Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.

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.

Evidence continues to emerge detailing the myriad of ways the gut microbiota influences host energy homeostasis. Among the potential mechanisms, short chain fatty acids (SCFAs), the byproducts of microbial fermentation of dietary fibers, exhibit correlative beneficial metabolic effects in humans and rodents, including improvements in glucose homeostasis. The underlying mechanisms, however, remain elusive. We here report that one of the main bacterially produced SCFAs, propionate, activates ileal mucosal free fatty acid receptor 2 to trigger a negative feedback pathway to lower hepatic glucose production in healthy rats in vivo. We further demonstrate that an ileal glucagon-like peptide-1 receptor-dependent neuronal network is necessary for ileal propionate and long chain fatty acid sensing to regulate glucose homeostasis. These findings highlight the potential to manipulate fatty acid sensing machinery in the ileum to regulate glucose homeostasis.

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.

The gut is anatomically positioned to play a critical role in the regulation of metabolic homeostasis, providing negative feedback via nutrient sensing and local hormonal signaling. Gut hormones, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), are released following a meal and act on local receptors to regulate glycemia via a neuronal gut-brain axis. Additionally, jejunal nutrient sensing and leptin action are demonstrated to suppress glucose production, and both are required for the rapid antidiabetic effect of duodenal jejunal bypass surgery. Strategies aimed at targeting local gut hormonal signaling pathways may prove to be efficacious therapeutic options to improve glucose control in diabetes.

In the originally published version of this article, the first name and surnames of author Melika Zadeh-Tahmasebi were incorrectly tagged and improperly designated. This has since been fixed online.

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Larvae of Chironomus riparius respond to ion-poor and brackish water (IPW, BW) conditions by activating ion uptake mechanisms in the anal papillae and reducing ion absorption at the rectum, respectively. The role that the Malpighian tubules play in ion and osmoregulation under these conditions is not known in this species. This study examines rates of fluid secretion and major cation composition of secreted fluid from tubules of C. riparius reared in IPW, freshwater (FW) and BW. Fluid secretion of tubules from FW and BW larvae was similar but tubules from IPW larvae secrete fluid at higher rates, are more sensitive to serotonin stimulation, and the secreted fluid contains less Na(+) . Therefore in IPW, tubules work in concert with anal papillae to eliminate excess water while conserving Na(+) in the hemolymph. Tubules do not appear to play a significant role in ion/osmoregulation under BW. Serotonin immunoreactivity in the nervous system and gastrointestinal tract of larval C. riparius was similar to that seen in mosquito larvae with the exception that the hindgut was devoid of staining. Hemolymph serotonin titer was similar in FW and IPW; hence, serotonin is not responsible for the observed high rates of fluid secretion in IPW. Instead, it is suggested that serotonin may work in a synergistic manner with an unidentified hormonal factor in IPW. Ion transport mechanisms in the tubules of C. riparius are pharmacologically similar to those of other insects.