Danna M. Breen

Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes

Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity, but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit, lowers glucose concentrations in nonobese type 2 diabetic rats. Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding, the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.

Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network

Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)–induced reduction in duodenal–mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut–brain–liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD–fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance—a 28 d HFD–induced model of obesity and a nicotinamide (NA)–streptozotocin (STZ)–HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.

Nutrient-Sensing Mechanisms in the Gut as Therapeutic Targets for Diabetes

The small intestine is traditionally viewed as an organ that mediates nutrient digestion and absorption. This view has recently been revised owing to the ability of the duodenum to sense nutrient influx and trigger negative feedback loops to inhibit glucose production and food intake to maintain metabolic homeostasis. Further, duodenal nutrient-sensing defects are acquired in diabetes and obesity, leading to increased glucose production. In contrast, jejunal nutrient sensing inhibits glucose production and mediates the early antidiabetic effect of bariatric surgery, and gut microbiota composition may alter intestinal nutrient-sensing mechanisms to regain better control of glucose homeostasis in diabetes and obesity in the long term. This perspective highlights nutrient-sensing mechanisms in the gut that regulate glucose homeostasis and the potential of targeting gut nutrient-sensing mechanisms as a therapeutic strategy to lower blood glucose concentrations in diabetes.

Resveratrol inhibits neointimal formation after arterial injury through an endothelial nitric oxide synthase-dependent mechanism

Revascularization procedures used for treatment of atherosclerosis often result in restenosis. Resveratrol (RSV), an antioxidant with cardiovascular benefits, decreases neointimal formation after arterial injury by a mechanism that is still not fully clarified. Our main objective was to address the role of nitric oxide synthases (NOSes) and more specifically the endothelial-NOS (eNOS) isoform as a mediator of this effect. RSV (4 mg/kg/day, s.c.) alone or in combination with the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) (2 mg/kg/day, s.c.) was given to Sprague-Dawley rats beginning at 3 days before arterial (carotid or aortic) injury. RSV reduced neointimal formation by 50% (P<0.01), decreased intimal cell proliferation by 37% (P<0.01) and reduced inflammatory markers such as PECAM and MMP-9 mRNA. These effects of RSV were all abolished by coadministration of l-NAME. Oral RSV (beginning at 5 days before arterial injury) reduced neointimal thickness after femoral wire injury in mice, however this effect was not observed in eNOS knockout mice. This is the first report of RSV decreasing neointimal cell proliferation and neointimal growth through an eNOS-dependent mechanism.

Duodenal Mucosal Protein Kinase C-δ Regulates Glucose Production in Rats

BACKGROUND & AIMS Activation of protein kinase C (PKC) enzymes in liver and brain alters hepatic glucose metabolism, but little is known about their role in glucose regulation in the gastrointestinal tract. We investigated whether activation of PKC-δ in the duodenum is sufficient and necessary for duodenal nutrient sensing and regulates hepatic glucose production through a neuronal network in rats. METHODS In rats, we inhibited duodenal PKC and evaluated whether nutrient-sensing mechanisms, activated by refeeding, have disruptions in glucose regulation. We then performed gain- and loss-of-function pharmacologic and molecular experiments to target duodenal PKC-δ; we evaluated the impact on glucose production regulation during the pancreatic clamping, while basal levels of insulin were maintained. RESULTS PKC-δ was detected in the mucosal layer of the duodenum; intraduodenal infusion of PKC inhibitors disrupted glucose homeostasis during refeeding, indicating that duodenal activation of PKC-δ is necessary and sufficient to regulate glucose homeostasis. Intraduodenal infusion of the PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) specifically activated duodenal mucosal PKC-δ and a gut-brain-liver neuronal pathway to reduce glucose production. Molecular and pharmacologic inhibition of duodenal mucosal PKC-δ negated the ability of duodenal OAG and lipids to reduce glucose production. CONCLUSIONS In the duodenal mucosa, PKC-δ regulates glucose homeostasis.

Lipid sensing in the gut, brain and liver

Elevation of lipid levels affects energy and glucose homeostasis. Organs such as the gut, brain and liver detect a rise in lipids and orchestrate a biochemical, molecular, neuronal and physiological network of responses that alters appetite and the rate of hepatic glucose production. The factors involved in these responses are unclear but the formation of esterified lipids (long-chain fatty acyl-CoAs) and subsequent activation of protein kinase Cδ remain a common sensing mechanism in all three organs. In this paper, we discuss the mechanisms underlying lipid sensing within the gut, brain and liver and their physiological impact on the regulation of glucose and energy homeostasis.

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.

Jejunal leptin-PI3K signaling lowers glucose production

The fat-derived hormone leptin binds to its hypothalamic receptors to regulate glucose homeostasis. Leptin is also synthesized in the stomach and subsequently binds to its receptors expressed in the intestine, although the functional relevance of such activation remains largely unknown. We report here that intrajejunal leptin administration activates jejunal leptin receptors and signals through a phosphatidylinositol 3-kinase (PI3K)-dependent and signal transducer and activator of transcription 3 (STAT3)-independent signaling pathway to lower glucose production in healthy rodents. Jejunal leptin action is sufficient to lower glucose production in uncontrolled diabetic and high-fat-fed rodents and contributes to the early antidiabetic effect of duodenal-jejunal bypass surgery. These data unveil a glucoregulatory site of leptin action and suggest that enhancing leptin-PI3K signaling in the jejunum lowers plasma glucose concentrations in diabetes.

In vivo effects of polyunsaturated, monounsaturated, and saturated fatty acids on hepatic and peripheral insulin sensitivity.

OBJECTIVE Free fatty acids (FFAs) cause insulin resistance and are often elevated in obesity. Chronic ingestion of diets rich in saturated fat induces more insulin resistance than diets rich in unsaturated fat, however, it remains unclear whether different FFAs cause distinct levels of insulin resistance in the short-term, which is relevant to the feeding and fasting cycle. Protein kinase C (PKC)-δ is implicated in hepatic insulin resistance. Therefore, we investigated the effects of short-term elevation of fatty acids with different degrees of unsaturation on hepatic insulin action and liver PKC-δ membrane translocation, a marker of activation. MATERIALS/METHODS Triglyceride emulsions of Soybean Oil+Heparin (polyunsaturated (POLY)), Olive Oil+Heparin (monounsaturated (MONO)), Lard Oil+Heparin (saturated (SATU)), or saline (SAL) were infused intravenously for 7h to elevate plasma FFA concentrations ~3-4 fold in rats. During the last 2h of infusion, a hyperinsulinemic-euglycemic clamp with tritiated glucose methodology was performed to examine hepatic and peripheral insulin sensitivity. RESULTS Surprisingly, SATU, MONO, and POLY impaired peripheral insulin sensitivity (glucose utilization divided by insulin) to a similar extent. Furthermore, all lipids induced a similar degree of hepatic insulin resistance compared to SAL. Although there were changes in hepatic content of lipid metabolites, there were no significant differences in liver PKC-δ membrane translocation across fat groups. CONCLUSIONS In summary, in the short-term, FFAs with different degrees of unsaturation impair peripheral insulin sensitivity and induce hepatic insulin resistance as well as hepatic PKC-δ translocation to the same extent.

Gut–brain signalling: how lipids can trigger the gut

The gut plays a unique role in the metabolic defence against energy excess and glucose imbalance. Nutrients, such as lipids, enter the small intestine and activate sensing mechanisms to maintain energy and glucose homeostasis. It is clear that a lipid‐induced gut‐brain axis exists and that cholecystokinin and a neuronal network are involved, yet the underlying mechanisms in gut lipid sensing that regulate homeostasis remain largely unknown. In parallel, studies underscore the importance of enzymes involved in lipid metabolism within the brain, such as adenosine monophosphate ‐activated protein kinase, to maintain homeostasis. In this review, we will first examine what is known regarding the mechanisms involved in this lipid‐induced gut‐brain neuronal axis that regulate food intake and hepatic glucose production. We will also discuss how enzymes that govern brain lipid metabolism could potentially reveal how lipids trigger the gut, and that both the gut and brain may share common biochemical pathways to sense lipids. Copyright