Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production.

Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR.

Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing.

High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.

Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis.

Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway.

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)-dependent glucose sensing to lower glucose production in high-fat-fed rats.

The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat-fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high fat-fed rats. In summary, our findings illustrate that leptin enhances LDHA-dependent glucose sensing in the hypothalamus to lower glucose production in high-fat-fed rodents in vivo.

Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway.

The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance of Lactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance of Lactobacillus and glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway.

Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the Dorsal Vagal Complex Regulate Insulin Action.

Mitochondria undergo dynamic changes to maintain function in eukaryotic cells. Insulin action in parallel regulates glucose homeostasis, but whether specific changes in mitochondrial dynamics alter insulin action and glucose homeostasis remains elusive. Here, we report that high-fat feeding in rodents incurred adaptive dynamic changes in mitochondria through an increase in mitochondrial fission in parallel to an activation of dynamin-related protein 1 (Drp1) in the dorsal vagal complex (DVC) of the brain. Direct inhibition of Drp1 negated high-fat-feeding-induced mitochondrial fission, endoplasmic reticulum (ER) stress, and insulin resistance in the DVC and subsequently restored hepatic glucose production regulation. Conversely, molecular activation of DVC Drp1 in healthy rodents was sufficient to induce DVC mitochondrial fission, ER stress, and insulin resistance. Together, these data illustrate that Drp1-dependent mitochondrial fission changes in the DVC regulate insulin action and suggest that targeting the Drp1-mitochondrial-dependent pathway in the brain may have therapeutic potential in insulin resistance.

Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity.

Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.

Targeting the gastrointestinal tract to treat type 2 diabetes.

The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

Activation of Short and Long Chain Fatty Acid Sensing Machinery in the Ileum Lowers Glucose Production in Vivo.

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.

Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology.

Emerging evidence suggests the gastrointestinal tract plays an important glucoregulatory role. In this perspective, we first review how the intestine senses ingested nutrients, initiating crucial negative feedback mechanisms through a gut-brain neuronal axis to regulate glycemia, mainly via reduction in hepatic glucose production. We then highlight how intestinal energy sensory mechanisms are responsible for the glucose-lowering effects of bariatric surgery, specifically duodenal-jejunal bypass, and the antidiabetic agents metformin and resveratrol. A better understanding of these pathways lays the groundwork for intestinally targeted drug therapy for the treatment of diabetes.