Frank Anthony Duca

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Journals/Publications

• Howard, E. J., Lam, T. K., & Duca, F. A. (2022). The Gut Microbiome: Connecting Diet, Glucose Homeostasis, and Disease. Annual review of medicine, 73, 469-481.
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  Type 2 diabetes rates continue to rise unabated, underscoring the need to better understand the etiology and potential therapeutic options available for this disease. The gut microbiome plays a role in glucose homeostasis, and diabetes is associated with alterations in the gut microbiome. Given that consumption of a Western diet is associated with increased metabolic disease, and that a Western diet alters the gut microbiome, it is plausible that changes in the gut microbiota mediate the dysregulation in glucose homeostasis. In this review, we highlight a few of the most significant mechanisms by which the gut microbiome can influence glucose regulation, including changes in gut permeability, gut-brain signaling, and production of bacteria-derived metabolites like short-chain fatty acids and bile acids. A better understanding of these pathways could lead to the development of novel therapeutics to target the gut microbiome in order to restore glucose homeostasis in metabolic disease.
• Yue, J. T., Duca, F. A., & Lam, T. K. (2022). Silencing gut CCK cells alters gut reaction to sugar. Nature neuroscience, 25(2), 136-138.
• Duca, F. A., Waise, T. M., Peppler, W. T., & Lam, T. K. (2021). The metabolic impact of small intestinal nutrient sensing. Nature communications, 12(1), 903.
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  The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.
• Geisler, C. E., Ghimire, S., Bruggink, S. M., Miller, K. E., Weninger, S. N., Kronenfeld, J. M., Yoshino, J., Klein, S., Duca, F. A., & Renquist, B. J. (2021). A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity. Cell reports, 35(13), 109301.
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  Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
• Martinez, T. M., Meyer, R. K., & Duca, F. A. (2021). Therapeutic Potential of Various Plant-Based Fibers to Improve Energy Homeostasis via the Gut Microbiota. Nutrients, 13(10).
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  Obesity is due in part to increased consumption of a Western diet that is low in dietary fiber. Conversely, an increase in fiber supplementation to a diet can have various beneficial effects on metabolic homeostasis including weight loss and reduced adiposity. Fibers are extremely diverse in source and composition, such as high-amylose maize, β-glucan, wheat fiber, pectin, inulin-type fructans, and soluble corn fiber. Despite the heterogeneity of dietary fiber, most have been shown to play a role in alleviating obesity-related health issues, mainly by targeting and utilizing the properties of the gut microbiome. Reductions in body weight, adiposity, food intake, and markers of inflammation have all been reported with the consumption of various fibers, making them a promising treatment option for the obesity epidemic. This review will highlight the current findings on different plant-based fibers as a therapeutic dietary supplement to improve energy homeostasis via mechanisms of gut microbiota.
• Smith, K. A., Pugh, J. N., Duca, F. A., Close, G. L., & Ormsbee, M. J. (2021). Gastrointestinal pathophysiology during endurance exercise: endocrine, microbiome, and nutritional influences. European journal of applied physiology, 121(10), 2657-2674.
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  Gastrointestinal symptoms are abundant among athletes engaging in endurance exercise, particularly when exercising in increased environmental temperatures, at higher intensities, or over extremely long distances. It is currently thought that prolonged ischemia, mechanical damage to the epithelial lining, and loss of epithelial barrier integrity are likely contributors of gastrointestinal (GI) distress during bouts of endurance exercise, but due to the many potential causes and sporadic nature of symptoms this phenomenon has proven difficult to study. In this review, we cover known factors that contribute to GI distress symptoms in athletes during exercise, while further attempting to identify novel avenues of future research to help elucidate mechanisms leading to symptomology. We explore the link between the intestinal microbiome, the integrity of the gut epithelia, and add detail on gut hormone and peptide secretion that could potentially contribute to GI distress symptoms in athletes. The influence of nutrition and dietary supplementation strategies are also detailed, where much research has opened up new ideas and potential mechanisms for understanding gut pathophysiology during exercise. The etiology of gastrointestinal symptoms during endurance exercise is multi-factorial with neuroendocrine, microbial, and nutritional factors likely contributing to specific, individualized symptoms. Recent work in previously unexplored areas of both microbiome and gut peptide secretion are pertinent areas for future work, and the numerous supplementation strategies explored to date have provided insight into physiological mechanisms that may be targetable to reduce the incidence and severity of gastrointestinal symptoms in athletes.
• Duca, F. A., & Lam, T. K. (2020). Bye, bye, bile: how altered bile acid composition changes small intestinal lipid sensing. Gut, 69(9), 1549-1550.
• Weninger, S. N., Lane, A. I., & Duca, F. A. (2020). 1898-P: Colonic Short-Chain Fatty Acids Lower Endogenous Glucose Production. Diabetes, 69(Supplement_1). doi:10.2337/db20-1898-p
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  Hyperglycemia is a hallmark characteristic of diabetes, resulting in elevated blood glucose levels, due in part to a chronic elevation in endogenous hepatic glucose production (GP). Recent work has highlighted the gut microbiota as a salient contributor to energy and glucose homeostasis. One potential mechanism may be through increased short-chain fatty acid (SCFA) signaling mechanisms. SCFAs are bacterial breakdown products of nondigestible dietary fibers, occurring mainly in the colon, and have been shown to improve glucose homeostasis. Interestingly, recent work has highlighted that ingested nutrients can activate small intestinal nutrient-sensing mechanisms to lower hepatic glucose production via a neuronal gut-brain-liver axis mediated via gut peptide signaling. However, no one has directly tested whether colonic SCFAs can regulate GP via a similar colonic neuronal mechanism. To test this, we directly infused SCFAs (acetate, propionate, butyrate; 10mM or 100mM) into the colon during a pancreatic euglycemic clamp, the gold standard for measuring endogenous glucose production and uptake, in high-fat diet (HFD) fed rats that we previously found to have diminished levels of SCFAs in the large intestine. Administration of either acetate, propionate or butyrate (10mM or 100mM) directly into the colon of HFD-fed rats resulted in an increased glucose infusion rate needed to maintain euglycemia, which was due to a significant decrease in endogenous GP compared to saline infusion. Furthermore, we found that this was mediated via GLP-1 receptor signaling, as co-administration of exendin-9 with either SCFA (10mM) abolished the GP-lowering effect. Additionally, portal levels of GLP-1 were significantly increased at the end of the pancreatic clamp in rats receiving infusion of acetate, butyrate, or propionate compared to saline. Taken together, this work demonstrates that colonic SCFAs can activate a GLP-1 receptor mediated pathway in the colon to lower endogenous GP. Disclosure A.I.L. Lane: None. S.N. Weninger: None. F. Duca: None. Funding National Institutes of Health (R01DK121804)
• Waise, T. M., Rasti, M., Duca, F. A., Zhang, S. Y., Bauer, P. V., Rhodes, C. J., & Lam, T. K. (2019). Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production. Nature communications, 10(1), 714.
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  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.
• Bauer, P. V., Duca, F. A., Waise, T. M., Dranse, H. J., Rasmussen, B. A., Puri, A., Rasti, M., O'Brien, C. A., & Lam, T. K. (2018). Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis. Cell metabolism, 27(3), 572-587.e6.
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  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.
• Duca, F. A., Bauer, P. V., Waise, T. M., Rasmussen, B. A., Abraham, M. A., Dranse, H. J., Puri, A., O'Brien, C. A., & Lam, T. K. (2018). Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell metabolism, 27(1), 101-117.e5.
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  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.
• Yue, J. T., Abraham, M. A., Bauer, P. V., LaPierre, M. P., Wang, P., Duca, F. A., Filippi, B. M., Chan, O., & Lam, T. K. (2016). Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity. Nature communications, 7, 13501.
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  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.

Presentations

• Duca, F. A., & Weninger, S. (2020, May). Oligofructose Improves Small Intestinal Nutrient-Sensing Mechanisms via the Small Intestinal Microbiota. American Diabetes Association 2020. Virtual.
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  Abstract was selected for oral presentation at ADA 2020
• Duca, F. A. (2017, May 16, 2017). The Role of Intestinal-Sensing Mechanisms in the Glucose-Lowering Effects of Antidiabetic Agents. Works in ProgressDepartment of Endocrinology, Diabetes & Metabolism- University of Arizona, College of Medicine.
• Duca, F. A. (2017, November 15). Gut feelings about metformin: glucoregulatory role of small intestinal sensing and the microbiota. Nutritional Sciences Seminar Series. University of Arizona: Nutritional Science Department.
• Duca, F. A. (2017, October 20). Gut feelings about metformin: Glucoregulatory role of small intestinal sensing and the gut microbiota. Old Dominion University Biological Seminar Series. Old Dominion University: ODU BIological Sciences Graduate Program.
• Duca, F. A. (2016, October). The role of intestinal nutrient sensing in obesity and diabetes. University of Arizona MicroLunch Seminar.

Poster Presentations

• Duca, F. A., & Lane, A. (2020, May). Colonic Short-Chain Fatty Acids Lower Endogenous Glucose Production. American Diabetes Association 2020. Virtual.
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  Poster presentation at ADA 2020
• Duca, F. A., & Martinez, T. (2020, May). Plant-Based Flours Reduce Body Weight and Adiposity in High-Fat Fed Rats. American Diabetes Association 2020. Virtual.
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  Poster Presentation at ADA 2020
• Duca, F. A., & Meyer, R. (2020, May). Postprandial Short-Chain Fatty Acid Concentrations in the Intestinal Lumen and Plasma. American Diabetes Association. Virtual.
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  Poster Presentation at ADA 2020