaling in the CNS that regulate energy and glucose homeostasis could unveil novel signaling molecules to lower body weight and glucose levels in obesity and diabetes.

Fatty acid sensing in the gut and the hypothalamus: In vivo and in vitro perspectives

The ability to properly sense both ingested and circulating nutrients is crucial for the maintenance of metabolic homeostasis. As such, both the gastrointestinal tract and the hypothalamus have demonstrated the capacity to sense and effectively respond to nutrients, such as fatty acids, to control food intake and glucose production to regulate energy and glucose homeostasis. In modern, Westernized societies, obesity and diabetes rates continue to rise unabated, due in part to an increase in highly palatable high-fat diet consumption. Thus, our understanding in the ability of the body to successfully monitor lipids is more vital than ever. This review details the current understanding of both the gut and the brain, specifically the hypothalamus, in sensing fatty acids. Highlighting both in vivo and in vitro studies, we explore some of the mechanisms upon which different fatty acids activate enteroendocrine and neural lipid-sensing signaling mechanisms to subsequently lower food intake and glucose production to ultimately regulate metabolic homeostasis. A better understanding of these lipid-sensing pathways could lay the groundwork for successful pharmacological targets for the treatment of obesity and diabetes.

Duodenal PKC-δ and Cholecystokinin Signaling Axis Regulates Glucose Production

OBJECTIVE Metabolism of long-chain fatty acids within the duodenum leads to the activation of duodenal mucosal protein kinase C (PKC)-δ and the cholecystokinin (CCK)-A receptor to lower glucose production through a neuronal network. However, the interfunctional relationship between duodenal PKC-δ and CCK remains elusive. Although long-chain fatty acids activate PKC to stimulate the release of CCK in CCK-secreting cells, CCK has also been found to activate PKC-δ in pancreatic acinar cells. We here evaluate whether activation of duodenal mucosal PKC-δ lies upstream (and/or downstream) of CCK signaling to lower glucose production. RESEARCH DESIGN AND METHODS We first determined with immunofluorescence whether PKC-δ and CCK were colocalized within the duodenal mucosa. We then performed gain- and loss-of-function experiments targeting duodenal PKC-δ and the CCK-A receptor and evaluated the impact on changes in glucose kinetics during pancreatic (basal insulin) clamps in rats in vivo. RESULTS Immunostaining of PKC-δ was found to colocalize with CCK in the duodenal mucosa. Intraduodenal coinfusion of either the CCK-A receptor antagonist MK-329 or CR-1409 with the PKC activator negated the ability of duodenal mucosal PKC-δ activation to lower glucose production during the pancreatic clamps in normal rats. Conversely, molecular and pharmacological inhibition of duodenal PKC-δ did not negate the ability of the duodenal CCK-A receptor agonist CCK-8 to lower glucose production, indicating that activation of duodenal PKC-δ lies upstream (and not downstream) of CCK signaling. Finally, intraduodenal PKC activator infusion failed to lower glucose production in rats with high-fat diet–induced duodenal CCK resistance. CONCLUSIONS In summary, activation of duodenal PKC-δ leads to the stimulation of CCK release and activation of the CCK-A receptor signaling axis to lower glucose production in normal rats, but fails to bypass duodenal CCK-resistance in high fat-fed rats.

Hypothalamic glucagon signals through the KATP channels to regulate glucose production

Insulin, leptin and GLP-1 signal in the mediobasal hypothalamus (MBH) to lower hepatic glucose production (GP). MBH glucagon action also inhibits GP but the downstream signaling mediators remain largely unknown. In parallel, a lipid-sensing pathway involving MBH AMPK→malonyl-CoA→CPT-1→LCFA-CoA→PKC-δ leading to the activation of KATP channels lowers GP. Given that glucagon signals through the MBH PKA to lower GP, and PKA inhibits AMPK in hypothalamic cell lines, a possibility arises that MBH glucagon-PKA inhibits AMPK, elevates LCFA-CoA levels to activate PKC-δ, and activates KATP channels to lower GP. We here report that neither molecular or chemical activation of MBH AMPK nor inhibition of PKC-δ negated the effect of MBH glucagon. In contrast, molecular and chemical inhibition of MBH KATP channels negated MBH glucagons effect to lower GP. Thus, MBH glucagon signals through a lipid-sensing independent but KATP channel-dependent pathway to regulate GP.