Our Focus

With our device-based clinical platform, we are working to transform metabolic disease treatment. Based on new discoveries in metabolic science, our investigational Revita™ duodenal mucosal resurfacing (DMR) procedure targets the upper intestine, or duodenum, with the aim of addressing a root cause of insulin resistance in two common metabolic diseases: type 2 diabetes and nonalcoholic steatohepatitis (NASH).

What Is Metabolic Disease?

The term “metabolic disease” refers to a broad group of conditions in which the body’s normal metabolic processes become disordered. The most common metabolic diseases—type 2 diabetes and nonalcoholic fatty liver disease / nonalcoholic steatohepatitis (NAFLD/NASH)—occur as a result of insulin resistance. Fractyl is working to develop a new way to reduce insulin resistance and thereby potentially treat disorders like type 2 diabetes and NASH that are caused by insulin resistance. Our innovative, minimally invasive, investigational procedure targets the duodenum with the goal of addressing an important cause of insulin resistance in patients with metabolic disease.

Insulin Resistancetop

Insulin is a hormone produced by the pancreas. The main role of insulin is to control blood sugar levels by helping cells take up glucose from the bloodstream.

Insulin Molecule

In people who develop insulin resistance, the body can no longer properly use the insulin it produces. This makes it difficult for cells to absorb glucose from the bloodstream. The pancreas makes even more insulin to help maintain normal blood sugar levels in people who develop insulin resistance (a state called hyperinsulinemia). In some individuals, however, the pancreas cannot keep up with the body’s increased insulin needs over time. Glucose starts to build up in the blood stream, which leads to type 2 diabetes. Even in patients without type 2 diabetes, insulin resistance can cause other metabolic diseases, such as nonalcoholic steatohepatitis (NASH).

Treating insulin resistance offers the potential to significantly improve patient health, reduce the costs of treating the complications related to these disorders and reduce the burden of metabolic diseases on patients, their caregivers and the healthcare system.

Insulin resistance is a root cause of type 2 diabetes and NASH.

Role of the Duodenumtop

The small intestine is the body’s largest hormone-producing organ, and hormones produced in the small intestine have long been known to play an important role in blood glucose regulation. Recent discoveries in metabolic science are now demonstrating that changes to the lining of the first segment of the small intestine—the duodenum—are associated with common metabolic disorders like type 2 diabetes.

After food passes through the stomach, it moves to the duodenum, which is the first part of the small intestine and the region where nutrient absorption begins in the gastrointestinal tract. The lining of the duodenum, or mucosa, is composed of several cell types, including hormone-producing cells. These hormone-producing cells sense the presence or absence of nutrients in the duodenum and send chemical signals to the body to help regulate insulin production and mediate glucose control.

A “Western-style” diet high in sugar and fat can cause significant changes in the duodenum over time, resulting in a thickened mucosa, abnormal nutrient absorption and alterations in the type and number of hormones released from the duodenum into the body, including hormones that help control insulin secretion and glucose homeostasis.1-5 This irregular chemical signaling is an important contributor to insulin resistance. We believe this abnormal signaling is potentially reversible.

These changes in the duodenal lining help explain the weight-independent improvement in insulin resistance and glycemic control that is seen after certain bariatric surgeries. Specifically, bariatric surgeries that cause food to bypass the duodenum—preventing nutrient contact with the altered mucosa—have been shown to be effective treatments for type 2 diabetes and NASH, highlighting the role of the gastrointestinal tract in regulating insulin sensitivity and glucose homeostasis.6-9

See duodenum references

1Verdam FJ, Greve JW, Roosta S, et al. Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab. 2011;96(2):E379–83.
http://www.ncbi.nlm.nih.gov/pubmed/21084402
2Theodorakis MJ, Carlson O, Michopoulos S, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 2006;290(3):E550–9.
http://www.ncbi.nlm.nih.gov/pubmed/16219666
3Gniuli D, Calcagno A, Dalla Libera L, et al. High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats. Diabetologia. 2010; 53(10):2233–40.
http://www.ncbi.nlm.nih.gov/pubmed/20585935
4Nguyen M, Horowitz M, Young RL, et al. Accelerated intestinal glucose absorption in morbidly obese humans: Relationship to glucose transporters, incretin hormones and glycemia. J Clin Endocrinol Metab. 2015;100(3):968–76.
http://www.ncbi.nlm.nih.gov/pubmed/25423571
5Salinari S, Carr RD, Guidone C, et al. Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. Am J Physiol Endocrinol Metab. 2013;305(1):E59–66.
http://www.ncbi.nlm.nih.gov/pubmed/23651846
6Zervos EE, Agle SC, Warren AJ, et al. Amelioration of insulin requirement in patients undergoing duodenal bypass for reasons other than obesity implicates foregut factors in the pathophysiology of type II diabetes. J Am Coll Surg. 2010;210(5):564-72, 572-4.
http://www.ncbi.nlm.nih.gov/pubmed/20421005
7Zhang X, Xiao Z, Yu HL, et al. Short-term glucose metabolism and gut hormone modulations after Billroth II gastrojejunostomy in non-obese gastric cancer patients with type 2 diabetes mellitus, impaired glucose tolerance and normal glucose tolerance. Arch Med Res. 2013;44(6):437-43.
http://www.ncbi.nlm.nih.gov/pubmed/23973197
8De Jonge C, Rensen SS, Verdam FJ, et al. Endoscopic duodenal-jejunal bypass liner rapidly improves type 2 diabetes. Obes Surg. 2013;23(9):1354-60.
http://www.ncbi.nlm.nih.gov/pubmed/23526068
9Aguirre, et al. An endoluminal sleeve induces substantial weight loss and normalizes glucose homeostasis in rats with diet-induced obesity. Obesity (Silver Spring). 2008;16(12):2585–92.
http://www.ncbi.nlm.nih.gov/pubmed/19279655

Revita™ DMRtop

Fractyl is developing Revita™ DMR as a solution to address the underlying intestinal basis of insulin resistance and the metabolic diseases that are driven by insulin resistance.

Revita™ DMR targets the area of the small intestine known as the duodenum.

Revita™ DMR is an investigational, minimally invasive, therapeutic procedure designed to remodel the lining of the upper part of the small intestine, or duodenum. It is intended as an outpatient therapy that can be performed in approximately one hour and allows patients to resume normal activities the following day. Our goal is to alter the body’s ability to respond to sugar and improve metabolic health for patients with diseases like type 2 diabetes and NASH.

Patients can be treated in standard endoscopic suites using Fractyl’s proprietary Revita™ System. The physician first introduces the Revita™ catheter through the mouth into the small intestine using a standard endoscope to visualize the catheter position. The physician then uses the Revita™ System to activate a precisely-controlled heated balloon at the end of the catheter to treat the lining of the duodenum. The lining of the duodenum contains cells that affect glucose control and insulin resistance. The catheter and endoscope are then removed, leaving no implant in the body.

We believe that treating the lining of the duodenum with the Revita™ DMR procedure has the potential to change the way patients with metabolic diseases are treated by targeting the underlying metabolic defect—insulin resistance—associated with such diseases.

Revita™ DMR is being actively studied in clinical trials and has not received CE marking in the European Union or approval from the Food and Drug Administration in the United States.

Additional Readingtop

Learn More: Type 2 diabetes – Progressive and not easily controlled

Despite a plethora of current treatment options, many patients with type 2 diabetes still have poor glucose control

  • Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med. 2013;368(17):1613-24.
    http://doi.org/10.1056/NEJMsa1213829

Type 2 diabetes management is challenging and costly

  • American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care. 2008;31 Suppl 1:S12–54.
    http://doi.org/10.2337/dc08-S012
  • Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014.
    http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf
  • Hex N, Bartlett C, Wright D, Taylor M, Varley D. Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med. 2012;29(7):855–62.
    http://doi.org/10.1111/j.1464-5491.2012.03698.x
  • Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. 1995;18(2):258–68.
    http://www.ncbi.nlm.nih.gov/pubmed/7729308
  • Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.
    http://doi.org/10.2337/dc08-9025
  • Zhuo X, Zhang P, Hoerger TJ. Lifetime direct medical costs of treating type 2 diabetes and diabetic complications. Am J Prev Med. 2013;45(3):253–61.
    http://doi.org/10.1016/j.amepre.2013.04.017

NAFLD/NASH is a serious public health problem and highly prevalent in patients with type 2 diabetes.
Independent of type 2 diabetes, patients with NAFLD/NASH exhibit abnormal glucose metabolism and many are insulin resistant

  • Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006;40 Suppl 1:S5–10.
    http://www.ncbi.nlm.nih.gov/pubmed/16540768
  • Ortiz-Lopez C, Lomonaco R, Orsak B, et al. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care. 2012;35(4):873–8.
    http://doi.org/10.2337/dc11-1849
  • Saponaro C, Gaggini M, Gastaldelli A. Nonalcoholic fatty liver disease and type 2 diabetes: common pathophysiologic mechanisms. Curr Diab Rep. 2015;15(6):607.
    http://doi.org/10.1007/s11892-015-0607-4
  • Vos MB, Lavine JE. Dietary fructose in nonalcoholic fatty liver disease. Hepatology. 2013;57(6):2525–31.
    http://doi.org/10.1002/hep.26299
  • Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol. 2013;10(11):627–36.
    http://doi.org/10.1038/nrgastro.2013.149
Learn More: Biology – Intestinal hormone changes drive type 2 diabetes

Dietary sugar and fat are major drivers of type 2 diabetes and NAFLD/NASH
Lifetime exposure increases risk

Lifetime exposure to dietary sugar and fat leads to mucosal changes in the small intestine
These changes alter the type and number of hormones released in the body, including those that modulate insulin secretion and glucose homeostasis

  • Theodorakis MJ, Carlson O, Michopoulos S, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 2006;290(3):E550–9.
    http://www.ncbi.nlm.nih.gov/pubmed/16219666
  • Verdam FJ, Greve JWM, Roosta S, et al. Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab. 2011;96(2):E379–83.
    http://www.ncbi.nlm.nih.gov/pubmed/21084402

Hormone changes cause hyperinsulinemia, hyperglucagonemia, and insulin resistance
Interaction of food with this mucosa has hormonal consequences throughout the body, manifest as insulin resistance

  • Adachi T, Mori C, Sakurai K, et al. Morphological changes and increased sucrase and isomaltase activity in small intestines of insulin-deficient and type 2 diabetic rats. Endocr J. 2003;50(3):271–9.
    http://www.ncbi.nlm.nih.gov/pubmed/12940455
  • Akash MS, Rehman K, Chen S. Goto-Kakizaki rats: its suitability as non-obese diabetic animal model for spontaneous type 2 diabetes mellitus. Curr Diabetes Rev. 2013;9(5):387–96.
    http://www.ncbi.nlm.nih.gov/pubmed/23855509
  • Bailey CJ, Flatt PR, Kwasowski P, Powell CJ, Marks V. Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets. Acta Endocrinol (Copenh). 1986;112(2):224–9.
    http://www.ncbi.nlm.nih.gov/pubmed/3526784
  • Flatt PR, Bailey CJ, Kwasowski P, Swanston-Flatt SK. Effects of diets rich in sucrose, coconut fat and safflowerseed oil on the development of the obese hyperglycaemic (ob/ob) syndrome in mice. Diabetes Res. 1990;13(1):23–8.
    http://www.ncbi.nlm.nih.gov/pubmed/2097092
  • Gniuli D, Calcagno A, Dalla Libera L, et al. High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats. Diabetologia. 2010;53(10):2233–40.
    http://doi.org/10.1007/s00125-010-1830-9
  • Morgan LM, Hampton SM, Tredger JA, Cramb R, Marks V. Modifications of gastric inhibitory polypeptide (GIP) secretion in man by a high-fat diet. Br J Nutr. 1988;59(3):373–80.
    http://www.ncbi.nlm.nih.gov/pubmed/3293660
  • Nguyen NQ, Debreceni TL, Bambrick JE, et al. Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia. J Clin Endocrinol Metab. 2015.100(3):968–76.
    http://doi.org/10.1210/jc.2014-3144
  • Pathak V, Gault VA, Flatt PR, Irwin N. Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice. Mol Cell Endocrinol. 2015;401:120–9.
    http://doi.org/10.1016/j.mce.2014.10.025
  • Ponter AA, Salter DN, Morgan LM, Flatt PR. The effect of energy source and feeding level on the hormones of the entero-insular axis and plasma glucose in the growing pig. Br J Nutr. 1991;66(2):187–97.
    http://www.ncbi.nlm.nih.gov/pubmed/1760441
  • Salinari S, Debard C, Bertuzzi A, et al. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance. PloS One. 2013;8(2):e56258.
    http://doi.org/10.1371/journal.pone.0056258
  • Salinari S, Carr RD, Guidone C, Bertuzzi A, Cercone S, Riccioni ME, Mingrone G. Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. Am J Physiol Endocrinol Metab. 2013;305(1):E59–66.
    http://www.ncbi.nlm.nih.gov/pubmed/23651846
  • Theodorakis MJ, Carlson O, Michopoulos S, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab. 2006;290(3):E550–9.
    http://doi.org/10.1152/ajpendo.00326.2004

Insulin resistance and hyperinsulinemia are precursors to metabolic diseases, including type 2 diabetes and NAFLD/NASH

In patients with insulin resistance, the pancreas first increases insulin production, but eventually decompensates
Insulin production can no longer meet the body’s metabolic demands

Avoiding nutrient contact with the duodenal mucosa can improve type 2 diabetes

  • Andreelli F, Amouyal C, Magnan C, Mithieux G. What can bariatric surgery teach us about the pathophysiology of type 2 diabetes? Diabetes Metab. 2009;35(6 Pt 2):499–507.
    http://doi.org/10.1016/S1262-3636(09)73456-1
  • Caiazzo R, Lassailly G, Leteurtre E, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260(5):893–8; discussion 898–9.
    http://doi.org/10.1097/SLA.0000000000000945
  • de Jonge C, Rensen SS, Verdam FJ, et al. Endoscopic duodenal-jejunal bypass liner rapidly improves type 2 diabetes. Obes Surg. 2013;23(9):1354–60.
    http://doi.org/10.1007/s11695-013-0921-3
  • Dirksen C, Hansen DL, Madsbad S, et al. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report. Diabetes Care. 2010;33(2):375–7.
    http://doi.org/10.2337/dc09-1374
  • Habegger KM, Al-Massadi O, Heppner KM, et al. Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia. Gut. 2014;63(8):1238–46.
    http://doi.org/10.1136/gutjnl-2013-304583
  • Irwin N, Flatt PR. Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Diabetologia. 2009;52(9):1724–31.
    http://doi.org/10.1007/s00125-009-1422-8
  • Jacobsen SH, Olesen SC, Dirksen C, et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obes Surg. 2012;22(7):1084–96.
    http://doi.org/10.1007/s11695-012-0621-4
  • Kindel TL, Yoder SM, Seeley RJ, D’Alessio DA, Tso P. Duodenal-jejunal exclusion improves glucose tolerance in the diabetic, Goto-Kakizaki rat by a GLP-1 receptor-mediated mechanism. J Gastrointest Surg. 2009;13(10):1762–72.
    http://doi.org/10.1007/s11605-009-0912-9
  • Laferrère B, Reilly D, Arias S, et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med. 2011;3(80):80re2.
    http://doi.org/10.1126/scitranslmed.3002043
  • Muñoz R, Carmody JS, Stylopoulos N, Davis P, Kaplan LM. Isolated duodenal exclusion increases energy expenditure and improves glucose homeostasis in diet-induced obese rats. Am J Physiol Regul Integr Comp Physiol. 2012;303(10):R985–93.
    http://doi.org/10.1152/ajpregu.00262.2012
  • Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741–9.
    http://doi.org/10.1097/01.sla.0000224726.61448.1b
  • Salinari S, le Roux CW, Bertuzzi A, Rubino F, Mingrone G. Duodenal-jejunal bypass and jejunectomy improve insulin sensitivity in Goto-Kakizaki diabetic rats without changes in incretins or insulin secretion. Diabetes. 2014;63(3):1069–78.
    http://doi.org/10.2337/db13-0856
  • Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes – 3-year outcomes. N Engl J Med. 2014;370(21):2002-13.
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  • Shimizu H, Eldar S, Heneghan HM, Schauer PR, Kirwan JP, Brethauer SA. The effect of selective gut stimulation on glucose metabolism after gastric bypass in the Zucker diabetic fatty rat model. Surg Obes Relat Dis. 2014;10(1):29–35.
    http://doi.org/10.1016/j.soard.2013.01.021
  • Zervos EE, Agle SC, Warren AJ, et al. Amelioration of insulin requirement in patients undergoing duodenal bypass for reasons other than obesity implicates foregut factors in the pathophysiology of type II diabetes. J Am Coll Surg. 2010;210(5):564–72:572–4.
    http://doi.org/10.1016/j.jamcollsurg.2009.12.025